Impact of oral administration of single strain Lactococcus lactis spp. cremoris on immune responses to keyhole limpet hemocyanin immunization and gut microbiota: A randomized placebo-controlled trial in healthy volunteers

IntroductionLactococcus lactis spp. cremoris has been associated with promising immunomodulatory results in preclinical trials. The aim of this study was to investigate the pharmacodynamic (PD) effects of three monoclonal microbial formulations of L. lactis spp. cremoris (EDP1066) on the immune response to keyhole limpet hemocyanin (KLH). Potential effects on the gut microbiota were also investigated.MethodsThe trial was registered on Netherlands Trial Register (trial ID NL7519, https://trialsearch.who.int). Eighty-one healthy subjects (median 28, range 18–59 years) were randomized to 28 days of enteric-coated capsules at five doses (n = 13) (1.5 * 1012 total cells daily), freeze-dried powder at one dose (n = 12) (3.0 * 1011 total cells daily) or five doses (n = 12), minitablets at one dose (n = 12) or five doses (n = 12), or placebo (n = 20) prior to KLH immunization. Antibody responses and circulating regulatory T cells (Tregs) were measured after KLH immunization, and skin responses were evaluated after a KLH rechallenge by laser speckle contrast imaging and multispectral imaging. Ex vivo lymphocyte (phytohemagglutinin) and monocyte (lipopolysaccharide (LPS)) cytokine release assays were explored in the minitablet-treated groups only. The prevalence of L. lactis spp. cremoris in the gastrointestinal tract and the impact on the fecal microbiota were assessed by qPCR and 16S rRNA sequencing, respectively.ResultsRepeated-measures analysis of covariances revealed no significant treatment effects on the antibody responses to KLH, number of Tregs, or KLH skin rechallenge outcomes. Ex vivo LPS-driven cytokine responses in whole blood were lower in the low dose minitablet group compared to placebo: tumor necrosis factor (estimated difference (ED) from placebo: −44.2%, 95% confidence interval (CI) −65.3% to −10.3%), interleukin (IL)-1β (ED −41.4%, 95% CI −63.5% to −5.8%), and IL-6 (ED −39.2%, 95% CI −56.8% to −14.5%). The fecal presence of L. lactis spp. cremoris increased during treatment by all EDP1066 formulations and normalized 5 days after the last dose. Microbiome α-diversity did not change by the treatments compared to placebo.DiscussionThe EDP1066 formulations did not affect the immune response to KLH immunization in healthy individuals. However, exposure to L. lactis spp. cremoris in minitablet formulation impacted ex vivo whole blood LPS cytokine response. The clinical impact of these effects awaits further investigations.Netherlands Trial Registertrialsearch.who.int, trial ID NL7519

OX40L Inhibition suppresses KLH-driven immune responses in healthy volunteers: a randomized controlled trial demonstrating proof-of-pharmacology for KY1005

The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty-four healthy male subjects (26.5 +/- 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure-response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (T-max) similar to 4 hours, geometric mean terminal half-life (t1/2) similar to 24 days). Cutaneous blood perfusion (estimated difference (ED) -13.4 arbitrary unit (AU), 95% confidence interval (CI) -23.0 AU to -3.8 AU) and erythema quantified as average redness (ED -0.23 AU, 95% CI -0.35 AU to -0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure-response analysis displayed a statistically significant treatment effect on anti-KLH antibody titers (IgG maximum effect (E-max) -0.58 AU, 95% CI -1.10 AU to -0.06 AU) and skin response (erythema E-max -0.20 AU, 95% CI -0.29 AU to -0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune-mediated disorders.Drug Delivery Technolog

Role of Wnt signaling on proliferation of menstrual blood derived stem cells

Aim: Menstrual blood derived stem cells (MenSCs) are unique stem cells that have been isolated and identified recently. The special traits of MenSCs can be related to the cell signaling pathways. In this study, in order to find out the role of Wnt signaling on MenSCs proliferation, we evaluated ß-catenin expression as a key participant in Wnt signaling pathway in response to Lithium chloride (LiCl). Methods: MenSCs were isolated from healthy women by combining gradient density centrifugation with plastic adherence. After characterization of the isolated cells, cell proliferation of MenSCs in presence of 10-15 mM LiCl was evaluated by MTT assay. ß-catenin expression of the treated cells was examined using immunofluorescence technique. Results: Flow cytometric analysis revealed that both mesenchymal and embryonic stem cell markers are expressed on menstrual blood stem cells. MTT value decreased depending on the LiCl concentration. The proliferation of MenSCs cultivated in culture media containing 15mM LiCl was approximately two fold less than those grown without LiCl (p<0.01). Moreover, nuclear accumulation of ß-catenin protein in cells treated by LiCl was greater than cells without LiCl. Conclusion: The MenSCs are stem cell populations with high proliferation ability and unique immunophenotyping properties. Our results demonstrated that Wnt signaling pathway regulates MenSCs proliferation via trans-localization of activated-ß-catenin protein

Sedative and Analgesic Effects of Entonox Gas Compared with Midazolam and Fentanyl in Synchronized Cardioversion

The purpose of this study was to determine if the Entonox gas could cause adequate analgesic and sedative effects in patients who need cardioversion. In this randomized not blinded clinical trial, the sedative and analgesic effects of midazolam and fentanyl were compared with Entonox. Eligible patients who need synchronized cardioversion because of dysrhythmia were randomly divided into two groups. The first group received intravenous midazolam and fentanyl; the second group received Entonox through a blower-dependent mask. Onset and end of sedation, sedation level, and pain score were recorded. There were nonsignificant differences between the two groups (22 patients in each group) regarding age, gender, weight, sedation level, and frequency and level of shock. The pain score recorded in the first group was 5.05 ± 1.32, and 3.9 ± 0.7 in the second group (P = 0.002). Furthermore, sedation duration and time to full recovery consciousness were shorter in the second group (P < 0.001). In the first group, seven patients needed additional doses to induce and maintain sedation. In addition, as a result of apnoea, four patients required airway support. None of them occurred in the second group. Entonox is a suitable medication in rapid cardioversion, as it has minimal side effects and adequate analgesic and sedative effects

Evaluation of the therapeutic effect of the plasma of recovered COVID-19 patients for treating the patients admitted to the intensive care unit

The novel coronavirus has infected about 141 million people around the world. So far, about 80.4 million people have been discharged, and nearly 3.01 million people have died (an estimated mortality rate of 2.13). The study aimed to investigate the effect of plasma therapy from recovered COVID-19 patients to treat the patients hospitalized in the intensive care unit (ICU) of the Shahid Mostafa Khomeini Hospital of Ilam in 2020. The present prospective study was conducted in 2019-2020. Overall, 57 cases of plasma therapy were analysed using the Cox proportional hazard regression model in STATA 12 software. The results showed in patients receiving plasma treatment, the hazard ratio was (HR = 0.68, 95 CI, 0.45-1.04), indicating a 32 lower risk of death in the COVID-19 patients who received plasma therapy compared to those who did not. However, this relationship does not reach statistical significance (p = 0.07). Plasma therapy seems to yield some efficacy among patients with severe COVID-19 and those who have no underlying diseases. It is recommended to be used in combination with pharmaceutical interventions, for example, Actemra, to assess its therapeutic efficiency. (c) 2021 The Author(s). Published by Elsevier Ltd

Hybrid recommendation by incorporating the sentiment of product reviews

Abstract Hybrid recommender systems utilize advanced algorithms capable of learning heterogeneous sources of data and generating personalized recommendations for users. The data can range from user preferences (e.g., ratings or reviews) to item content (e.g., description or category). Prior studies in the field of recommender systems have primarily relied on “ratings” as the user feedback, when building user profiles or evaluating the quality of the recommendation. While ratings are informative, they may still fail to represent a comprehensive picture of actual user preferences. In contrast, there are other types of feedback data that differently or complementarily represent users and their preferences, including the reviews and the sentiments encapsulated within them. Such data can reveal important parts of a user’s profile that are not necessarily correlated with user ratings, and hence, they potentially reflect a different side of the user’s profile. In this paper, we propose a novel form of hybrid recommender system, capable of analyzing the reviews and extracting their sentiments that are incorporated into the recommendation process. We used advanced algorithms to generate recommendations for users capable of incorporating additional data, such as the review sentiment. We conducted analyses and showed that sentiments of user reviews are not always highly correlated with the ratings (e.g., in music domain). This might mean that sentiment can be indicative of a different aspect of user preferences and can be used as an alternative signal of user feedback. Hence, we have used both ratings and sentiments of reviews when evaluating our proposed hybrid recommender system. We selected two common datasets for the evaluation, Amazon Digital Music and Amazon Video Games, and showed the superior performance of the proposed hybrid recommender system compared to different baselines. The comparison were made in two evaluation scenarios, namely, when the ratings were considered the user feedback and when sentiments of the review were considered the user feedback

The relationship between dyspepsia and increased radiotracer uptake in the gastric wall during 99mTc-MIBImyocardial perfusion imaging

AbstractBackground and purpose: There are evidences indicating increased 99mTc-MIBI uptake by the gastric wall in myocardial perfusion SPECT connected with dyspepsia symptoms. In this study we aimed at investigating the frequency and structure of dyspeptic symptoms in patients showing gastric wall hyperactivity in 99mTc-MIBI myocardial perfusion SPECT and to determine any association between the existing symptoms and this scintigraphic finding.Materials and Methods: 1120 consecutive outpatients referred for myocardial perfusion SPECT were interviewed about the dyspeptic symptoms, current gastric medications and previous gastroduodenal interventions. The intensity of gastric wall activity was graded qualitatively as A or hyperactive gastric wall (equivalent to the heart activity) and B (less than heart activity).Results: Increased gastric wall uptake was seen in 1.78% of the patients. Dyspeptic symptoms were present in 80% and 19.3% of A and B patients, respectively (P<0.001). The dyspeptic symptoms were classified as ulcer-like in 37.5%, dysmotility-like in 43.75% and GERD-like in 18.75% of the dyspeptic A patients. Considering the classification of dyspepsia, there was no significant difference between the different groups. All of the eight different symptoms of dyspepsia had significantly higher prevalence in group A (all P values were less than 0.001). The history of previous upper GI endoscopy past history of previous gastroduodenal surgery and frequency of current use of gastric medications were significantly higher in group A.Conclusion: Although the clinical role of gastric wall hyperactivity detection is not yet clearly defined, report of this infrequent accidental finding should be part of the report of radionuclide imaging of the heart and may identify a category of patients, who require additional diagnostic gastrointestinal investigation to specify other possible noncardiac origins of their pain (and even the only origin of patients symptoms)