Multicentric reticulohistiocytosis with oral and laryngeal involvement in association with autoimmune/inflammatory syndrome induced by adjuvants (ASIA): expanding the spectrum of two uncommon entities.

Multicentric reticulohistiocytosis (MRH) is the most frequent entity in the group of reticulohistiocytoses. It is usually accompanied by a symmetrical erosive polyarthritis and is frequently associated with cancer and autoimmune disorders. Autoimmune syndrome induced by adjuvants (ASIA) is an inflammatory syndrome triggered by adjuvants such as those contained in vaccines or by silicone implants. Here we report a 71-years old female with a history of breast cancer treated with surgery and subsequent prosthesis who developed a systemic hyperinflammatory syndrome including seronegative symmetric polyarthritis, multiple skin lesions and two large nodular lesions in the oral cavity and larynx. Clinical picture was consistent with a clinical diagnosis of ASIA, with breast implant rupture and/or vaccination against SARS-CoV-2 as possible triggers. Histopathology of skin, oral and laryngeal nodules revealed cutaneous/mucous and submucosal infiltration of large epithelioid mononuclear or binucleated cells with fine granular ground glass-like cytoplasm and round to kidney-shaped nuclei with prominent nucleoli, without atypical features or relevant pleomorphism, accompanied by sparse giant cells and lymphocytes. These cells stained positive for CD68 and CD45 and negative for S100, CD1a, and markers of epithelial or neural/melanocytic differentiation, altogether consistent with a diagnosis of reticulohistiocytosis. Clinic-pathological correlation allowed the final diagnosis of MRH. To our knowledge, this is the first report of a co-occurrence of MRH with ASIA and this is relevant to broaden the spectrum of those both rare diseases.

An Overview of the Types of Adjuvants Used in the Vaccination Industry And Their Mechanisms of Action.

The widespread use of efficient vaccines against infectious diseases is regarded as one of the most significant advancements in public health and techniques for preventing and protecting against infectious diseases and cancer. Because the purpose of vaccination is to elicit an appropriate, powerful, and long-lasting immune response against the pathogen, compounds such as adjuvants must be used to enhance these responses. Adjuvants have been widely used since their discovery to boost immune responses, prevent diseases, and activate protective immunity. Today, several types of adjuvants with varying properties are available for specific applications. Adjuvants are supramolecular substances or complexes that strengthen and prolong the immune response to antigens. These compounds have long-term immunological effects and are low in toxicity. They also lower the amount of antigen or the number of immunogenic reactions needed to improve vaccine efficacy and are used in specific populations. This article provides an overview of the adjuvants commonly used in the vaccination industry, their respective mechanisms of action, and discusses how they function to stimulate the immune system. Understanding the mechanisms of action of adjuvants is crucial for the development of effective and safe vaccines.

Immune thrombocytopenia (ITP) - could it be part of autoimmune/inflammatory syndrome induced by adjuvants (ASIA)?

Immune thrombocytopenia (ITP) is a complex autoimmune disorder characterized by thrombocytopenia and an increased bleeding risk, arising from autoantibody-mediated platelet destruction and impaired megakaryocyte function. The pathogenesis of ITP involves a multifaceted interplay of genetic predispositions, immune dysregulation, and environmental triggers, though the precise mechanisms remain uncertain. Several infectious agents, mostly viruses, have been implicated in both acute and chronic ITP through mechanisms such as molecular mimicry, direct bone marrow suppression, and immune dysregulation. Vaccinations, particularly those containing adjuvants like aluminum and those capable of inducing molecular mimicry, have also been associated with ITP, either as a new onset or as a relapse in preexisting cases. The role of drugs, particularly quinine, quinidine and certain antibiotics, in inducing ITP through various immunological pathways further illustrates the diverse etiologies of this condition. The multiple triggers of the disease raise the question of whether ITP may be classified as an autoimmune/inflammatory syndrome induced by adjuvants (ASIA). This condition encompasses a range of autoimmune and inflammatory symptoms triggered by adjuvants, such as silicones, polypropylene meshes, metal implants, and mineral oils present in various medical materials and medications. Similar to that observed in some cases of ITP, adjuvants can trigger autoimmune or autoinflammatory responses via molecular mimicry, epitope spreading, and polyclonal activation. This narrative review explores the underlying environmental factors related to ITP and examines ITP triggers that could potentially support an association between ITP and ASIA syndrome.

Extraction and immunomodulatory effects of acid Lagenaria siceraria (Molina) Standl. Polysaccharide on chickens.

Herbal polysaccharides are extensively studied as vaccine adjuvants due to their safety and potent immunoenhancing activity. This study aimed to analyze the structure of Lagenaria siceraria (Molina) Standl polysaccharide (LSP50) and investigate its adjuvant activity for the H9N2 vaccine in broiler chickens. Structural analysis revealed that LSP50 primarily consisted of rhamnose, arabinose, xylose, mannose, glucose, and galactose with molar ratios of 23.12: 12.28: 10.87: 8.26: 2.64: 22.82 respectively. The adjuvant activity of LSP50 was evaluated, which showing significant enhancements compared to the H9N2 group. Parameters including the immune organ index, H9N2 specific IgG level, cytokines contents (IFN-γ, IL-2, IL-4, and IL-5), and the proportion of CD3e+CD8aT+cells were significantly increased in the LSP50 group (P < 0.05). Additionally, sequencing results showed that LSP50 modulates the immune response by regulating PLA2G12B and PTGDS genes involved in the arachidonic acid pathway. These findings were further validated through qPCR analysis to affirm the reliability of the sequencing data. In conclusion, our results demonstrate that LSP50 exhibits potent adjuvant activity, enhancing both cellular and humoral immunity.

Effect of formulations and adjuvants on the properties of acetamiprid solution and droplet deposition characteristics sprayed by UAV.

While the pesticide formulations are widely used for pest control, the combined effects of these formulations with adjuvants on droplet behavior, spraying characteristics, and pest control still need to be studied. To clarify their impact on droplet behavior, spraying characteristics, and control efficacy, six formulations of acetamiprid and six adjuvants were examined. A series of laboratory and field experiments were conducted to analyze the physicochemical properties, toxicity against cotton aphids, droplet deposition characteristics, and droplet drift. The results indicated that 5% acetamiprid micro-emulsion (ME) enhanced the physicochemical features and effectiveness in pest control compared to other formulations. The nongjianfei considerably enhanced the efficiency of all acetamiprid formulations when added. The addition of selected adjuvants to pesticide formulations improved the performance of certain physicochemical properties such as viscosity and surface tension and led to higher aphid mortality rates, demonstrating enhanced pest control effectiveness during the present study. In the field experiments, the combination effect of acetamiprid formulations and adjuvants exhibited a higher droplet size, coverage, and density within the cotton canopy. However, 5% acetamiprid ME was found to be most effective followed by nongjianfei. Furthermore, 5% acetamiprid ME with adjuvant reduced the droplet drift and provided better deposition when compared with other formulations. Overall, the combination of specific formulations and adjuvants led to improved physicochemical properties, enhanced droplet deposition characteristics, reduced spray drift, and increased pesticide deposition. These findings highlighted the significance of selecting appropriate pesticide formulations and adjuvants and provided a solid foundation for efficient pesticide spraying through UAVs.

Optimizing Pain Management in Cardiac Surgery: A Review of Analgesic Adjuvants.

PURPOSE OF REVIEW: Pain management following cardiac surgery is a critical component in optimizing both short- and long-term patient outcomes, with poor pain management associated with significant acute and chronic opioid use, opioid dependence and a significant rate of opioid related adverse drug events. The significant burden of both acute and chronic pain following cardiac surgery has given rise to the need for multimodel analgesic strategies, to optimize outcomes and minimize side effects. RECENT FINDINGS: While significant research has focused recently on the additive value of peripheral nerve blocks, less emphasis has been given to the value of non-opioid based analgesics in preference to traditional opioid based anesthetic and analgesic strategies. In this review, we examine the evidence for several common analgesics, highlighting the evidence supporting efficacy following cardiac surgery, as well as the safety concerns with each agent. We demonstrate the value of a multimodal analgesic strategy to reduce pain scores and improve patient-centered outcomes, and highlight the need for further studies of combination analgesic strategies.

How do adjuvants enhance immune responses?

By altering which peptide antigens are presented to CD4+ T cells, adjuvants affect the specificity of the immune response.

Efficacy and safety of adjuvant intrathecal dexamethasone during spinal anesthesia: A systematic review and meta-analysis.

The use of intrathecal (IT) dexamethasone during subarachnoid block (SAB) has not been evaluated. There are no pooled data available to decide on the optimal regimen of IT dexamethasone during SAB, irrespective of the type of surgery. There is uncertainty about its dosage, effectiveness, and safety, and a need to establish clear guidelines on its use. Our objective was to evaluate the effectiveness and safety of use of IT dexamethasone during SAB. We performed a meta-analysis (PROSPERO, CRD42022304944) of trials that included patients who underwent a variety of surgical procedures under SAB. Patients received concomitant IT dexamethasone as an adjuvant to spinal local anesthetics. The analyzed outcomes included sensory and motor effects as well as adverse and/or beneficial side effects. Subgroup analysis was planned based on different doses used. Trial sequential analysis (TSA) was used to estimate the required sample size information (RIS) for each outcome. Eighteen studies (2531 participants) were included in this analysis. Addition of IT dexamethasone (4-8 mg) to heavy bupivacaine effectively prolonged the duration of sensory blockade (mean difference, MD = 63.8 minutes; [95% confidence interval, CI, 33.1-94.5], P < 0.0001), two-segment regression time (MD = 20.1[95% CI, 0.96-39.2], P = 0.04) and first rescue analgesic time (MD = 143.3 [95% CI, 90.3-196.0], P = 0.001). Subgroup analyses revealed superior effects of 8 mg dose over 4 mg for sensory and analgesic effects. The effect of dexamethasone on duration of motor blockade was inconclusive. Additionally, lower risk ratios (RRs) were recorded for spinal anesthesia-related hypotension (RR = 0.74 [95% CI, 0.6-0.9], P = 0.0003) and nausea/vomiting (RR = 0.62 [95% CI, 0.41-0.93], P = 0.02) in the dexamethasone group. For outcomes such as sensory blockade, analgesia, and hypotension, the required information size was reached during TSA. In conclusion, IT dexamethasone, used as an adjuvant to spinal local anesthetic, especially at the dose of 8 mg, increases sensory blockade duration and the time for request of the first rescue analgesic. SAB-induced side effects such as hypotension, nausea, and vomiting are lesser with the use of IT dexamethasone. However, further studies are necessary to draw meaningful conclusions on its safety profile.

Systemic Multifunctional Nanovaccines for Potent Personalized Immunotherapy of Acute Myeloid Leukemia.

Hematological malignancies (HM) like acute myeloid leukemia (AML) are often intractable. Cancer vaccines possibly inducing robust and broad anti-tumor immune responses may be a promising treatment option for HM. Few effective vaccines against blood cancers are, however, developed to date partly owing to insufficient stimulation of dendritic cells (DCs) in the body and lacking appropriate tumor antigens (Ags). Here it is found that systemic multifunctional nanovaccines consisting of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and Toll-like receptor 9 (TLR9) agonists - muramyl dipeptide (MDP) and CpG, and tumor cell lysate (TCL) as Ags (MCA-NV) induce potent and broad immunity against AML. MCA-NV show complementary stimulation of DCs and prime homing to lymphoid organs following systemic administration. Of note, in orthotopic AML mouse models, intravenous infusion of different vaccine formulations elicits substantially higher anti-AML efficacies than subcutaneous administration. Systemic MCA-NV cure 78% of AML mice and elicit long-term immune memory with 100% protection from rechallenging AML cells. Systemic MCA-NV can also serve as prophylactic vaccines against the same AML. These systemic nanovaccines utilizing patient TCL as Ags and dual adjuvants to elicit strong, durable, and broad immune responses can provide a personalized immunotherapeutic strategy against AML and other HM.

Bacterial Extracellular Vesicles: Potential Therapeutic Applications, Challenges, and Future Prospects.

Almost all cell types naturally secret extracellular vesicles (EVs) in the extracellular space with variable metabolic cargo facilitating intracellular communication, posing immune-modulation capacity. Thus, "bacterial extracellular vesicles" (BEVs), with their great immunoregulatory, immune response stimulation and disease condition-altering potential, have gained importance in the medical and therapeutic industry. Various subtypes of BEVs were observed and reported in the literature, such as exosomes (30-150 nm), microvesicles (100-1000 nm), apoptotic bodies (1000-5000 nm), and oncosomes (1000-10,000 nm). As biological systems are complex entities, inserting BEVs requires extra high purity. Various techniques for BEV isolation have been employed alone or with other strategies, such as ultracentrifugation, precipitation, size-exclusion chromatography, affinity-based separation, ultrafiltration, and field-flow fractionation. But to date, no BEV isolation method is considered perfect as the lack of standard protocols limits their scale-up. Medical research has focused on BEVs to explore their diverse therapeutic potential. This review particularly focused on the recent advancements in the potential medical application of BEVs, current challenges, and prospects associated with their scale-up.

Use of Adjuvant Compositions Based on Squalene Ensures Induction of Neutralizing Antibodies against SARS-CoV-2.

Squalene-based adjuvant compositions that can provide effective induction of specific humoral immune response have been developed. Recombinant receptor-binding domain (RBD) of surface S-protein of SARS-CoV-2 was used to evaluate the properties of the composition. Immunization of mice with the developed squalene-based compositions in combination with RBD allows obtaining high titers of specific antibodies: from 105 to 2×106. The blood sera from immunized mice exhibit neutralizing activity against SARS-CoV-2 Delta variant (B.1.617.2) with a titer up to 1:2000.

Components, Formulations, Deliveries, and Combinations of Tumor Vaccines.

Tumor vaccines, an important part of immunotherapy, prevent cancer or kill existing tumor cells by activating or restoring the body's own immune system. Currently, various formulations of tumor vaccines have been developed, including cell vaccines, tumor cell membrane vaccines, tumor DNA vaccines, tumor mRNA vaccines, tumor polypeptide vaccines, virus-vectored tumor vaccines, and tumor-in-situ vaccines. There are also multiple delivery systems for tumor vaccines, such as liposomes, cell membrane vesicles, viruses, exosomes, and emulsions. In addition, to decrease the risk of tumor immune escape and immune tolerance that may exist with a single tumor vaccine, combination therapy of tumor vaccines with radiotherapy, chemotherapy, immune checkpoint inhibitors, cytokines, CAR-T therapy, or photoimmunotherapy is an effective strategy. Given the critical role of tumor vaccines in immunotherapy, here, we look back to the history of tumor vaccines, and we discuss the antigens, adjuvants, formulations, delivery systems, mechanisms, combination therapy, and future directions of tumor vaccines.

Vaccine adjuvants for infectious disease in the clinic.

Adjuvants, materials added to vaccines to enhance the resulting immune response, are important components of vaccination that are many times overlooked. While vaccines always include an antigen to tell the body what to vaccinate to, of equal importance the adjuvant provides the how, a significant factor in producing a complete response. The adjuvant space has been slow to develop with the first use of an adjuvant in a licensed vaccine occurring in the 1930s, and remaining the only adjuvant in licensed vaccines for the next 80 years. However, with vaccination at the forefront of protection against new and complex pathogens, it is important to consider all components when designing an effective vaccine. Here we summarize the adjuvant space in licensed vaccines as well as the novel adjuvant space in clinical trials with a specific focus on the materials utilized and their resulting impact on the immune response. We discuss five major categories of adjuvant materials: aluminum salts, nanoparticles, viral vectors, TLR agonists, and emulsions. For each category, we delve into the current clinical trials space, the impact of these materials on vaccination, as well as some of the ways in which they could be improved. Adjuvants present an exciting opportunity to improve vaccine responses and stability, this review will help inform about the current progress of this space. Translational impact statement: In the aftermath of the COVID-19 pandemic, vaccines for infectious diseases have come into the spotlight. While antigens have always been an important focus of vaccine design, the adjuvant is a significant tool for enhancing the immune response to the vaccine that has been largely underdeveloped. This article provides a broad review of the history of adjuvants and, the current vaccine adjuvant space, and the progress seen in adjuvants in clinical trials. There is specific emphasis on the material landscape for adjuvants and their resulting mechanism of action. Looking ahead, while the novel vaccine adjuvant space features exciting new technologies and materials, there is still a need for more to meet the protective needs of new and complex pathogens.

Functional chia (Salvia hispanica L.) co-product protein hydrolysate: An analysis of biochemical, antidiabetic, antioxidant potential and physicochemical properties.

Protein hydrolysates with antioxidant potential have been reported to act as adjuvants in preventing and treating type-2 diabetes (T2D). This work investigated the biochemical, antidiabetic, antioxidant potential, and physicochemical properties of chia meal protein hydrolysate (CMPH). Bands smaller than 14 kDa were observed in the electrophoretic profile. The predominant amino acids were hydrophobic and aromatic. CMPH had the potential to inhibit α-amylase (IC50: 1.76 ± 0.13 mg/mL), α-glucosidase (IC50: 0.42 ± 0.13 mg/mL), and DPP-IV (IC50: 0.46 ± 0.14 mg/mL). Antioxidant activity for ABTS (IC50: 0.236 mg/mL), DPPH (8.83 ± 0.52%), and ORAC (IC25: 0.115 mg/mL). Against chia meal protein isolate (CMPI), CMPH has a broad solubility (pH 2-12.46). Particle size (624.5 ± 247.3 nm), low PDI (0.22 ± 0.06), ζ-potential (-31.1 ± 2.5 mV), and surface hydrophobicity (11,183.33 ± 2024.11) and the intrinsic fluorescence peak of CMPH was lower than that of CMPI. CMPH represents an alternative to add value to the agri-food co-product of the chia seed oil industry, generating food ingredients with outstanding antidiabetic and antioxidant potential.

Chimeric lipoproteins for leptospirosis vaccine: immunogenicity and protective potential.

Leptospirosis, a neglected zoonotic disease, is caused by pathogenic spirochetes belonging to the genus Leptospira and has one of the highest morbidity and mortality rates worldwide. Vaccination stands out as one of the most effective preventive measures for susceptible populations. Within the outer membrane of Leptospira spp., we find the LIC12287, LIC11711, and LIC13259 lipoproteins. These are of interest due to their surface location and potential immunogenicity. Thorough examination revealed the conservation of these proteins among pathogenic Leptospira spp.; we mapped the distribution of T- and B-cell epitopes along their sequences and assessed the 3D structures of each protein. This information aided in selecting immunodominant regions for the development of a chimeric protein. Through gene synthesis, we successfully constructed a chimeric protein, which was subsequently expressed, purified, and characterized. Hamsters were immunized with the chimeric lipoprotein, formulated with adjuvants aluminum hydroxide, EMULSIGEN®-D, Sigma Adjuvant System®, and Montanide™ ISA206VG. Another group was vaccinated with an inactivated Escherichia coli bacterin expressing the chimeric protein. Following vaccination, hamsters were challenged with a virulent L. interrogans strain. Our evaluation of the humoral immune response revealed the production of IgG antibodies, detectable 28 days after the second dose, in contrast to pre-immune samples and control groups. This demonstrates the potential of the chimeric protein to elicit a robust humoral immune response; however, no protection against challenge was achieved. While this study provides valuable insights into the subject, further research is warranted to identify protective antigens that could be utilized in the development of a leptospirosis vaccine. KEY POINTS: • Several T- and B-cell epitopes were identified in all the three proteins. • Four different adjuvants were used in vaccine formulations. • Immunization stimulated significant levels of IgG2/3 in vaccinated animals.

Transforming Aquaculture through Vaccination: A Review on Recent Developments and Milestones.

Aquaculture has rapidly emerged as one of the fastest growing industries, expanding both on global and on national fronts. With the ever-increasing demand for proteins with a high biological value, the aquaculture industry has established itself as one of the most efficient forms of animal production, proving to be a vital component of global food production by supplying nearly half of aquatic food products intended for human consumption. As in classic animal production, the prevention of diseases constitutes an enduring challenge associated with severe economic and environmental repercussions. Nevertheless, remarkable strides in the development of aquaculture vaccines have been recently witnessed, offering sustainable solutions to persistent health-related issues challenging resilient aquaculture production. These advancements are characterized by breakthroughs in increased species-specific precision, improved vaccine-delivery systems, and innovations in vaccine development, following the recent advent of nanotechnology, biotechnology, and artificial intelligence in the -omics era. The objective of this paper was to assess recent developments and milestones revolving around aquaculture vaccinology and provide an updated overview of strengths, weaknesses, opportunities, and threats of the sector, by incorporating and comparatively discussing various diffuse advances that span across a wide range of topics, including emerging vaccine technologies, innovative delivery methods, insights on novel adjuvants, and parasite vaccine development for the aquaculture sector.

Antimicrobial Strategies Proposed for the Treatment of S. pseudintermedius and Other Dermato-Pathogenic Staphylococcus spp. in Companion Animals: A Narrative Review.

The treatment of dermato-pathogenic Staphylococcus spp., particularly Staphylococcus pseudintermedius, in companion animals presents significant challenges due to rising antimicrobial resistance. This review explores innovative strategies to combat these infections. We examined novel antimicrobials and the repurposing of existing drugs to enhance their efficacy against resistant strains. Additionally, we evaluate the potential of natural products, nanomaterials, and skin antiseptics as alternative treatments. The review also investigates the use of antimicrobial peptides and bacteriophages, highlighting their targeted action against staphylococcal pathogens. Furthermore, the role of adjuvants in antibiotic treatments, such as antimicrobial resistance breakers, is discussed, emphasizing their ability to enhance therapeutic outcomes. Our analysis underscores the importance of a multifaceted approach in developing effective antimicrobial strategies for companion animals, aiming to mitigate resistance and improve clinical management of staphylococcal skin infections.

Targeting anticancer immunity in melanoma tumour microenvironment: unleashing the potential of adjuvants, drugs, and phytochemicals.

Melanoma poses a challenge in oncology because of its aggressive nature and limited treatment modalities. The tumour microenvironment (TME) in melanoma contains unique properties such as an immunosuppressive and high-density environment, unusual vasculature, and a high number of stromal and immunosuppressive cells. In recent years, numerous experiments have focused on boosting the immune system to effectively remove malignant cells. Adjuvants, consisting of phytochemicals, toll-like receptor (TLR) agonists, and cytokines, have shown encouraging results in triggering antitumor immunity and augmenting the therapeutic effectiveness of anticancer therapy. These adjuvants can stimulate the maturation of dendritic cells (DCs) and infiltration of cytotoxic CD8+ T lymphocytes (CTLs). Furthermore, nanocarriers can help to deliver immunomodulators and antigens directly to the tumour stroma, thereby improving their efficacy against malignant cells. The remodelling of melanoma TME utilising phytochemicals, agonists, and other adjuvants can be combined with current modalities for improving therapy outcomes. This review article explores the potential of adjuvants, drugs, and their nanoformulations in enhancing the anticancer potency of macrophages, CTLs, and natural killer (NK) cells. Additionally, the capacity of these agents to repress the function of immunosuppressive components of melanoma TME, such as immunosuppressive subsets of macrophages, stromal and myeloid cells will be discussed.

The analgetic effect of adjuvants in local infiltration analgesia - a systematic review with network meta-analysis of randomized trials.

BACKGROUND: Local infiltration analgesia is commonly used for postoperative pain control after several surgical procedures including intra- and peri-articular as well as wound infiltration. Even though, various adjuvants injected with the local anesthetic have been studied in pairwise comparison or compared to peripheral nerve blocks, the question which adjuvant or combination of adjuvants is the most effective in prolonging the duration of different types of local infiltration analgesia (LIA) has not been answered conclusively. OBJECTIVE: The objective of this network meta-analysis was to determine the analgesic effectiveness and safety of adjuvants in local infiltration analgesia. DESIGN: Systematic review of randomized controlled trials with network meta-analyses. DATA SOURCES: A comprehensive literature search in Embase, CENTRAL, MEDLINE and Web of Science was performed up to March 2023. RESULTS: The best interventions to prolong the duration of analgesia were dexamethasone (Ratio of Means (ROM) 3.33) followed by the combinations of clonidine + morphine (ROM 3.35) and morphine + magnesium sulfate (ROM 2.92), fentanyl (ROM 2.27), ketorolac (ROM 2.26), buprenorphine (ROM 2.04), morphine (ROM 1.93), magnesium sulfate (ROM 1.91), clonidine (ROM 1.89), dexmedetomidine (ROM 1.74) and tramadol (ROM 1.58). Serious adverse events were not reported with either investigated adjuvant. CONCLUSION: There is moderate evidence that dexamethasone is the most effective adjuvant to prolong the duration of analgesia in LIA. The evidence for the alpha-2 agonists dexmedetomidine and clonidine is also moderate, but their effectivity to prolong analgesia stays behind dexamethasone. Clonidine and dexmedetomidine had a small detectable effect on pain scores, yet below clinical relevance, but the largest effect on MEQ consumption. The effects of different opioids were homogenous for all endpoints. The prespecified subgroup analysis of LIA of the knee did not show significantly different results than the pooled analysis. STUDY REGISTRATION: PROSPERO 2020 CRD42020176154 (28.04.2020).