Search

Cholinergic urticaria (CholU) is a chronic inducible urticaria, characterised by itchy pinpoint wheals up to 3 mm in diameter, surrounded by a prominent flare, that occur following an exposure to characteristic triggers such as active or passive heating, physical exercise, emotions, hot or spicy foods. Key pathophysiologic mechanisms include immediate hypersensitivity to autologous sweat antigens, functional sweating disorders, impaired acethylcholine metabolism, abnormal skin vascular permeability and disturbed skin innervation. Clinical manifestations of CholU may vary from typical itchy pinpoint urticarial lesions, angioedema to anaphylaxis. Atypical CholU forms include cholinergic pruritus, cholinergic dermographism, cold cholinergic urticaria and persistent cholinergic erythema. The diagnosis of cholinergic urticaria relies on patients history, сlinical manifestations and challenge tests. Treatment options include nonsedating H1 antihistamines in standard or increased doses. The evidence is accumulating for the use of biological treatment with omalizumab in cholinergic urticaria. The prospect of personalized treatment of cholinergic urticaria include autologous sweat desensitization. The main research efforts in ColdU are directed at optimizing diagnostic approaches and developing innovative therapeutic options.

This study aimed to evaluate the effects of hesperidin (HE) on in vitro osteoclastogenesis and dietary supplementation on mouse periodontal disease and femoral bone phenotype. RAW 264.7 cells were stimulated with RANKL in the presence or absence of HE (1, 100 or 500 µM) for 5 days, and evaluated by TRAP, TUNEL and Western Blot (WB) analyses. In vivo, C57BL/6 mice were given HE via oral gavage (125, 250 and 500 mg/kg) for 4 weeks. A sterile silk ligature was placed between the first and second right maxillary molars for 10 days and microcomputed tomography (μCT), histopathological and immunohistochemical evaluation were performed. Femoral bones subjected or not to dietary HE (500 mg/kg) for 6 and 12 weeks were evaluated using μCT. In vitro, HE 500 µM reduced formation of RANKL-stimulated TRAP-positive(+) multinucleated cells (500 µM) as well as c-Fos and NFATc1 protein expression (p < 0.05), markers of osteoclasts. In vivo, dietary HE 500 mg/kg increased the alveolar bone resorption in ligated teeth (p < 0.05) and resulted in a significant increase in TRAP+ cells (p < 0.05). Gingival inflammatory infiltrate was greater in the HE 500 mg/kg group even in the absence of ligature. In femurs, HE 500 mg/kg protected trabecular and cortical bone mass at 6 weeks of treatment. In conclusion, HE impaired in vitro osteoclastogenesis, but on the contrary, oral administration of a high concentration of dietary HE increased osteoclast numbers and promoted inflammation-induced alveolar bone loss. However, HE at 500 mg/kg can promote a bone-sparing effect on skeletal bone under physiological conditions.

GEN1042 (DuoBody®-CD40x4-1BB) is an investigational, novel, agonistic, bispecific antibody that combines targeting and conditional activation of CD40 and 4-1BB on immune cells for priming and (re-) activation of tumor-specific immune responses. We previously showed that GEN1042 induces conditional CD40 and 4-1BB agonist activity, leading to dendritic-cell maturation and enhanced T-cell activation and effector functions in vitro. However, dysfunction of exhausted T cells in the solid tumor microenvironment may represent a potential resistance mechanism to checkpoint inhibitors/agonists. Here we utilized a multi-omics approach to evaluate whether GEN1042 could reverse T-cell exhaustion in vitro. Publicly available single cell RNA sequencing datasets were harmonized across multiple solid-tumor indications (including treatment-naïve and anti-PD-1 and/or anti-CTLA-4 pretreated samples) and analyzed for expression of CD40, 4-1BB and PD-1 on various immune-cell subsets based on their transcriptomic signatures to characterize target prevalence. In vitro mixed lymphocyte reaction (MLR) functional assays were performed where unstimulated healthy donor CD3+ T cells or CD3+ T cells exhausted by repeated stimulation with anti-CD3/CD28 beads were co-cultured with allogeneic lipopolysaccharide (LPS)-matured dendritic cells. Cultures were analyzed for cytokine secretion and expression of cell surface proteins. In the unstimulated T cell/mDC MLR assay, concurrent treatment with GEN1042 and PD-1 blockade potentiated IFNγ, TNFα and IL-2 production compared with either compound alone. In the T-cell exhaustion MLR assay, T cells showed increased expression of inhibitory receptors (e.g., TIM-3, LAG-3) and exhibited hyporesponsiveness for both proliferation and cytokine secretion upon restimulation with anti-CD3/CD28 beads. Here, the combined functional effect of GEN1042 plus PD-1 blockade further potentiated IFNγ secretion compared to single agent activity and induced IL-2 at similar levels to that observed for GEN1042 alone. These data suggest that, in addition to enhancing T-cell effector functions during T cell priming, GEN1042 can amplify the magnitude of the immune response in combination with PD-1 blockade by re-establishing the functional activity of dysfunctional T cells. GEN1042 is currently being evaluated in patients with advanced solid tumors in a phase 1/2 clinical trial (NCT04083599). Citation Format: Vanessa M. Spires, Gregg Masters, Christina Yu, Matt Hancock, Monique N. Luijten, Alexander Muik, Kristina Nuermberger, Friederike Gieseke, Tahamtan Ahmadi, Özlem Türeci, Maria Jure-Kunkel, Ugur Sahin, Mark Fereshteh, Homer C. Adams, Jordan M. Blum. GEN1042 (DuoBody-CD40x4-1BB)®in combination with PD-1 blockade reverses T-cell exhaustion in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3281.

Aims To describe the use of laser, endoscopic balloon dilatation with jet ventilation anaesthesia in the treatment of pregnant women with idiopathic subglottic stenosis. Materials and methods This is a case review of pregnant women with idiopathic subglottic stenosis, presenting to a tertiary referral centre with worsening breathlessness. Data were extracted from patient case notes. Results Four women underwent surgical management of subglottic stenosis in pregnancy. One patient required two procedures during the course of their pregnancy due to restenosis. All women had improvement in symptoms post-operatively and went on to deliver healthy babies at term. Conclusion Endoscopic balloon dilatation of idiopathic subglottic stenosis is a safe and viable treatment option in pregnancy and should be offered as first-line treatment in symptomatic women.

In this study we combined the organizational behavior literature with international human resource management theory to investigate expatriates in the context of the interrelationship of the Big Five personality traits, cultural intelligence, cross-cultural adjustment, and entrepreneurship. We used a data sample of 230 individuals to empirically confirm that expatriates' personality, cultural intelligence, and cross-cultural adjustment are key factors in successful expatriate entrepreneurship in a cross-cultural context. Our results provide a deeper understanding of the antecedents of entrepreneurship that affect expatriates' entrepreneurial performance in an overseas posting.

Purpose: This article reviews narrative therapy (NT) publications specific to Hong Kong over a period of 20 years. Methods: Three search strategies are adopted: using the Hong Kong Baptist University OneSearch database and Google Books index, and sending soliciting emails to local scholars and practitioners. Four research questions are asked: (a) how many related publications? (b) who are the targets? (c) who are the authors? (d) what is the type of publication? Results: In total, there are 127 publications identified. The first NT publication is dated 1996. The most common target group is “People with Problem” (48.8%). Most authors are academics (78.7%). The publications are mostly Journal Articles (68.5%). Conclusions: Co-construction between academics and practitioners, co-researching as the landscape for co-constructing an NT community, and finally, the co-deconstruction process of local narratives are recommended as future tasks for Hong Kong related NT publications.

Purpose: This article reviews research work on special education needs in Greater China during the past 5 decades. Methods: All searches are done on online search engines to determine the (a) volume of the related research work, (b) targets of the research studies, (c) types of SENs addressed, and (d) type of research work. Results: 828 publications are identified, among which the majority are published in the Mainland China and Taiwanese contexts. The most common target groups are “children” (51.3%). The studies mostly focus on ASD with 467 articles (56.4%), and 600 articles (72.5%) are descriptive, empirical, or correlational. Conclusion: There is a shift of research target group from person of interest to caregivers; importance of collective shame in the Chinese culture; and increase in research in the Greater China context. More support for research related to SEN in Greater China and acknowledging cultural relevance are recommended.

Background Euglycaemic ketoacidosis (EKA) is an infrequent but serious condition which usually follows a period of starvation, severe vomiting or illness in individuals with or without diabetes. Ketoacidosis is associated with materno-fetal morbidity and mortality necessitating prompt diagnosis and management. Physiological increases in insulin resistance render pregnancy a diabetogenic state with increased susceptibility to ketosis. COVID-19 is associated with worse clinical outcomes in patients with diabetes and is an independent risk factor for ketoacidosis in normoglycaemic individuals. Case presentations We describe two cases of SARS-CoV-2 positive pregnant women presenting with normoglycaemic metabolic ketoacidosis. Both cases were associated with maternal and fetal compromise, requiring aggressive fluid and insulin resuscitation and early delivery. Conclusion We discuss possible physiology and propose a management strategy for euglycaemic ketoacidosis in pregnancy.

Background The majority of simple renal cysts diagnosed postnatally are asymptomatic and rarely require treatment unless they become symptomatic or complex. We hypothesised that prenatally-detected simple renal cysts would have a similar harmless outcome. Aims To establish the natural history and postnatal outcome of prenatally-diagnosed simple renal cysts. Study design Single-centre retrospective case-series review (12-year period). Subjects All patients with prenatally-diagnosed simple renal cysts (defined as a solitary, non-septated, non-communicating cyst in an otherwise normal kidney). Outcome measures Prenatal and postnatal changes to cyst size, persistence, resolution or modification of diagnosis. Data is presented as the proportion of patients or median (range). Results 30 cysts were detected (2 bilateral, 26 unilateral) in 28 fetuses (median gestational age of 23 [20–36] weeks). Median maximum diameter was 15 (4–35) mm at initial diagnosis and 17.5 (4–100) mm across all prenatal scans. On follow-up scans diagnosis was modified in 16 (53%) to: multicystic dysplastic kidney (MCDK), dilated duplex kidney, hydronephrosis, urinoma, renal agenesis and adrenal mass. 12 (40%) cysts resolved. 2 (7%) asymptomatic cysts persisted at one year postnatally. Cyst maximum diameter in the modified diagnosis group (21.5 [10−100] mm) was significantly larger than the simple cyst group (12 [4–20] mm) (P = 0.03). Conclusions Our study revealed the challenges of prenatal ultrasound imaging, with modified diagnoses in over half the cases. Kidneys with solitary cysts could evolve into multicystic kidneys or involute completely, which suggests a true alteration in morphology rather than sonographic error. Persistent simple cysts in an otherwise normal kidney, however, resolved spontaneously or remained asymptomatic. Prenatally-detected simple cysts should be monitored with serial imaging.

Mode of delivery and intrapartum analgesia for women with Chiari I malformation pose a challenge to the obstetrician and anaesthetist. Clinicians often advocate caesarean section delivery under general anaesthetic to prevent an uncontrolled rise in intracranial pressure or a fall in cerebrospinal fluid pressure during labour that may result in neurological complications, or rarely, brainstem herniation. This case report discusses a woman with hitherto undiagnosed Chiari I malformation who delivered by CS due to obstetric concerns, but remained asymptomatic throughout the preceding labour and in spite of multiple epidural insertion attempts. We discuss considerations for future pregnancies, and review the literature to challenge the view that women with Chiari I need planned caesarean or must avoid epidural/spinal analgesia; instead presenting evidence to support the safety and suitability of vaginal delivery and neuroaxial block in labouring parturients with this condition.

Background/Objective: Every year in the United States, 32,000 individuals are diagnosed with Multiple Myeloma (MM) and 13,000 die from the disease. MM is a cancer of the plasma cells and while treatment exists, MM remains incurable. Our overall goal is to identify biologically and therapeutically relevant cell surface targets to develop MM immunotherapy. Methods: Given the genomic heterogeneity of MM, we performed surface analysis of seven MM cell lines by Mass-Spectrometry (MS), generating a pool of candidate proteins. Lacking specific tools for studying cell surface proteins, we developed an integrated computational tool with five distinct databases, and scored the likelihood of cell surface location for each molecule. One point was given for each database a protein appeared in. A protein receiving a score of three or more was considered a cell surface protein with high confidence. However, about one third of the candidates were not detected by the computational tool, thus requiring manual curation. We used UniProt and GeneCards to determine the subcellular locations of the unannotated IDs, and further confirmed their location with the computational tool. Results: Of the 5,454 UniProt IDs produced by MS, 2,026 were not annotated. Causes of an unannotated ID included having an obsolete ID, being an isoform, and/or not being located on the cell surface. Through manual annotation, 8 unique cell surface IDs were added to the existing 448. The 456 targets were further analyzed based on their expression profiles in both MM and normal tissues resulting in 94 of the most promising targets, some of which would have been missed without manual curation. Conclusion/Potential Impact: Public genomic databases are often incomplete and may contain errors making manual curation a necessary step in error reduction. Left unchecked, promising surface targets could have been overlooked hindering the creation of potentially curative immunotherapies.

Red light-emitting polymeric micro- and nanofibers were made by electrohydrodynamic co-casting of two fluids. One fluid contains a 10 wt% concentration europium (III) complex dissolved in a dimethylformamide (DMF) solvent. The europium complex, an Eu3+ compound with the nominal formula of Eu(BA)3phen/PAN, consists of polyacrylonitrile (PAN), 1,10-phenanthroline (phen), and benzoic acid (BA). The other fluid consists of iron metal oxide nanoparticles dispersed in a solution containing 10 wt% polyacrylonitrile polymer in DMF solvent. The two fluids were electrohydrodynamically co-cast onto a soft tissue paper using a stainless steel coaxial nozzle. The intensity of the electric field used for the co-casting was 1.5 kV/cm. Scanning electron microscopic observation on the fibers obtained from the co-casting was made. The size of the fibers ranges from several hundreds of nanometers to several microns. Energy dispersive X-ray spectroscopic analysis of the fibers confirmed that the major elements included C, O, Fe, and Eu. The fluorescence of the two types of fibers was tested under the excitation of a UV light source. It was found that when the europium complex-containing solution was the sheath fluid and the iron-containing solution was the core, the prepared fibers showed red light-emitting behavior under ultraviolet light. Time-dependent fluorescence shows the two-stage decaying behavior. The first stage lasts about 2000 s and the intensity of fluorescence decreases linearly. The second stage reveals the slow decaying behavior and it lasts longer than 3 h. Based on the bi-exponential data fitting using a processing MATLAB code, the fluorescence-related constants were extracted. A bi-exponential formula was proposed to describe the time-dependent fluorescence behavior of the fiber made by the europium complex-containing solution as the sheath fluid. The decaying in the fluorescence shows two different stages. The first stage lasts about 2000 s and it is characterized by a fast decaying model. The intensity of fluorescence decreases linearly. The second stage has a slow decaying feature. It takes over 3 h for the fluorescence to die out completely. Bi-exponential data fitting shows that the time constant for the decay of fluorescence is about 10,000 s.

Multiple myeloma (MM) is an incurable malignancy of mature plasma cells. Despite major advances in the therapeutic armamentarium of MM, only 50% of patients survive more than 5 years after diagnosis, with significantly lower rates (21%) for high-risk patients. Chimeric Antigen Receptor (CAR) T-cell therapy targeting BCMA (B-cell maturation antigen) shows high response rates in relapsed/refractory patients. However, most patients have disease remission that lasts less than 18 months, prompting the search for additional and synergistic therapeutic approaches. We unbiasedly mapped the cell surface proteome of MM by integrating Mass-Spectrometry (MS) and RNA-seq analyses from 7 MM cell lines and 904 primary MM patient samples bearing high-risk cytogenetics. To identify cell surface proteins, we ran a pool of 4,761 proteins and 16,000+ transcripts through five repositories. An integrated scoring database was developed by scoring each ID based on the number of databases (0-5) it was identified in, with 0 if the molecule was not found in any and 5 if the protein was found in all five. We identified 402 proteins with a surface score of 3 or higher in MM cell lines and patient samples by transcriptomics and proteomics. We prioritized the 326 candidates that were more highly expressed in patients. Based on functional enrichment analyses, we found the proteins formed three main networks with immune mechanisms representing the largest cluster (227 out of 326 cell surface proteins) followed by transporters and adhesion proteins.Based on a pipeline we previously established (1), we further selected 97 candidates minimally expressed in normal tissues. This list included current therapeutic targets such as BCMA, SLAMF7, ITGB7 and LY9. Validation in primary patient samples by western blot and flow-cytometric analyses, enabled the identification of 10 top candidates (CCR1, CD320, FCRL3, IL12RB1, ITGA4, LAX1, LILRB4, LRRC8D, SEMA4A, SLAMF6) that resulted most frequently and highly expressed. We found that LAX1, LILRB4 and SEMA4A significantly impact myeloma patient overall survival based on Kaplan-Meier analysis in the MM Research Foundation (MMRF) cohort (2). CCR1, IL12RB1, LILRB4 and SEMA4A were upregulated by the treatment with Bortezomib or Venetoclax that conversely, decreased BCMA expression in MM U266 cells. By stratifying the patient population, we found that the SEMA4A and LAX1 were up-regulated in patients with t(4;14) compared to patients with no cytogenetic abnormality; LILRB4 in patients with t(14;16) and CCR1 patients with t(14;16) and t(14;20). By calculating co-expression levels CCR1-LILRB4 and CCR1-FCRL3 resulted co-expressed in 100% of patients. For safety purposes (3), we excluded candidates with high (>55%) protein abundance in highly-purified normal hematopoietic stem cells and activated T-cells, narrowing down the list to 6 top candidates (CCR1, FCRL3, IL12RB1, LILRB4, LRRC8D, SEMA4A). To define the function of this group of promising cell surface targets, we used a CRISPR/Cas9 inducible system in KMS11 MM cells. We found that knock-out of CCR1, LRRC8D and SEMA4A individually reduces the MM cell growth by ~60%, 50% and 50% respectively, and almost completely abrogates MM cell migration through porous chambers by >80%. By co-culturing irradiated KO and control MM cells with healthy donor T-cells we also found that lack of CCR1 increased T-cell proliferation by 50% compared to controls and enhanced killing of MM cells, suggesting that CCR1 may suppress T-cell mediated immune responses in addition to play a role in MM cell survival and migration. This study suggests the contribution of an altered MM surfaceome to disease development and may lead to potential novel immunotherapeutic approaches for high-risk MM. References 1. Perna F et al., Cancer Cell 2017 3. Dong C et al., in press Oncogene 2021 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The article is written with the aim to highlight the possibility of using economic methods in management of monoproduct company, reducing its risks of bankruptcy as low as practicable. The key problems in the activities of such enterprises have been determined, their detailed characteristics has been provided, potential risks have been evaluated, and recommendations to minimize them have been proposed. Ensuring an integrated and one-time implementation of the activities referred to in the article will provide an opportunity for a significant improvement in the real state of affairs at enterprises. It is specified that using the methods for system analysis can give considerable impetus in preserving or even enhancing the financial stability of any enterprise.

Drawing upon human capital theory, we empirically tested the relationships among human capital management, employees' value and uniqueness, and organizational competitiveness. To do this, we adopted a quantitative approach via multiple regression analysis with 183 participants from Taiwan and Mainland China. Results showed that human capital development and deployment were positively associated with both value and uniqueness of employees in Taiwan and also in Mainland China. This indicated that development and deployment practices, such as training and job design, were conducive to increasing employees' value and uniqueness. In addition, the positive relationship between human capital and employees' value that was observed in a Mainland Chinese context was not observed in Taiwan, which indicates that contextual differences affected methods of attracting talented employees. We found it surprising that in neither Taiwan nor Mainland China were organizations capable of retaining unique employees. Practical and theoretical implications of our findings are discussed.

Consider the task of estimating a 3-order $n \times n \times n$ tensor from noisy observations of randomly chosen entries in the sparse regime. We introduce a similarity based collaborative filtering algorithm for estimating a tensor from sparse observations and argue that it achieves sample complexity that nearly matches the conjectured computationally efficient lower bound on the sample complexity for the setting of low-rank tensors. Our algorithm uses the matrix obtained from the flattened tensor to compute similarity, and estimates the tensor entries using a nearest neighbor estimator. We prove that the algorithm recovers a finite rank tensor with maximum entry-wise error (MEE) and mean-squared-error (MSE) decaying to $0$ as long as each entry is observed independently with probability $p = \Omega(n^{-3/2 + \kappa})$ for any arbitrarily small $\kappa > 0$. More generally, we establish robustness of the estimator, showing that when arbitrary noise bounded by $\varepsilon \geq 0$ is added to each observation, the estimation error with respect to MEE and MSE degrades by $\text{poly}(\varepsilon)$. Consequently, even if the tensor may not have finite rank but can be approximated within $\varepsilon \geq 0$ by a finite rank tensor, then the estimation error converges to $\text{poly}(\varepsilon)$. Our analysis sheds insight into the conjectured sample complexity lower bound, showing that it matches the connectivity threshold of the graph used by our algorithm for estimating similarity between coordinates.

OBJECTIVE: Gestational diabetes mellitus is defined as "diabetes recognized in the second or third trimester that is not clearly overt diabetes". Evidence relating to women with hyperglycemia early in pregnancy is limited. We aimed to evaluate women diagnosed with hyperglycemia early in pregnancy (eGDM) and compared them to those with pregestational established type 2 diabetes mellitus (T2DM) and gestational diabetes diagnosed routinely at 24-28-week gestation (rtGDM) to determine if the length of exposure to hyperglycemia adversely affected outcomes. METHODS: Forty consecutive women with eGDM who attended a multidisciplinary antenatal clinic were reviewed. Two separate BMI-matched control groups were identified, recognized pregestational T2DM (n = 80) and rtGDM (n = 80). Baseline demographics and outcomes were compared. RESULTS: A higher proportion of women in the eGDM and T2DM group required insulin and the incidence of hypertensive disorders was similarly increased compared with the rtGDM group (88.6, 77.0 versus 8.1%, p

In this work, iron oxide nanoparticle loaded carbon fibers were prepared by electrohydrodynamic co-casting a polymer and particle mixture followed by carbonization. The precursor used to generate carbon fibers was a linear molecular chain polymer: polyacrylonitrile (PAN). A solution containing iron (II, III) oxide (Fe3O4) particles and the PAN polymer dissolved in dimethylformamide (DMF) was electrohydrodynamically co-cast into fibers. The fibers were stabilized in air and carbonized in hydrogen at elevated temperatures. The microstructure and composition of the fibers were analyzed using scanning electron microscopy (SEM). A quantitative metallographic analysis method was used to determine the fiber size. It was found that the iron (II, III) oxide particles distributed uniformly within the carbonized fibers. Photosensitivity of the particle containing fibers was characterized through measuring the open circuit potential of the fiber samples under the visible light illumination. Potential applications of the fibers for photovoltaics and photonic sensing were discussed.