Strong Stimulus Research Articles

Less is more: Removing a modality of an expected olfactory-visual stimulation enhances brain activation.

In recent years, multisensory integration of visual and olfactory stimuli has extensively been explored resulting in the identification of responsible brain areas. As the experimental designs of previous research often include alternating presentations of unimodal and bimodal stimuli, the conditions cannot be regarded as completely independent. This could lead to effects of an expected but surprisingly missing sensory modality. In our experiment, we used a common functional magnetic resonance imaging (fMRI) study design with alternating strong unimodal and bimodal olfactory‐visual food stimuli, in addition to a slight overhang of the bimodal stimuli in an effort to examine the effects of removing a visual or olfactory congruent stimulus for older people (41–83 years). Our results suggest that the processing of olfactory and visual stimuli stays intact over a wide age‐range and that the utilization of strong stimuli does not lead to superadditive multisensory integration in accordance with the principle of inverse effectiveness. However, our results demonstrate that the removal of a stimulus modality leads to an activation of additional brain areas. For example, when the visual stimulus modality is missing, the right posterior superior temporal gyrus shows higher activation, whereas the removal of the olfactory stimulus modality leads to higher activation in the amygdala/hippocampus and the postcentral gyrus. These brain areas are related to attention, memory, and the search of the missing stimulus. Consequently, careful attention must be paid to the design of a valid, multimodal sensory experiment while also controlling for cognitive expectancy effects that might confound multimodal results.

An azabenz-annulated perylenediimide with tetraphenylethene units: Aggregation-induced emission, mechanochromic fluorescence, and cell imaging

Organic materials with strong solid-state fluorescence and sensitive stimuli responsiveness are highly desired for both fundamental research and practical applications. We report herein an azabenz-annulated perylenediimide (AzaBPDI)-based dye, AzaBP-TPE, which contains tetraphenylethene units in the planar aromatic structure. AzaBP-TPE undergoes typical intramolecular charge transfer, aggregation-induced emission, and mechanochromic fluorescence. In the solid state, AzaBP-TPE emits bright-yellow light with a photoluminescence quantum yield of 27%, and this emission becomes red fluorescence when MCF is induced, by using mechanical force to collapse the crystalline structure. Moreover, bright-yellow fluorescence can be recovered by exposing AzaBP-TPE powder to chloroform vapor. Notably, AzaBP-TPE nanoparticles can penetrate live cells and emit red light and, therefore, can be applied as a functional dye in bio-imaging.

The role of gingival mechanoreceptors in the tactile function of dental implants

Dental implants seem to restore some degree of tactile function. The aim of this study was to investigate the role of gingival mechanoreceptors in dental-implant osseoperception at the cortical-response level. The gingiva of the upper-left canine implant was stripped off under local anesthesia in five cats. We used intrinsic-signal optical imaging (ISOI) to measure the population-response characteristics of the feline oral-related cortex when separately applying punctate mechanical stimuli to the left canine implant and right intact natural canine. These response characteristics were compared under local anesthesia after removal of the gingiva. Under local anesthesia, the signal strength of the implant was significantly weaker than that of the tooth under weak but not under strong stimulus. After the gingiva was stripped off, the signal strength of the implant was significantly weaker than that of the tooth at all strengths of stimulus. Based on the evoked cortical responses, the gingiva was involved in the maximal tactile function of the implant.

Productive linkages in a segmented economy: the role of services in the export performance of German manufacturing

This article analyzes the causes that affect the export performance of the German manufacturing sector. By applying a subsystem approach to input–output analysis, we take into account the interlinkages between manufacturing and services. In particular, we consider two types of relationships that influence manufacturing competitiveness: the wage squeeze in services due to institutional factors and outsourcing; and the role played by knowledge-intensive business services (KIBS) as innovation drivers. Taking vertically integrated sectors as units of analysis, an export model is estimated. We find that labor costs play only a minor role for international competitiveness, while non-price factors are the main drivers of German exports. Therefore, although the wage squeeze in services is the centerpiece in the unit labor costs and export prices moderation, it is of minor importance for export growth. Conversely, the growing integration of KIBS provides a strong stimulus for non-price competitiveness and export growth.

P064 IMU-838, a Small Molecule DHODH Inhibitor in Phase 2 Clinical Trial for Ulcerative Colitis, Shows Potent Anti-inflammatory Activity in Cell-Culture-Based and In Vivo Systems

Abstract Background IMU-838 (vidofludimus calcium) is a well-tolerated and orally available small molecule inhibitor of dihydroorotate dehydrogenase (DHODH) and is currently in phase 2 clinical development for ulcerative colitis (UC). Here, we investigated the effect of IMU-838 on different immune cell subsets and analysed the mechanism of action in more detail in T cells. Methods The effect of IMU-838 on regulatory macrophages (Mregs) was investigated by adding IMU-838 or anti-TNFα antibodies (infliximab, adalimumab), alone or in combination, in a mixed lymphocyte reaction assay, determining Mregs (CD206+CD14+) by FACS analysis. To investigate the effect of IMU-838 on human T and B cells, PBMC were stimulated with PHA (48h) or Oligonucleotide 2006-PTO (70h), respectively. An affinity-dependent effect of IMU-838 was assessed on CD8 T cells from OT-I and OT-III mice, containing a high and a low affinity T cell receptor (TCR), respectively, for OVA257-264 peptide. These cells were stimulated with ovalbumin (OVA) peptide loaded splenocytes or anti-CD3/anti-CD28 for 3 days. Oxidative phosphorylation (OXPHOS) and glycolysis in murine T cells was investigated by the Seahorse/Agilent technique in murine CD4 and CD8 T cells activated with anti-CD3/anti-CD28 with or without IMU-838. Results IMU-838 slightly induced Mregs, but strongly and dose-dependently decreased TNFα and IL-6 secretion. Anti-TNFα antibodies alone strongly induced Mregs, but also increased IL-6 levels. When IMU-838 was added, Mregs induction was even higher, and IL-6 was reduced. Besides reducing proinflammatory cytokines secreted by macrophages, IMU-838 also inhibits proliferation of activated B and T cells, as well as inflammatory T cell cytokine secretion, IL-17A, IL-17F and IFNγ, and increased apoptosis up to 3-fold compared to vehicle control. By investigating IMU-838’s role on affinity related activity status of T cells, it was shown that IMU-838 strongly inhibited cell proliferation in the peptide stimulated high affinity, but not in the low affinity, CD8 T cells. Peptide stimulated high affinity T cells show an upregulation of OXPHOS and glycolysis pathways, which are involved in the generation of the cell’s energy supply, compared to low affinity cells. IMU-838 strongly inhibited OXPHOS and glycolysis in both CD4 and CD8 T cells. Conclusion IMU-838 reduces the proinflammatory immune cell response by inducing Mregs, reducing pro-inflammatory cytokine secretion and reducing immune cell proliferation. DHODH is only important in cells that received a strong stimulus and are highly metabolically active. Therefore, IMU-838 will only specifically target these cells and will still allow for a normal immune response, representing a huge safety advantage for treatment of IBD patients.

Breathing Dissipative Soliton Molecule Switching in a Bidirectional Mode‐Locked Fiber Laser

Breathing optical solitons propagating in a dissipative nonlinear system can interact and bind stably, forming an optical soliton molecule that presents striking molecule‐like dynamics. To date, the breathing soliton pair has been mainly observed in the microcavity platform, and the peculiar dynamic evolution of breathing soliton molecules (BSMs) remains largely unexplored in mode‐locked fiber lasers. Herein, the transient switching dynamics of BSMs in a bidirectional ultrafast fiber laser is revealed, specifically triggered at different parameter spaces of saturable absorption with manipulation polarizations that maintain constant pulse separation or undergo strong repulsion and kink after switching. All‐optical switching of breather molecules and significantly increasing multiple soliton molecules’ switching of two or three solitons between states with different binding separations by applying a strong stimulus with periodic pump modulation is demonstrated. The instantaneous pulse breakup can be induced by the collision of bidirectional breathing solitons in each switching, which is characteristic of the breathing solitons in a bidirectional fiber laser and further corroborated by numerical simulation. The study unveils new perspectives into the ultrafast transient process of BSMs in various dissipative systems.

Has China's Free Trade Zone policy expedited port production and development?

China's free trade zone (FTZ) policy satisfies China's objective demand to get geared to the economic globalization trend and forms an essential part of China's opening-up strategy, creating new opportunities for Chinese seaports. Seaport development is subject to its throughput and the import and export trade scale of the city where it's located, but the growth rates of the two are not synchronized. To identify the impacts of FTZ policies on China's free trade seaports, with port throughput and import and export trade scale of the city taken into consideration, this article selects four Chinese seaports, namely Shanghai Port, Tianjin Port, Guangzhou Port, and Fuzhou Port, which are located in the FTZ establishment earlier, and bases the study on the port throughputs and import and export trade volumes of their cities from 2000 to 2020 for empirical testing with the allometric growth model and linear scale factors. The results show that the impacts of FTZ policies exhibit differences from region to region. Specifically, the FTZ promotion policies have lagging impacts on Shanghai Port and Tianjin Port. The Guangdong Free Trade Zone's policies have a short-term continuous promoting impact on Guangzhou Port's production. In contrast, Fujian Free Trade Zone's policies are a strong stimulus to the development of Fuzhou Port. The empirical test about the FTZ policies' impacts on seaport development will provide a theoretical basis for figuring out the critical role of FTZ in promoting the high-quality development of seaports and boost the coordinated development of ports and urban economies.

Chung-Ang Auditory Database of Korean Emotional Speech: A Validated Set of Vocal Expressions With Different Intensities

A growing body of evidence indicates that intensity plays a role in emotion perception. However, only a few databases have been explicitly designed to provide emotional stimuli that are expressed at varying intensities. We developed and validated a Korean audio-only database of emotional expressions. Eighteen actors were recorded using twenty-five sentences with strong and moderate intensities for “neutral,” “happiness,” “sadness,” “anger,” “fear,” and “boredom” emotions. Twenty-five native Korean-speaking adults completed the emotion identification and naturalness rating tasks. All listeners were presented with the full set of 5400 recordings in a six-alternative forced-choice paradigm, yielding 135000 judgements for identification and naturalness, respectively. Raw and unbiased hit rates were calculated, with identification responses significantly above chance level for every emotion at both intensities. The overall raw hit rates reached 87% and 78% for the strong and moderate stimuli, respectively, indicating that strong emotional expressions were more accurately identified than their moderate counterparts. Similarly, a recognition advantage for strong intensity over moderate intensity was observed for each emotion at both intensities. High inter- and intra-rater reliabilities were found in listeners’ identifying emotion categories and assigning naturalness ratings, respectively. Further, there was a strong association between identification accuracy and the degree of naturalness; more natural variants of an emotion were more accurately identified than its less natural counterparts. These results confirm that the proposed database will serve as a valuable source for emotion research. This database is available for research purposes upon request from the corresponding author.

ПРИЙОМИ ВИКОРИСТАННЯ АВТЕНТИЧНИХ ТЕКСТІВ НА ЗАНЯТТЯХ ІЗ АНГЛІЙСЬКОЇ МОВИ

Introduction. The article determines the peculiarities of practical using of original texts in modern teaching of foreign language. Texts are used when studying the themes of everyday communication. Adapted and authentic texts are proposed in the process of learning. The students’ interests for historical and current events in Great Britain are taking into account. The lecture in class focuses attention of future specialists on the realities which are represented in the culture of different countries. Firsthand view of current events requires uses the Internet’s sources. The purpose of the article is to assign ways of using the local history texts at the lessons of English. It is necessary to sort out the criteria of selection of such texts. It is required to find out a succession of working with the local history texts. The other aim is to characterize the most effective tasks in the process of using the local history texts in class. The active methods of using the authentic and the local history texts are presented in the lessons. There are searching for information and studying it independently, and addition of insufficient information. There are also doing different exercises and using basic knowledge of students. In the selection of the local history texts such criteria are sorted out: topicality, information value, visualization, systematic reading, and simplicity. Texts must satisfy the requirements of the curriculum and be reliability too. Understanding of the original texts is extended under conditions of doing tasks at the different stages of working with these texts. There are pre-reading, reading and after-reading stages. Results. Using of the original texts helps students to receive and remember considerable informational scope. Texts are a strong stimulus to have a good command of a foreign language. Originality. In the process of reading and analyze the authentic texts, students do different tasks directed at improving their language skills. Future specialists activate their knowledge, search additional information and prepare historical references in concrete themes. Students fix important data and comment received facts in the process of reading. They also learn to compare the realities of native and foreign countries, discuss information in small groups and as a team. Students do visualizations for their presentations and choose creative tasks as they wish. Conclusion. Reading and analyzing of the authentic and the local history texts stimulate students’ informative activity and share their mental outlook. Firsthand view of English culture and modern opinion about the realities helps students to compare peculiarities in different countries, say their own opinion in English.

IoT technologies for wine supply chain traceability: potential application in the Southern Apulia Region (Italy)

The high value and volume of Italian wine production determines a strong stimulus for counterfeiting, which generates negative consequences for grape growers, winemakers and consumers. In this context, IoT technologies and the blockchain can serve as tools to ensure traceability, transparency and efficiency along the whole wine supply chain.Using primary data collected through interviews to the main grape growers and wineries involved in the wine supply chain in the Southern Apulia Region and secondary data, acquired from previous scientific literature, the study proposes a framework for the traceability and efficiency of the wine supply chain based on a combination of blockchain, Radio-Frequency Identification (RFID) and Near Field Communication (NFC) tags, Serial Shipping Container Codes (SSCC) and Quick Response (QR) codes. The developed framework allows for the systematic storage of information about commodities and processes throughout the supply chain, from grape growers to wine consumption and packaging disposal and/or reuse (forward and reverse flows). In addition, it ensures the transparency, safety, and security of all processes involved within the wine supply chain, serving as a quality information management tool. The information collected along the wine supply chain is entered into the management system by farmers, winemakers and bottlers and is accessible to all of them, while the distributors, consumers and the bottle reverse logistics operators, can only consult all of the information stored on the blockchain in order to know the origin, the quality, the processing and the authenticity of wines, without being able to enter data and/or modify the existent information.

The Triumph of Peace: International Congresses and European Society in the Time of Courts and Alliances

The formation of the first state system in Europe took place from the conclusion of the Peace of Westphalia in 1648, as a result of the Thirty Years' War (1618-1648), to the Utrecht (1713) and Rastatt-Baden (1714) Congresses which finished the end of the war of the Spanish Succession. The legal fixation of the Westphallian system was accompanied by its public perception and acceptance. First of all, this was demonstrated by International Congresses, which were not only a common negotiation process, but also a place of representation of the significance and culture of each state. In fact, the European Congress was a carefully designed triumph of peace within the continent, which required considerable funds, was widely covered in the press and glorified in celebrations, paintings, the release of commemorative medals, poetry and even fashion. The article presents the most striking examples of the analysis of the representation forms of Peace Congresses. The author believes that negotiations between states and the conclusion of peace made a significant contribution to the civilization heritage of Europe. The factor of transition from war to peace was the strongest stimulus for the transformation of the government structure in line with the monopolization of power, the development of trade, the banking system, productive forces and culture, which changed people's attitude to their own personality and environment. The publicity of International Congresses can also be considered as incentive for the development of the Law of Nations and as an act of humanitarian diplomacy. Peace Congresses were designed to minimize the heavy legacy of military conflicts in the historical memory.

Effective description of bistability and irreversibility in apoptosis

Apoptosis is a mechanism of programmed cell death in which cells engage in a controlled demolition and prepare to be digested without damaging their environment. In normal conditions, apoptosis is repressed until it is irreversibly induced by an appropriate signal. In adult organisms, apoptosis is a natural way to dispose of damaged cells and its disruption or excess is associated with cancer and autoimmune diseases. Apoptosis is regulated by a complex signaling network controlled by caspases, specialized enzymes that digest essential cellular components and promote the degradation of genomic DNA. In this work, we propose an effective description of the signaling network focused on caspase-3 as a readout of cell fate. We integrate intermediate network interactions into a nonlinear feedback function acting on caspase-3 and introduce the effect of pro-apoptotic stimuli and regulatory elements as a saturating activation function. We show that activation dynamics in the theory is similar to previously reported experimental results. We compute bifurcation diagrams and obtain cell fate maps describing how stimulus intensity and feedback strength affect cell survival and death fates. These fates overlap within a bistable region that depends on total caspase concentration, regulatory elements, and feedback nonlinearity. We study a strongly nonlinear regime to obtain analytical expressions for bifurcation curves and fate map boundaries. For a broad range of parameters, strong stimuli can induce an irreversible switch to the death fate. We use the theory to explore dynamical stimulation conditions and determine how cell fate depends on stimulation temporal patterns. This analysis predicts a critical relation between transient stimuli intensity and duration to trigger irreversible apoptosis. We derive an analytical expression for this critical relation, valid for short stimuli. Our description provides distinct predictions and offers a framework to study how this signaling network processes different stimuli to make a cell fate decision.

Neurotransmitter regulation rather than cell-intrinsic properties shapes the high-pass filtering properties of olfactory bulb glomeruli.

GABAergic periglomerular (PG) cells in the olfactory bulb are proposed to mediate an intraglomerular 'high-pass' filter through inhibition targeted onto a glomerulus. With this mechanism, weak stimuli (e.g. an odour with a low affinity for an odourant receptor) mainly produce PG cell-driven inhibition but strong stimuli generate enough excitation to overcome inhibition. PG cells may be particularly susceptible to being activated by weak stimuli due to their intrinsically small size and high input resistance. Here, we used dual-cell patch-clamp recordings and imaging methods in bulb slices obtained from wild-type and transgenic rats with labelled GABAergic cells to test a number of predictions of the high-pass filtering model. We first directly compared the responsiveness of PG cells with that of external tufted cells (eTCs), which are a class of excitatory cells that reside in a parallel but opposing position in the glomerular circuitry. PG cells were in fact found to be no more responsive than eTCs at low levels of sensory neuron activity. While PG cells required smaller currents to be excited, this advantage was offset by the fact that a given level of sensory neuron activity produced much smaller synaptic currents. We did, however, identify other factors that shaped the excitation/inhibition balance in a manner that would support a high-pass filter, including glial glutamate transporters and presynaptic metabotropic glutamate receptors. We conclude that a single glomerulus may act as a high-pass filter to enhance the contrast between different olfactory stimuli through mechanisms that are largely independent cell-intrinsic properties. KEY POINTS: GABAergic periglomerular (PG) cells in the olfactory bulb are proposed to mediate a 'high-pass' filter at a single glomerulus that selectively blocks weak stimulus signals. Their efficacy may reflect their intrinsically small size and high input resistance, which allows them to be easily excited. It was found that PG cells were in fact no more likely to be activated by weak stimuli than excitatory neurons. PG cells fired action potentials more readily in response to a fixed current input, but this advantage for excitability was offset by small synaptic currents. Glomeruli nevertheless display an excitation/inhibition balance that can support a high-pass filter, shifting from unfavourable to favourable with increasing stimulus strength. Factors shaping the filter include glial glutamate transporters and presynaptic metabotropic glutamate receptors. It is concluded that a single glomerulus may act as a high-pass filter to enhance stimulus contrast through mechanisms that are largely independent of cell-intrinsic properties.

Physical Activity and DNA Methylation in Humans.

Physical activity is a strong stimulus influencing the overall physiology of the human body. Exercises lead to biochemical changes in various tissues and exert an impact on gene expression. Exercise-induced changes in gene expression may be mediated by epigenetic modifications, which rearrange the chromatin structure and therefore modulate its accessibility for transcription factors. One of such epigenetic mark is DNA methylation that involves an attachment of a methyl group to the fifth carbon of cytosine residue present in CG dinucleotides (CpG). DNA methylation is catalyzed by a family of DNA methyltransferases. This reversible DNA modification results in the recruitment of proteins containing methyl binding domain and further transcriptional co-repressors leading to the silencing of gene expression. The accumulation of CpG dinucleotides, referred as CpG islands, occurs at the promoter regions in a great majority of human genes. Therefore, changes in DNA methylation profile affect the transcription of multiple genes. A growing body of evidence indicates that exercise training modulates DNA methylation in muscles and adipose tissue. Some of these epigenetic markers were associated with a reduced risk of chronic diseases. This review summarizes the current knowledge about the influence of physical activity on the DNA methylation status in humans.

Current frontiers in quantum chemical simulations of NIR spectra – Polymers, biomolecules, aqueous matrix and interpretation of instrumental difference of handheld spectrometers

Analytical near-infrared (NIR) spectroscopy has developed rapidly over the past few decades and is today of incredible value for academic, industrial and institutional laboratories. These developments are closely related to the development of instruments and miniaturization, as well as the methods of multivariate analysis. The strong stimulus for the development of NIR spectroscopy originating from the application field resulted in the advancement of this technique to suite unitarian goals. By contrast, less actively explored have been the foundations of NIR spectroscopy. Much of the information contained in the NIR spectrum is still not easily accessible for the purpose of basic research. In the past few years, a promising development has been made in application of the methods of computational chemistry to NIR spectroscopy. In this article, the current frontier of this advancement is summarized. The scope of the recent accomplishments shifts closer to the challenging real-life problems, such as interactions of the analysed molecules with the matrix, including the aqueous environment. Particular attention was given to the interpretation of the chemical factors underlying instrumental differences between miniaturized NIR spectrometers using different technology and optical solutions. The applicability of the methods of computational chemistry to unravel intricate NIR spectral features of complex molecules such as biomolecules and polymers should be highlighted as well.

Body injuries in male morphotypes of the Amazon River prawn (Macrobrachium amazonicum)

ABSTRACT Fights between individuals in a population can be motivated by several factors, such as disputes over food, shelter and sexual partners. The present study aimed to evaluate the pattern of injury occurrence in the Amazon River prawn (Macrobrachium amazonicum). Prawns and environmental factors were sampled monthly, from February 2012 to September 2013, in the Tietê River, São Paulo, Brazil. Individuals were classified into eight different demographic classes and analyzed macroscopically for body injuries, which were separated into four categories (0–4). From the 2,234 prawns collected, 124 presented one or more types of physical damages. The males of dominant castes presented the highest amount of injuries, suggesting that these groups get involved more frequently in disputes. Possibly, reproductive events are a strong stimulus for the occurrence of fights in freshwater prawns since the greatest amount of injuries was observed in the period of reproductive peaks.

Clinical Features and Treatment Outcomes of Large Granular Lymphocytic Leukemia Coexisting with Autoimmune Diseases

Introduction:Large granular lymphocytic leukemia (LGLL) is a rare, indolent malignancy arising from cytotoxic T cells (T-LGLL, ~85%) or NK cells [chronic NK-cell lymphoproliferative disorder (CLPD-NK), ~15%]. When treatment is needed, single-agent immunosuppressive therapeutics are usually used, including low-doses of methotrexate (MTX), cyclophosphamide (Cy), and cyclosporine A (CSA). The coexistence of LGLL with autoimmune diseases (ADs) especially rheumatoid arthritis (RA) and Felty Syndrome (FS) has been reported in some patients (pts), suggesting a role of initial strong antigenic stimuli from autoantigens in the pathogenesis of LGLL. However, it remains unclear whether AD-associated LGLLs have unique clinical features or treatment outcomes. We have recently published the largest retrospective study of 319 LGLL cases (Dong et al. 2021). Here we report the outcomes of the LGLL pts with coexisting ADs.Methods:All patients who presented to Moffitt Cancer Center from 2001 to 2020 with a diagnosis of coexistence of T-LGLL or CLPD-NK and AD were included. Diagnostic criteria, treatment and response evaluation were reported elsewhere (Dong et al. 2021). Comparison of response rates was performed using Fisher's exact test or Chi-square test when appropriate. Median survival was estimated using Kaplan-Meier method and compared with log-rank test. Multivariate analysis was not done due to limitation of sample size. All analyses were done using SAS 9.4.Results:The patient characteristics are listed in Table 1. Among the 83 pts, 77 (92.8%) had T-LGLL and 6 (7.2%) had CLPD-NK. The most common ADs were RA [38 (45.8%)], followed by FS 13 (15.7%), and inflammatory bowel disease, polymyalgia rheumatica and vasculitis [5 (6%) each]. 33 (39.8%) pts needed treatment for LGLL. Three of the 5 pts who underwent NGS testing were positive for STAT3 mutation.In our practice, we favor MTX as the frontline therapy for LGLL with coexisting ADs such as RA. The treatments and responses are presented in Table 2. Among the 29 pts who received MTX, 24 (82.8%) had response, including 6 (20.7%) complete response (CR). Among the 11 pts treated with Cy, 9 (81.8%) had response and 5 (45.5%) had CR. CSA was used in 6 pts and had response in 3 (50.0%) and CR in 2 (33.3%). The response rates were not different between MTX, Cy and CSA, neither were the CR rates, although the statistical testing was limited by sample size. Consistent with our previous findings in LGLL, the response to growth factor (GCSF) was low and only 1 of 4 pts responded. Compared to the 131 LGLL pts without co-existing AD in our series, AD-associated LGLL had higher response rates to MTX, Cy or CSA (61.9% vs 78.3%, respectively, p=0.04).Interestingly, pts with CLPD-NK were less likely to respond to CSA, MTX or Cy compared to pts with T-LGLL [1/5 (20%) vs 35/41 (85.4%), p=0.006]. The type of AD, age, splenomegaly, anemia, neutropenia, thrombocytopenia or STAT3 mutation were not associated with response.With a median follow-up of 5.2 (IQR 2.0-9.5) years, the median survival was 10.9 (95% CI 8.1-not estimable) years. Anemia and thrombocytopenia were associated with worse survival (figures 1 and 2). The median survival for pts with vs without anemia was 8.1 (95% CI 3.9-not estimable) years vs not estimable (95% CI 8.7-not estimable), p=0.01. The median survival for pts with vs without thrombocytopenia was 8.4 (95% CI 3.8-10.1) years vs 13.3 (95% CI 8.1-not estimable) years, p=0.05. The type of LGLL, blood LGL count, splenomegaly, or neutropenia were not associated with survival.Conclusions:The majority (~80 %) of LGLL pts with AD responded to MTX, Cy or CSA, although CR rate was low (20-45%). Interestingly, CLPD-NK pts were less likely to respond compared to T-LGLL which could be attributed to a small sample size and warrants an expanded case study. Anemia and thrombocytopenia were associated with worse survival. Future studies will be of interest to evaluate the hematological responses of LGLL in patients with coexisting ADs treated with FDA-approved biological agents for AD such as TNF inhibitors, IL-6 antagonists and T-Cell co-stimulation blocker. Such studies may provide insights into LGLL treatment as both diseases may share some common pathogenic pathways. [Display omitted] DisclosuresSokol: Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure:Rituximab and alemtuzumab have not been approved by FDA for LGL leukemia.

Phase II Trial of Elotuzumab in Combination with Carfilzomib, Lenalidomide and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM) after One Prior Line of Therapy

Introduction: The treatment for RRMM in first relapse typically involves a triplet combination, with choice influenced by the type of treatment already received, and the initial response. Elotuzumab (Elo), an anti-SLAMF7 immunostimulatory monoclonal antibody, mediates plasma cell killing by activating signals in NK cells and via antibody-dependent cell-mediated cytotoxicity. Carfilzomib (K) and lenalidomide (R) can activate NK cells and enhance NK cell-mediated lysis, whereas dexamethasone (d) can potentiate these strong pro-inflammatory stimuli by altering NK cell activating receptor expression and by sensitizing T cells to anergy signaling. Here, we report the preliminary results of a phase II study of Elo in combination with KRd (Elo-KRd) for MM in first relapse [ClinicalTrials.gov Identifier: NCT03361306].Methods: Patients with RRMM (biochemical and/or clinical) aged at least 18 years who had received one prior line of systemic therapy and had measurable disease were included. Patients refractory to bortezomib and/or R were eligible. Patients with plasma cell leukemia (PCL) were not excluded. Treatment consisted of 4 cycles of Elo-KRd Induction (Elo 10 mg/kg IV once weekly on days 1,8,15, 22; K 20/27 mg/m 2 IV on days 1,2,8,9,15,16 ;R 25 mg oral daily on days 1-21; d 28 mg oral and 8 mg IV once weekly on days 1,8,15, 22) repeated every 28 days, followed by Elo-R maintenance (Elo 10 mg/kg IV every 2 weeks on days 1,15 for cycles 1-2 then 20 mg/kg IV on day 1 of each cycle; R 15 mg or last tolerated dose oral on days 1-21), cycle 5 and beyond until progression or unacceptable toxicity The primary endpoint of the study was very good partial response or better (≥VGPR) after 4 cycles of induction therapy. Secondary endpoints included overall response rate (ORR), overall survival (OS), progression free survival (PFS), minimal residual disease (MRD) and safety. Results are summarized with frequencies and proportions for categorical data, including response, and descriptive statistics for continuous data. Median survival outcomes were estimated with Kaplan Meier methods.Results: A total of 15 patients were enrolled by the data cut-off of 04/23/2021. Median age was 64 (range, 46-74) years; 13% of patients were ≥70 years old. Patients were uniformly distributed within revised ISS stages I/II/III at time of diagnosis, 33.3% in each category. Six (40%) patients had high-risk features: 4 with chromosomal abnormalities [del17p, t(4;14) or t(14;16)], 1 primary PCL and 1 extramedullary MM (lymph nodes and muscles). Twelve (80.0%) were refractory to R, 5 (33.3%) were refractory to bortezomib, one (3.3%) had prior Daratumumab exposure, and 12 (80.0%) had undergone autologous stem cell transplantation. Twelve patients completed 4 cycles of Elo-KRd induction while 3 patients discontinued treatment (due to disease progression) prior to completing induction. At end of induction, the ORR was 66.7% including ≥VGPR in 33.3% (5/15), CR in 13.3%. Rate of ≥VGPR as best response during study was 53.3% (8/15), with an ORR of 80%. MRD-negative (10 -5) rate post-induction was 20% (3/15). After a median follow-up of 23.1 months (range, 3.8 to 38.6 months), the median PFS is 11.5 months (95% CI 1.9, 18), and median OS is not reached (95%CI 10.1, NA). Grade 3/4 treatment-emergent adverse events (TEAEs) occurring in ≥10% of patients were neutropenia (n=5), thrombocytopenia (n=3), hypophosphatemia (n=4), fatigue (n=3), thromboembolic event (n=2), and second neoplasms (n=1, renal cell carcinoma). Grade 3/4 infection rate was 13.3% (2/15). No patient discontinued treatment due to an adverse event. We intend to update the analysis of the study results at the meeting.Conclusions: Elo-KRd was well tolerated and demonstrated activity in this high-risk patient population comparable to other contemporary approved triplet combinations in this population. DisclosuresBhutani: Amgen, BMS, Takeda: Speakers Bureau; Sanofi: Consultancy; Janssen, MedImmune, Takeda, Celgene, BMS, Cerecor, Celularity: Research Funding. Atrash: Jansen: Research Funding, Speakers Bureau; AMGEN: Research Funding; GSK: Research Funding. Foureau: TeneoBio, Celgene: Research Funding; Cytognos: Honoraria. Paul: Janssen Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Speakers Bureau; Bristol Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months; Genentech: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees. Symanowski: Carsgen: Consultancy; Immatics: Consultancy, Other: DSMB Member; Eli Lilly: Consultancy, Other: DSMB Member. Voorhees: AbbVie Inc, Bristol-Myers Squibb Company; Consulting Agreement: GlaxoSmithKline, Novartis, Oncopeptides: Other: Advisory Committee; Bristol-Myers Squibb Company.: Other: Data Safety & Monitoring. Usmani: Array BioPharma: Consultancy, Research Funding; Abbvie: Consultancy; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau.

Comparison of the hemodynamic response of dexmedetomidine versus additional intravenous lidocaine with propofol during tracheal intubation: a randomized controlled study

BackgroundLaryngoscopy and tracheal intubation are strong stimuli that cause a reflex increase in blood pressure (BP), heart rate (HR), and serum catecholamine level. These can lead to myocardial infarction or cerebrovascular accidents. The purpose of this study is to compare the efficacy of dexmedetomidine and lidocaine combined with propofol in attenuating the hemodynamic response following laryngoscopy and endotracheal intubation.MethodsThis study was a randomized controlled study and adhered to the CONSORT guidelines. One-hundred and six patients undergoing elective general anesthesia with endotracheal intubation were divided randomly into two groups. Group D received dexmedetomidine (1 μg kg− 1) before induction. Group LP received lidocaine (1.5 mg kg− 1) before induction with additional propofol (0.5 mg kg− 1) before laryngoscopy. The primary endpoint was hemodynamic including systolic (S) BP, diastolic (D) BP, mean arterial blood pressure (MAP) and HR measured before and after induction and ≤ 10 min after intubation. Secondary outcome was complications/adverse effects.ResultsAfter induction, the mean SBP, DBP, MAP and HR decreased significantly from baseline in both groups except for mean HR in group LP at 1 min. Differences in mean values of SBP, DBP, and MAP were significantly lower in group D after intubation at 4–10 min (P < 0.05). Group LP had a non-inferior effect in blunting BP at all time points except 1 and 2 min after induction, and 2 min after intubation. The mean difference in HR in group D was significantly lower than that in group LP at all time points (P < 0.001). Group D had significantly more episodes of bradycardia (18.87% vs. 0%, P = 0.001) and hypotension (52.83% vs. 15.09%, P < 0.001) than did group LP.ConclusionLidocaine (1.5 mg kg− 1) with additional propofol (0.5 mg kg− 1) had a non-inferior effect compared with dexmedetomidine (1 μg kg− 1) in attenuating the hemodynamic response following laryngoscopy and endotracheal intubation, and had fewer adverse effects.Trial registrationThai Clinical Trial Registry, (TRTC20190206002). Retrospectively registered 4 February 2019.

Comparison of Sodium Lactate Infusion and Carbon Dioxide Inhalation Panic Provocation Tests: A Meta-analysis.

Sodium lactate (NaL) infusion and carbon dioxide (CO2) inhalation are proven to provoke acute panic attacks (PAs) in patients with panic disorder (PD). A systematic literature search and meta-analysis were performed to compare the effect sizes of these methods. Odds ratios were calculated for each of the original studies and were pooled using the random-effects model. Either NaL or CO2 provocations significantly increased the rates of PAs in individuals with PD compared to those in healthy controls. However, the effect size of NaL infusion (OR=25.13, 95% CI=15.48-40.80) was significantly greater than that of CO2 inhalation (OR=10.58, 95%CI=7.88-14.21). The evidence for the efficacy of the two panic provocation tests is very strong. Yet, the results support the superiority of NaL infusion over CO2 inhalation challenge as a panic provocation test. Thus, lactate seems a much stronger stimulus than CO2 for the brain suffocation detector.