Local Reactions Research Articles

Managing systemic reactions and venom immunotherapy in vespid-venom allergy: observations from a retrospective study of Portuguese patients.

Background. Vespula spp. and Polistes spp. are relevant species in South Europe, with Vespa velutina nigrithorax (VVN) being considered a public health problem. We aimed to characterize a cohort of Portuguese patients referred for large local reaction (LLR) and/or systemic reaction (SR) to vespids. In patients treated with venom immunotherapy (VIT), induction protocol and frequency of adverse reactions were evaluated. Methods. Retrospective study including patients with LLR and SR to vespids referred to our Immunoallergology Department (2008-2022). Results. A total of 129 patients were evaluated, the majority were male adults (n = 77, 59.7%), from rural areas. From these, 51 patients had SR (Mueller classification: 7.8% grade I, 19.6% grade II, 37.3% grade III, 35.3% grade IV). We found no differences regarding the levels of total serum IgE, basal serum tryptase value, sIgE levels to the eliciting venom or their molecular components, regarding the severity of the SR that motivated the referral to our clinic. In the SR group, previous LLR Hymenoptera sting were reported in 15.7%. Thirty-eight patients (74.5%) initiated VIT: 22 with wasp venom, 14 with paper wasp venom and 2 with Vespa velutina venom. There was one mild systemic reaction, not requiring adrenaline and 4 LLR. Re-stings after VIT occurred in 16 patients, without any systemic or local reactions. Currently, eleven patients remain under VIT. Conclusions. Most vespid-venom allergic patients are male adults from rural areas. Sensitization to wasp venom was present in 52.9%, paper wasp in 33.3% and Vespa velutina in 13.7%. The frequency of adverse reactions during both induction and maintenance phases appears to be low. Despite a reduced sample size, our experience with VVN VIT, suggests its safety.

Phase 2 study to evaluate the novel mitochondrial PRX3 inhibitor, RSO-021, as an intrapleural monotherapy and in combination with IV paclitaxel in patients with malignant pleural effusion due to mesothelioma or another advanced solid tumor.

TPS8124 Background: Tumor cells generate elevated levels of reactive oxygen species (ROS), leading to increased expression and activity of critical ROS scavenging pathways. Peroxiredoxin 3 (PRX3) is the principal peroxide scavenging enzyme in mitochondria. RSO–021 is a novel small molecule PRX3 inhibitor that inactivates PRX3 through direct covalent adduction of active site cysteine residues, in turn inducing oxidative stress that is incompatible with tumor cell survival. Preclinical studies of RSO-021 show that it selectively inhibits mitochondrial PRX3 in vitro and is highly effective in a variety of tumor models, including mesothelioma and many solid tumors. RSO-021 has completed phase 1 evaluation in patients with advanced mesothelioma or solid tumors with predominant pleural disease and malignant pleural effusions. The phase 1 data supported weekly intrapleural dosing of RSO-021 at the 90 mg dose level, with acceptable safety and early signals of efficacy. Some patients were able to receive >30 weeks of treatment. Pre- and post-dose primary prophylaxis for local inflammatory reactions to intrapleural injection was instituted during dose escalation, using corticosteroids, NSAIDS and paracetamol. It also became clear that RSO-021 should not be administered to patients with a dry pleural tap, due to risk of extravasation. Methods: The objectives of this open-label, multi-center, 4-arm phase 2 study (MITOPE) are to confirm the efficacy, safety, tolerability, and pharmacology of weekly intrapleural RSO-021 administration. Exploratory endpoints include target engagement as well as biomarkers of response and inflammation. The study explores 2 different RSO-021 doses (90 mg/wk and 45 mg/wk) per FDA Project Optimus, both as monotherapy and in combination with IV paclitaxel 175 mg/m2 every 3 weeks at until progression or limiting toxicity. Each arm at each dose has a 2-stage Simon design (12-21 patients) requiring 1 response to trigger stage 2 (null/target response rate 3%/20% and type I/type II error 0.05/0.8) for a maximum of 168 patients in the trial. Three of the 4 study arms are investigating the antitumor activity of RSO-021 monotherapy (arms 1-3) and the fourth is assessing the paclitaxel combination. Eligibility (by arm) requires: newly diagnosed treatment-naïve mesothelioma with pleural effusion; mesothelioma with pleural effusion that progressed on ≥1 standard of care (SoC) regimen; solid tumor with predominant pleural/lung disease and effusion that progressed on ≥1 SoC regimen; and breast, epithelial ovarian or non-small cell lung cancer with predominant pleural/lung disease and effusion that progressed on ≥1 SoC regimen. The first patient was treated in 4Q2023 and the trial is actively recruiting to all 4 arms at 9 UK sites. Additional sites are planned. Clinical trial information: NCT05278975 .

Phase 1/2 of EO2463 immunotherapy as monotherapy and in combination with lenalidomide and/or rituximab in indolent NHL (EONHL1-20/SIDNEY).

7058 Background: Follicular and marginal zone B cell lymphoma (FL; MZL) demonstrate an indolent course with heterogeneous outcomes anda potential for spontaneous remissions indicating immune system intervention. Therapeutic immunization is therefore an attractive approach but new antigens that evoke a strong immune response are needed. EO2463 expands pre-existing memory CD8+ T cells recognizing non-self protein sequences from gut bacteria which cross-react with B cell antigens and can kill HLA-A2 restricted cells (T2) loaded with target peptides. EO2463 includes 4 HLA-A2 synthetically produced epitopes which exhibit molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor), as well as a the CD4 helper-epitope UCP2 derived from hTERT. EO2463 is being used to drive anti-tumor activity against B cell malignancies. Methods: Patients (pts) with FL and MZL, stage 1-3A, and HLA-A2, are eligible. In the safety lead-in pts with relapsed/refractory (R/R) disease were given EO2463 SC q2 weeks (w) x 4, then q4w, for a max of 12 months; at w7 lenalidomide (20 mg/day for 21/28 days up to 12 cycles) is added (EL), and if no complete remission (CR) at w19, rituximab (375 mg/m2 IV, q1w x 4, then q4w x 4) is also added (ER2). Doses evaluated: 150 μg and 300μg/peptide. Results: 3 pts received 150 μg/peptide and 6 pts 300 μg/peptide (EO2463 1 pat, EL 2 pts, ER2 6 pts): 2 MZL, 7 FL pts with median 2 lines (range 1-4) of prior systemic therapy. No related grade ≥3 adverse events were seen with EO2463 monotherapy. Most common related events were grade 1 to 2 local administration site reactions in 5/9 pts. Adverse events during combination treatment were as expected for R2. PET-CT on w6 after EO2463 monotherapy suggested clinical activity in 4/9 pts (1 PR, 1 pt size reduction 15%, 1 pt 20% reduced tracer uptake, 1 pt 5/6 target lesions reduced metabolic activity). Overall objective responses (OR) were seen in 6/9 pts (67%; 1st OR on EO2463 1 pat, EL 4 pts, ER2 1 pat), with CR in 5/9 (56%) pts; median time to response was 18w (range 8-43w), response ongoing in 5 pts, range 24-76w. Expansion of specific CD8+ T cells against mimic peptides and targeted B cell antigens were detected in all responding pts, incl. 2 pts with no measurable B cells at baseline (prior anti-CD20). Expansion of specific T cells was detected at w5 in 5/6 pts and was maintained as long as currently tested (up to w94, 43w after last EO2463 dose). No decline in expansions were seen after start rituximab. Conclusions: EO2463 (300 μg/peptide) monotherapy, EL, and ER2 are well tolerated, with encouraging clinical activity with EO2463 monotherapy and with subsequent CR in 5/9 pts on combo. Rapid and durable expansion of specific CD8+ T cells was seen in all responding pts, consistent with the preclinical hypothesis. Additional cohorts investigate EO2463 alone or in combination in newly diagnosed or R/R pts. Results will be reported at the meeting. Clinical trial information: NCT04669171 .

ASSESSMENT OF PHARMACOLOGICAL ACTIVITY OF THE FLAVONOID FRACTION OF THE HERBS SERPUHA CORONANA

Introduction. It is urgent to search for plants that can become sources of biologically active substances for the creation of new highly effective and safe medicines. One of these plants is the crowned sickle (Serratula coronata L.). The value of crowned serpuha is determined by its high content of phytoecdysteroids and flavonoids. The purpose of the work is to study the acute toxicity, anti-inflammatory activity and capillary-strengthening effect of the flavonoid fraction of the herb Serpucha crown. Material and methods. In the Department of Experimental Pharmacology of the Federal State Budgetary Institution VILAR, a study of the pharmaco-logical activity of the flavonoid fraction of the herb Serpucha crowned was carried out. Acute toxicity parameters were assessed using the Kerber method. The toxicity class of the test substance was determined according to GOST 12.1.007-76 "Harmful substances. Classification and general safe-ty requirements." The anti-inflammatory effect of the flavonoid fraction of the herb Serpucha crown was studied in models of formaldehyde edema and interstitial edema. The effectiveness of the anti-inflammatory effect of the flavonoid fraction of the herb crowned serpentine in vitro experiments was assessed by the rate of the enzymatic reaction catalyzed by inducible NO synthase. The activity of the iNOS enzyme in experiments was assessed by the rate of the reaction catalyzed by iNOS in vitro at 37 C. The study of the capillary-strengthening effect of the flavonoid fraction of the herb Serpucha crowned was carried out according to the "Method for determining the reactivity of skin capillaries to inflammatory stimuli" on a model of local in-flammatory reaction (xylene inflammation) in rats. Results. When studying the acute toxicity of the flavonoid fraction of the herb Serpucha crown, LD50 values were not established, since doses of the studied extract administered into the stomach of mice did not cause death of the animals. In accordance with the classification of toxicity of chemical substances according to GOST 12.1.007-76 "Harmful substances. Classification and general safety requirements", the flavonoid fraction of the herb crowned Serpucha is a low-hazard substance. As a result of the analysis of the data obtained, it was established that the flavonoid fraction of the herb serpukha crowned in doses of 100 and 200 mg/kg has an anti-inflammatory effect, significantly reducing formaldehyde edema in animals by 18 and 20%, respectively, compared with the control group of animals. It was established that the flavonoid fraction of the herb Serpucha crowned at a dose of 200 mg/kg has a pronounced anti-exudative effect, significantly reducing interstitial edema in animals by 22% compared to the control group of an-imals. In vitro experiments, the flavonoid fraction of the herb Serpucha crown inhibits the rate of the iNOS reaction by 1.5 times compared to the con-trol, which indicates the presence of pronounced anti-inflammatory activity of this sample. The studied fraction has a pronounced capillary-strengthening effect under the conditions of an experimental model of xylene inflammation, reducing the permeability of the vascular wall. Conclusions. The results of the studies indicate that the flavonoid fraction of the herb Serpucha crown, in terms of acute toxicity, belongs to the cat-egory of low-hazard substances and has a pronounced anti-inflammatory and capillary-strengthening effect.

Correlation of previous local vaccination site “flares” during immunotherapy for metastatic melanoma with complete responses to therapy.

e21534 Background: mRNA vaccines have been shown to stimulate T-cells targeting patient-specific tumor neoantigens. When combined with immune checkpoint inhibitors (ICI) in a randomized Phase II trial, mRNA vaccines demonstrated improvement in recurrence free survival and distant metastasis free survival compared to ICI alone. We retrospectively examined patients (pts) with advanced melanoma treated more than 5 years ago on clinical trials with adjuvant NYESO1 or mRNA vaccine therapies (VT) then ICI upon recurrence and analyzed biomarkers correlating with treatment response. Methods: This retrospective study examined 22 pts with advanced melanoma treated between 2004-2017 with adjuvant vaccine therapies (VT). 10 of the 22 pts subsequently developed recurrent disease and were treated with ICI. We evaluated disease free interval following ICI, sex, age, BRAF status, HLA type, site of primary and metastatic disease, initial vaccine treatment, vaccine toxicities, stage and sites of melanoma recurrence, ICI treatment, response and toxicities, vaccine site flares or cutaneous immune related adverse events (irAEs) following ICI. Results: Of the 22 patients (11 male, 11 female) treated with adjuvant VT, median age at first vaccine was 53 years old. HLA type was known for 11 pts. Stage at initial VT was IIB to IIIC. 14 pts recurred following adjuvant VT. Median time from vaccine initiation to melanoma recurrence was 3.2 years (range 6.5 months to 11 years). 10 pts received ICI for recurrent melanoma, 3 pts received ipilimumab, 2 anti-PD1 monotherapy, 4 ipilimumab and nivolumab, and 1 nivolumab/relatlimab. Stage at first ICI was IIIB to IV M1d. 9 pts experienced cutaneous irAEs. 7 pts experienced local vaccine site flare reactions following ICI treatment. Additionally, 2 pts experienced vitiligo, 2 with dermatologic flares (bullous pemphigoid and psoriatic rash), 2 with generalized rash that resolved with steroid cream. 1 pt did not experience rash, vaccine site flare, nor irAE dermatologic flare. Of the pts who recurred, 2 pts had BRAF V600E mutations, and 1 of these pts experienced vaccine flare, the other did not. 1 pt with a BRAF Q16L mutation did not have vaccine flare. 6 out of 7 BRAF wild type pts who recurred and received ICI experienced a localized vaccine site flare. Median disease-free interval following ICI treatment was 1.5 years (range 3 months to 9 years). All 10 pts are disease-free and off ICI being closely monitored. Conclusions: Evidence of prior localized vaccination “flare” may be a biomarker for a complete immunologic response in pts with metastatic disease treated with immunotherapy. ICI targeting CTLA-4 and/or PD-1 both triggered this localized vaccination site response, suggesting that T cell memory and immunologic activation against melanoma antigens translate into clinical responses.

Settlement at transition zones in railway tracks – is modelling the soil as a 2-D continuum important?

Abstract While most recent models of railway tracks include the nonlocal nature of the foundation reaction force, few studies have investigated the influence of its nonlocal nature on the response. Accounting for the nonlocal nature of the foundation force is computationally expensive and increases the complexity of the model, thus, knowing when and when not to account for it is important. This paper aims to shed light on the influence of the nonlocal, both in time and space, reaction force provided by the foundation on the transient response at railway transition zones. To this end, a 2-D system in which the soil layer is modelled as a visco-elastic continuum is compared to an equivalent 1-D system with a local foundation reaction force (i.e., Winkler foundation). Results show that, in general, the response of the 2-D system with shallow and/or stiff soil layers can be well captured by the equivalent 1-D model. However, for medium-to-deep and/or soft soil layers, the nonlocality of the foundation reaction force is influential and the transient response at transition zones cannot be satisfactorily captured by 1-D models. Finally, the ballast settlement is also poorly captured for medium-to-deep and/or soft soil layers, with the main cause being the inability of the 1-D model to separate between ballast and soil stresses, and not the locality of the reaction force.

A phase II, multicenter, open-label study of polyPEPI1018 in combination with atezolizumab in participants with relapsed or refractory microsatellite-stable metastatic colorectal (MSS mCRC) cancer (Oberto-301).

3594 Background: The efficacy of checkpoint inhibitor immunotherapy in MSI-H mCRC has not been replicated in MSS mCRC. Therefore, additional interventions are needed to convert immunologically “cold” MSS CRC to “hot” tumors resembling MSI-H tumors. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 shared tumor antigens which demonstrated early evidence of clinical activity in first-line MSS mCRC. Methods: Patients with MSS mCRC who have progressed on 2-3 lines of prior chemotherapy regimen received PolyPEPI1018 (1.2 mg, sc) and atezolizumab (1,200 mg, iv) Q3W until disease progression or unacceptable toxicity. The primary endpoint was safety. A Simon 2-stage design was applied. Data on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and correlation studies will be presented. Results: 18 patients (66 % female) were enrolled for stage 1 of the study. Median age was 54 years (range 38–79), 50% had liver metastases and 67% received at least 3 lines of prior therapies. PD-L1 expression was <1% for 85% of patients. The combination was well-tolerated; most common side effect related to treatment was Grade (Gr) 1-2 local skin reaction (n=22). Gr 2 events (n=2) at least possibly related to treatment were nausea, pyrexia and increased blood alkaline phosphatase. There were no Gr 3-5 events or study discontinuation due to treatment AE. The ORR was 0% and the DCR was 61%. The mPFS was 2.7 months (95%CI 1.4-4.0) and the mOS was not reached (95%CI 8.75 – NE months) at the data cut-off date. Ex-vivo FluoroSpot identified 13/16 subjects with robust, vaccine-specific CD8+ and/or CD4+ T cell responses detected against multiple vaccine antigens. For patients with available biopsy pairs (n=8), both the average PD-L1 expression (IC%, p=0.029) and the density of CD8+ tumor-infiltrating lymphocytes (TILs, p=0.019) were significantly increased, post-treatment. Patients with increased PFS (> 12 weeks) had both higher levels of post-treatment PD-L1 (p=0.007) and TILs (p=0.016) than patients with PFS ≤ 12 weeks. Conclusions: PolyPEPI1018 in combination with atezolizumab was well-tolerated with no Grade 3 AEs observed. Despite no objective tumor responses could be detected, correlative data suggest contribution of PolyPEPI1018-induced immune responses to the modulation of tumor microenvironment and to improved disease control. The study did not proceed to stage 2; it is on-going for the collection of survival data. Clinical trial information: NCT05243862 .

Mistletoe Extract in Patients With Advanced Pancreatic Cancer.

Patients with advanced pancreatic cancer have limited survival and few treatment options. We studied whether mistletoe extract (ME), in addition to comprehensive oncological treatment and palliative care, prolongs overall survival (OS) and improves health-related quality of life (HRQoL). The double-blind, placebo-controlled MISTRAL trial was conducted in Swedish oncology centers. The main inclusion criteria were advanced exocrine pancreatic cancer and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. The subjects were randomly assigned to ME (n=143) or placebo (n=147) and were stratified by study site and by eligibility (yes/no) for palliative chemotherapy (June 2016-December 2021). ME or placebo was injected subcutaneously three times a week for nine months. The primary endpoint was overall survival (OS); one of the secondary endpoints was the HRQoL dimension global health/QoL (EORTC-QLQ-C30), as assessed at seven time points over nine months. Trial registration: EudraCT 2014-004552-64, NCT02948309. No statistically significant benefit of adding ME to standard treatment was seen with respect to either OS or global health/ QoL. The adjusted hazard ratio for OS was 1.13 [0.89; 1.44], with a median survival time of 7.8 and 8.3 months for ME and placebo, respectively. The figures for the HRQoL dimension "global health/QoL" were similar in the two groups (p=0.86). The number, severity, and outcome of the reported adverse events were similar as well, except for more common local skin reactions at ME injection sites (66% vs. 1%). ME is unlikely to have a clinically significant effect on OS or the HRQoL dimension global health/QoL when administered in patients with advanced pancreatic cancer in addition to comprehensive cancer care.

M1 macrophage-derived exosomes promote intervertebral disc degeneration by enhancing nucleus pulposus cell senescence through LCN2/NF-κB signaling axis

Intervertebral disc degeneration (IVDD) is the primary factor contributing to low back pain (LBP). Unlike elderly patients, many young IVDD patients usually have a history of trauma or long-term abnormal stress, which may lead to local inflammatory reaction causing by immune cells, and ultimately accelerates degeneration. Research has shown the significance of M1-type macrophages in IVDD; nevertheless, the precise mechanism and the route by which it influences the function of nucleus pulposus cell (NPC) remain unknown. Utilizing a rat acupuncture IVDD model and an NPC degeneration model induced by lipopolysaccharide (LPS), we investigated the function of M1 macrophage-derived exosomes (M1-Exos) in IVDD both in vivo and in vitro in this study. We found that M1-Exos enhanced LPS-induced NPC senescence, increased the number of SA-β-gal-positive cells, blocked the cell cycle, and promoted the activation of P21 and P53. M1-Exos derived from supernatant pretreated with the exosome inhibitor GW4869 reversed this result in vivo and in vitro. RNA-seq showed that Lipocalin2 (LCN2) was enriched in M1-Exos and targeted the NF-κB pathway. The quantity of SA-β-gal-positive cells was significantly reduced with the inhibition of LCN2, and the expression of P21 and P53 in NPCs was decreased. The same results were obtained in the acupuncture-induced IVDD model. In addition, inhibition of LCN2 promotes the expression of type II collagen (Col-2) and inhibits the expression of matrix metalloproteinase 13 (MMP13), thereby restoring the equilibrium of metabolism inside the extracellular matrix (ECM) in vitro and in vivo. In addition, the NF-κB pathway is crucial for regulating M1-Exo-mediated NPC senescence. After the addition of M1-Exos to LPS-treated NPCs, p-p65 activity was significantly activated, while si-LCN2 treatment significantly inhibited p-p65 activity. Therefore, this paper demonstrates that M1 macrophage-derived exosomes have the ability to deliver LCN2, which activates the NF-κB signaling pathway, and exacerbates IVDD by accelerating NPC senescence. This may shed new light on the mechanism of IVDD and bring a fresh approach to IVDD therapy.Graphical

Влияние дисбиотических нарушений и локальной воспалительной реакции репродуктивного тракта на развитие преждевременных родов

Влияние дисбиотических нарушений и локальной воспалительной реакции репродуктивного тракта на развитие преждевременных родов

Efficacy and safety of stem cell transplantation for multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials

Multiple sclerosis (MS) is a common autoimmune neurological disease affecting patients’ motor, sensory, and visual performance. Stem Cell Transplantation (SCT) is a medical intervention where a patient is infused with healthy stem cells with the purpose of resetting their immune system. SCT shows remyelinating and immunomodulatory functions in MS patients, representing a potential therapeutic option. We conducted this systematic review and meta-analysis that included randomized control trials (RCTs) of SCT in MS patients to investigate its clinical efficacy and safety, excluding observational and non-English studies. After systematically searching PubMed, Web of Science, Scopus, and Cochrane Library until January 7, 2024, nine RCTs, including 422 patients, were eligible. We assessed the risk of bias (ROB) in these RCTs using Cochrane ROB Tool 1. Data were synthesized using Review Manager version 5.4 and OpenMeta Analyst software. We also conducted subgroup and sensitivity analyses. SCT significantly improved patients expanded disability status scale after 2 months (N = 39, MD = − 0.57, 95% CI [− 1.08, − 0.06], p = 0.03). SCT also reduced brain lesion volume (N = 136, MD = − 7.05, 95% CI [− 10.69, − 3.4], p = 0.0002). The effect on EDSS at 6 and 12 months, timed 25-foot walk (T25-FW), and brain lesions number was nonsignificant. Significant adverse events (AEs) included local reactions at MSCs infusion site (N = 25, RR = 2.55, 95% CI [1.08, 6.03], p = 0.034) and hematological disorders in patients received immunosuppression and autologous hematopoietic SCT (AHSCT) (N = 16, RR = 2.33, 95% CI [1.23, 4.39], p = 0.009). SCT can improve the disability of MS patients and reduce their brain lesion volume. The transplantation was generally safe and tolerated, with no mortality or significant serious AEs, except for infusion site reactions after mesenchymal SCT and hematological AEs after AHSCT. However, generalizing our results is limited by the sparse number of RCTs conducted on AHSCT. Our protocol was registered on PROSPERO with a registration number: CRD42022324141.

An Attenuated Vaccine Virus of the Neethling Lineage Protects Cattle against the Virulent Recombinant Vaccine-like Isolate of the Lumpy Skin Disease Virus Belonging to the Currently Established Cluster 2.5.

Lumpy skin disease (LSD) is an emerging transboundary and highly infectious viral disease mainly affecting cattle. The fact that it was initially confined to Africa and then spread beyond its geographical range to other regions, including the Middle East, Turkey, Europe, the Balkans, Russia and Asia, is an indication of the underestimation and neglect of this disease. Vaccination is considered the most effective way to control the spread of LSDV, when combined with other control measures. LSD is now on the rise in Southeast Asia, where the circulating virus belongs to recombinant lineage 2.5. In this study, we evaluated the efficacy of an attenuated LSDV strain belonging to the Neethling cluster 1.1 by challenge with a virulent recombinant vaccine-like LSDV isolate "Mongolia/2021" belonging to cluster 2.5. Some of the vaccinated animals showed an increase in body temperature of 1-1.5 °C above the physiological norm, without clinical signs, local reactions, vaccine-induced viremia or generalization, demonstrating the efficacy and safety of the vaccine strain against a recombinant strain. Furthermore, all the vaccinated animals showed strong immune responses, indicating a high level of immunogenicity. However, the control group challenged with "Mongolia/2021" LSD showed moderate to severe clinical signs seen in an outbreak, with high levels of virus shedding in blood samples and nasal swabs. Overall, the results of the present study demonstrate that the attenuated LSDV Neethling strain vaccine has a promising protective phenotype against the circulating strains, suggesting its potential as an effective tool for the containment and control of LSD in affected countries from Southeast Asia.

Особенности системных и местных иммунных реакций у кольских саамов и русских, проживающих на Крайнем Севере.

The features of systemic and local immune reactions in the Kola Sami and Russians living in the Far North were studied. A decrease in the total number of leukocyte cells in the Sami was established, associated with frequent registration of leukopenia, lymphopenia, and neutropenia. A deficiency in the phagocytic activity of neutrophils in the blood and secretions of the mucous membranes and an increase in the content of lymphocytes with CD4+ and CD8+ receptors were revealed. In Russian residents, leukocytosis, lymphocytosis, neutrophilia, monocytosis and eosinophilia were more often recorded with an increase in the content of natural killer cells, IL-6 and IL-10. The Sami and Russians are characterized by high levels of IgE, which have more pronounced cytotoxicity and indicate strain on the immune mechanisms. The Sami have higher levels of leukocyte migration into mucosal-associated tissue of the mucous membranes, which is associated with a decrease in the sorption capacity of epithelial cells, the phagocytic activity of neutrophils and the concentrations of secretory immunoglobulins.

Impact of a Novel Antiseptic Lavage Solution on Acute Periprosthetic Joint Infection in Hip and Knee Arthroplasty.

Background: Periprosthetic joint infection (PJI) represents a challenge following hip or knee arthroplasty, demanding immediate intervention to prevent implant failure and systemic issues. Bacterial biofilm development on orthopedic devices worsens PJI severity, resulting in recurrent hospitalizations and significant economic burdens. The objective of this retrospective cohort study is to evaluate the efficacy of this novel antiseptic solution, never previously evaluated in vivo, in managing early post-operative or acute hematogenous PJI following primary hip and knee joint replacements. Methods: The inclusion criteria consist of patients with total hip arthroplasty (THA) or knee arthroplasty diagnosed with acute PJI through preoperative and intraoperative investigations, in accordance with the MSIS ICM 2018 criteria. The minimum required follow-up was 12 months from the cessation of antibiotic therapy. This novel antiseptic lavage solution is composed of ethanol, acetic acid, sodium acetate, benzalkonium chloride and water. Data included demographic characteristics, diagnostic criteria, surgical techniques, post-operative treatment and follow-up outcomes. Results: A total of 39 patients treated with Debridement, Antibiotics Pearls and Retention of the Implant (DAPRI) procedures using this solution between May 2021 and April 2023 were analyzed. At a mean follow-up of 24.6 ± 6.4 months, infection recurrence-free survival rates were 87.2%, with no local allergic reactions or relevant systemic adverse effects detected. Persistent PJI necessitated two-stage revision surgery. Conclusions: This novel antiseptic lavage solution shows promise as an adjunctive tool in the treatment of PJI, demonstrating support in infection control while maintaining a favorable safety profile.

Review of Evolocumab for the Reduction of LDL Cholesterol and Secondary Prevention of Atherosclerotic Cardiovascular Disease.

Elevated low-density lipoprotein cholesterol (LDL-C) is a major causal factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide. Statins are the recommended first-line lipid-lowering therapy (LLT) for patients with primary hypercholesterolemia and established ASCVD, with LLT intensification recommended in the substantial proportion of patients who do not achieve levels below guideline-recommended LDL-C thresholds with statin treatment alone. The proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody evolocumab has demonstrated significant LDL-C reductions of 60% in the clinical trial and open-label extension settings, with LDL-C reductions observed early post-evolocumab initiation and maintained long term, during up to 8.4 years of follow-up. Evolocumab therapy, when added to a statin, also conferred a significant reduction in major cardiovascular (CV) events, including a 20% reduction in the composite of CV death, myocardial infarction (MI), or stroke. The absolute benefits were enhanced among various patient types at high and very high risk for secondary ASCVD (e.g., with recent MI, multiple events or peripheral artery disease). Importantly, evolocumab treatment resulted in incremental CV risk reductions during the extended follow-up, including a 23% reduction in CV mortality and no apparent LDL-C level below which there is no further CV risk reduction. Hence, the evolocumab clinical data support the need for early and significant LDL-C lowering, especially in vulnerable ASCVD patients, in order to derive the greatest benefit in the long term. Importantly, evolocumab had no impact on any treatment emergent adverse events apart from a small increase in local injection site reactions. A growing body of real-world evidence (RWE) for evolocumab in heterogeneous populations is consistent with the trial data, including robust LDL-C reductions below guideline-recommended thresholds, a favourable safety profile even at the lowest levels of LDL-C achieved, and a high treatment persistence rate of 90%. Altogether, this review highlights findings from 50 clinical trials and RWE studies in 51,000 patients treated with evolocumab, to demonstrate the potential of evolocumab to address the healthcare gap in LDL-C reduction and secondary prevention of ASCVD in a variety of high- and very high-risk patients.

Markers of enterocyte damage, microbial translocation, and systemic inflammation following 9 h of heat exposure in young and older adults.

Heat stress induced damage to the gastrointestinal barrier can induce local and systemic inflammatory reactions implicated in heat-stroke. Gastrointestinal barrier damage has been shown to be greater in older relative to young adults following hyperthermia. However, comparisons between young and older adults have been limited to brief exposures (3 h), which may not reflect the duration of heat stress experienced during heat waves. We therefore evaluated markers of intestinal epithelial damage (log transformed intestinal fatty acid binding protein, IFABPLOG), microbial translocation (soluble cluster of differentiation 14, sCD14LOG), and systemic inflammation (tumour necrosis factor alpha, TNF-αLOG; interleukin 6, IL-6LOG; C-reactive protein, CRP) in 19 young (interquartile range: 21-27years; 10 females) and 37 older (68-73years; 10 females) adults before and after 9 h of rest in 40°C (9% relative humidity). The magnitude of the increase in IFABPLOG was 0.38 log pg/mL (95% CI, 0.10, 0.65 log pg/mL) greater in the older relative to young cohort (P=0.049) after 9 h heat exposure. At baseline both IL-6LOG and CRP concentrations were higher in the older (IL-6: 2.67 (1.5) log pg/mL, CRP: 0.28 (1.5) mg/mL) relative to the young (IL-6: 1.59 log pg/mL, SD 1.2; CRP: 0.11mg/mL, SD 1.7) group (both P≤0.001). The change in IL-6 and CRP was similar between groups following 9 h heat exposure (IL-6: P=0.053; CRP: P=0.241). Neither sCD14LOG and TNF-αLOG were different between groups at baseline nor altered after 9 h heat exposure. Our data indicate that age may modify intestinal epithelial injury following 9 h of passive heat exposure.

Relative bioavailability, immunogenicity, and safety of two adalimumab-adbm formulations in healthy volunteers: a double-blind, randomized, single-dose, parallel-arm Phase I trial (VOLTAIRE-HCLF)

ABSTRACT Objective VOLTAIRE-HCLF compared the relative bioavailability of citrate-free high-concentration and reference formulations of the biosimilar adalimumab-adbm (Cyltezo®), including pharmacokinetic (PK) profiles, immunogenicity, and safety profiles in healthy volunteers. Methods Healthy volunteers (N = 200) aged 18–55 years and with body mass index of 18.5–29.9 kg/m2 and no prior exposure to adalimumab were randomized in a 1:1 ratio to receive a single subcutaneous injection of either adalimumab-adbm 40 mg/0.4 mL (high-concentration formulation) or 40 mg/0.8 mL (reference formulation). Participants completed 13 follow-up visits over 57 days, followed by a safety follow-up period of up to 70 days. Results The main PK parameters were similar for the high-concentration and reference groups. For all primary endpoints, the geometric mean ratios and 90% confidence intervals of AUC0–1344, AUC0–∞, and Cmax for both groups were entirely within the standard 80–125% bioequivalence acceptance range at 101.88% (93.31–111.23%), 105.38% (95.06–116.81%), and 91.29% (84.38–98.76%), respectively. There were no differences in the proportion of anti-drug antibody-positive participants or in the distribution of anti-drug antibody titers between the two formulations at any time point after drug dosing. Participants who were given the high-concentration formulation of adalimumab-adbm experienced a lower incidence of adverse events and local reactions than those who were given the reference formulation. Conclusions Overall, the high-concentration and reference adalimumab-adbm formulations had highly similar PK and immunogenicity profiles and were safe and well tolerated. Clinical trial registration NCT05203289

Safety and Efficacy of VIT against Wasp Venom in Ultra-Rush Protocols in Patients Older Than 60 Years.

Allergen immunotherapy remains a widely recognized and widely used method for the treatment of selected allergic diseases. Currently, according to the European Academy Of Allergy and Clinical Immunology (EAACI) guidelines, venom immunotherapy (VIT) may be considered for patients over 60. Nevertheless, no separate studies have confirmed the efficacy and safety of this therapy. This study aimed to evaluate the short-term effectiveness of VIT against wasp allergens in an ultra-rush protocol for older patients compared to young patients. Among the 113 patients included in this study, 51 were older than 60 years (Group A), and 62 formed the control "young group" (age range: 18-35 years). All patients were desensitized to wasp venom using the ultra-rush protocol according to Muller and aqueous solutions of vaccines containing wasp venom. A basophil activation test (Basotest, Orpegen Pharma, Germany) and intracutaneous tests with dilutions of wasp allergen and specific IgE to extract wasp venom were performed at the start and after six months of VIT. The safety of VIT was assessed on the basis of the international Mueller scale. One hundred and eleven patients with confirmed wasp allergies completed six months of VIT: 51 participants over 60 years of age (Group A) and 60 young people (Group B). No systemic adverse reactions were observed during the VIT induction phase. However, large local reactions were noted in 17% of older patients and 20% of young patients at a similar level (p > 0.05). During maintenance VIT, two mild grade I systemic reactions were confirmed in young patients. These symptoms resolved spontaneously. There were no such reactions in older patients. The effectiveness of VIT was tested using BAT. There was a statistically significant reduction in CD63 reactivity in 86% of patients in Group A, and a comparable and substantial decrease in 84% of young patients in Group B. According to the BAT test, the mean reductions in the area under the curve (AUC) after six months of VIT were significant (p < 0.05) and comparable between Groups A and B: -6.52 vs. 7.21. VIT against wasp venom is safe and effective in short-term observation, and is comparable to that used for young patients.

Phase II trial of vaccination with autologous, irradiated melanoma cells engineered by adenoviral mediated gene transfer to secrete granulocyte-macrophage colony stimulating factor in patients with stage III and IV melanoma.

In the era of immune checkpoint blockade, the role of cancer vaccines in immune priming has provided additional potential for therapeutic improvements. Prior studies have demonstrated delayed type hypersensitivity and anti-tumor immunity with vaccines engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). The safety, efficacy and anti-tumor immunity of GM-CSF secreting vaccine in patients with previously treated stage III or IV melanoma needs further investigation. In this phase II trial, excised lymph node metastases were processed to single cells, transduced with an adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1x106, 4x106, or 1x107 tumor cells, and were injected intradermally and subcutaneously at weekly and biweekly intervals. The primary endpoints were feasibility of producing vaccine in stage III patients and determining the proportion of patients alive at two years in stage IV patients. GM-CSF vaccine was successfully developed and administered in all 61 patients. Toxicities were restricted to grade 1-2 local skin reactions. The median OS for stage III patients (n = 20) was 71.1 (95% CI, 43.7 to NR) months and 14.9 (95%CI, 12.1 to 39.7) months for stage IV patients. The median PFS in stage III patients was 50.7 (95%CI, 36.3 to NR) months and 4.1 (95% CI, 3.0-6.3) months in stage IV patients. In the overall population, the disease control rate was 39.3% (95%CI, 27.1 to 52.7%). In stage III patients, higher pre-treatment plasma cytokine levels of MMP-1, TRAIL, CXCL-11, CXCL-13 were associated with improved PFS (p<0.05 for all). An increase in post-vaccination levels of IL-15 and TRAIL for stage III patients was associated with improved PFS (p=0.03 for both). Similarly, an increase in post-vaccination IL-16 level for stage IV patients was associated with improved PFS (p=0.02) and clinical benefit. Vaccination with autologous melanoma cells secreting GM-CSF augments antitumor immunity in stage III and IV patients with melanoma, is safe, and demonstrates disease control. Luminex data suggests that changes in inflammatory cytokines and immune cell infiltration promote tumor antigen presentation and subsequent tumor cell destruction. Additional investigation to administer this vaccine in combination with immune checkpoint inhibitors is needed.

Failure Following Revision Total Hip Arthroplasty After Cobalt-Chrome Femoral Heads are Placed on a Retained Femoral Stem

BackgroundFailure due to trunnionosis with adverse local tissue reaction (ALTR) has been reported with cobalt-chrome (CoCr) heads in total hip arthroplasty (THA); however, there are limited data on the use of these heads in the revision setting. The purpose of this study was to analyze the outcomes of patients who underwent revision THA with a retained femoral component and received a CoCr femoral head on a used trunnion. MethodsIn this retrospective review, we identified all patients who underwent revision THA with a retained femoral component and received a CoCr femoral head between February 2006 and March 2014. Demographic factors, implant details, and postoperative complications, including the need for repeat revisions, were recorded. In total, 107 patients were included (mean age 67 years, 74.0% women). Of the 107 patients, 24 (22.4%) required repeat revisions. ResultsPatients who required repeat revision were younger than those who did not (mean age: 62.9 versus 69, P = .03). The most common indications for repeat revision were instability (8 of 24, 33.3%), ALTR (5 of 24, 20.8%), and infection (4 of 18, 16.7%). Evidence of ALTR or metallosis was identified at the time of reoperation in 10 of the 24 patients who underwent re-revision (41.7%). ConclusionsThe placement of a new CoCr femoral head on a used trunnion during revision THA with a retained femoral component carries a significant risk of complication (22.4%) and should be avoided when possible.