Anti-inflammatory Therapy Research Articles

Non-invasive vagus nerve stimulation in anti-inflammatory therapy: mechanistic insights and future perspectives

Non-invasive vagus nerve stimulation (VNS) represents a transformative approach for managing a broad spectrum of inflammatory and autoimmune conditions, including rheumatoid arthritis and inflammatory bowel disease. This comprehensive review delineates the mechanisms underlying VNS, emphasizing the cholinergic anti-inflammatory pathway, and explores interactions within the neuro-immune and vagus-gut axes based on both clinical outcomes and pre-clinical models. Clinical applications have confirmed the efficacy of VNS in managing specific autoimmune diseases, such as rheumatoid arthritis, and chronic inflammatory conditions like inflammatory bowel disease, showcasing the variability in stimulation parameters and patient responses. Concurrently, pre-clinical studies have provided insights into the potential of VNS in modulating cardiovascular and broader inflammatory responses, paving the way for its translational application in clinical settings. Innovations in non-invasive VNS technology and precision neuromodulation are enhancing its therapeutic potential, making it a viable option for patients who are unresponsive to conventional treatments. Nonetheless, the widespread adoption of this promising therapy is impeded by regulatory challenges, patient compliance issues, and the need for extensive studies on long-term efficacy and safety. Future research directions will focus on refining VNS technology, optimizing treatment parameters, and exploring synergistic effects with other therapeutic modalities, which could revolutionize the management of chronic inflammatory and autoimmune disorders.

Update on Diagnosis and Management of Kawasaki Disease: A Scientific Statement From the American Heart Association

Kawasaki disease (KD), an acute self-limited febrile illness that primarily affects children <5 years old, is the leading cause of acquired heart disease in developed countries, with the potential of leading to coronary artery dilation and coronary artery aneurysms in 25% of untreated patients. This update summarizes relevant clinical data published since the 2017 American Heart Association scientific statement on KD related to diagnosis, cardiac imaging in acute KD treatment, and long-term management. Criteria defining North American patients at high risk for developing coronary artery aneurysms who may benefit from more intensive initial treatment have been published. Advances in cardiovascular imaging have improved the ability to identify coronary artery stenosis in patients with KD, yet knowledge gaps remain regarding optimal frequency of serial imaging and the best imaging modality to identify those at risk for inducible myocardial ischemia. Recent data have advanced the understanding of safety and dosing for several anti-inflammatory therapies in KD. New anticoagulation medication, myocardial infarction management, transition of health care for patients with KD, and future directions in research are discussed.

Abstract 4115645: NLRP3 Inflammasome Inhibition With Dapansutrile in Type 2 Diabetes and Elevated Systemic Inflammation: Rationale and Design of the DAPAN-DIA study

Background: Monoclonal antibodies against IL-1β decrease inflammation, improve insulin secretion and glycaemia, and reduce residual CV risk, but must be injected and are associated with higher incidence of fatal infection. There remains an unmet need for an oral treatment for T2D patients at risk for cardiometabolic complications to safely reduce IL-1β-mediated inflammation chronically&with low risk of immunosuppression. In an initial dose-range finding study in heart failure patients with T2D, we reported evidence of anti-hyperglycaemic efficacy and improvement in LVEF with dapansutrile an oral specific inhibitor of the NLRP3 inflammasome. Objectives: To investigate the potential of preventing the transition to organ complications, The EU funded consortium INTERCEPT-T2D in collaboration with US based biotech Olatec Therapeutics has launched a clinical trial of anti-inflammatory therapy with dapansutrile targeting T2D patients with low-grade inflammation. Methods: Dapansutrile in Diabetes and Complications (DAPAN-DIA, NCT06047262) aims to determine whether NLRP3 inhibition with dapansutrile has the potential to not only improve glycaemia but also reduce micro- and macro-vascular risk and complications from diabetes. DAPAN-DIA is a multicenter, pbo-controlled, prospective, randomized, double-blind trial conducted in Switzerland, France, Belgium and Germany. A total of 300 patients with T2D, HbA1c >7.5% and hsCRP>1.5 mg/L are being randomized to either dapansutrile 1000 mg BID or matching PBO tablets for 6 months (2:1 ratio dapansutrile: pbo). The primary endpoint is change from baseline HbA1c. Secondary endpoints include biomarkers associated with diabetic complications, progression of MASLD as well as chronic inflammation (IL-1 β, IL-6 and hsCRP). A subject-assessed QoL questionnaire is also collected. To detect an absolute difference of 0.5% in HbA1c between groups, approximately 300 subjects will be randomized 2:1 ratio to achieve 80% power, assuming a standard deviation of 1.2% in change from baseline in HbA1c at week 26. Results: The trial has launched and currently is enrolling subjects. Conclusions: DAPAN-DIA is the first placebo-controlled, adequately powered, large, multi-center study with an oral NLRP3-specific Inhibitor, dapansutrile. The trial will generate important data on a new clinically relevant dimension in T2D care where consideration at diagnosis of inflammatory parameters are of importance for the transition to T2D-related complications.

Abstract 4124313: An unusual case of pericardial mass

A 30-year-old male electrician presented with two days of fever and positional left shoulder pain and was found to have elevated inflammatory markers and a large pericardial effusion with echocardiographic evidence of tamponade for which he underwent pericardiocentesis. He was discharged on a course of anti-inflammatory therapy with presumed diagnosis of idiopathic pericarditis based on negative cytology. He returned 6 months later with several weeks of upper respiratory infection symptoms as well as new abdominal discomfort and emesis. On presentation, his vital signs were notable for tachycardia to 113 and cardiac exam was notable for tachycardia, regular rhythm, no rubs or murmurs, nondisplaced precordial impulse, normal jugular venous pressure with Kussmaul sign, and pulsus paradoxus of 6. An electrocardiogram showed sinus tachycardia with diffuse ST segment changes (Figure A). His cardiac biomarkers were unremarkable (troponin 21). His labs revealed normocytic anemia with hemoglobin of 11 and erythrocyte sediment rate above assay. Echocardiogram demonstrated a circumferential complex pericardial effusion with echocardiographic evidence of early tamponade (Figure B, C). A pericardiocentesis was attempted with inability to advance wire within pericardial space. A malignancy workup was initiated. CT demonstrated multi-station thoracic and lower cervical lymphadenopathy, moderate left pleural effusion, and an intrapericardial mass with associated pericardial effusion (Figure D). Cardiac magnetic resonance imaging demonstrated a circumferential intrapericardial non-mobile mass measuring up to 22 mm in thickness posteriorly and the mass was isointense to myocardium indicating low-fat content (Figure E). A supraclavicular lymph node biopsy was obtained with immunohistochemical staining positive for WT1 and calretinin, consistent with metastatic epithelioid mesothelioma of pericardial versus pleural etiology (Figure F). A PET-CT subsequently showed a FDG-avid circumferential anterior pericardial mass and multiple pleural-based lesions concerning for metastatic mesothelioma. He was initiated on pemetrexed/carboplatin systemic chemotherapy. With systemic therapy, his disease has been stable for 6 months. Pericardial mesothelioma is a rare malignancy. This case underscores the diagnostic challenges associated with pericardial mesothelioma and the importance of cancer workup as part of the pericardial effusion workup.

Management of patients with Crohn's disease – from history to modern approaches

Since the isolation of Crohn's disease as a separate pathology, significant progress has been made both in the diagnosis of the disease and in approaches to the treatment of patients with this pathology. The active introduction of biologics and the top-down approach into clinical practice in patients with negative prognosis factors has led to a significant improvement in treatment results and prognosis in patients. The use of the most effective anti-inflammatory therapy during the «therapeutic window of opportunity» – up to 18 months – is the key to achieving remission, or minimal activity of Crohn's disease by suppressing inflammation and preventing irreversible structural damage to the intestinal wall and, as a result, the development of complications. The article presents an excursion into the history of the discovery of this disease, which is still far from its completion. The approaches to the treatment of patients with this pathology are highlighted with an explanation of the current position based on data from meta-analyses and systematic reviews. A demonstration of a patient with a penetrating phenotype of Crohn's disease in the form of a perianal lesion and a history of oncopathology is presented. Ustekinumab therapy can be considered as an optimal management strategy for patients with Crohn's disease with unfavorable prognosis factors.

Precision medicine in intestinal ischemia: the emerging role of biomarkers.

Intestinal ischemia (IIs) is a significant gastrointestinal condition characterized by reduced blood flow to the bowel, leading to inflammation and injury. Early diagnosis and management are crucial for preventing severe complications. Under this point of view, circulating biomarkers can enhance patient stratification and guide therapeutic decisions. Fatty acid-binding proteins (FABPs), specifically I-FABP and L-FABP, are small cytosolic proteins released upon enterocyte membrane integrity loss, with elevated plasma levels indicating early intestinal ischemia. Stromal Cell-Derived Factor-1 (SDF-1) regulates stem cell function and shows significantly higher levels in patients with IIs and cardiovascular disease compared to controls. D-Lactate, a bacterial fermentation byproduct, is another significant marker, with higher serum levels observed in intestinal ischemia cases. Alpha-glutathione S-transferase combats intracellular oxidative stress, with significantly elevated levels in acute mesenteric ischemia patients. Additionally, SM22, a small smooth muscle protein, shows higher plasma levels in patients with transmural ischemia compared to those with mucosal ischemic lesions and healthy controls. These biomarkers are promising for their roles in early detection and differentiation of IIs from other gastrointestinal conditions. Therapeutic strategies, including anti-inflammatory therapies, have shown efficacy in managing IIs symptoms and preventing recurrence. This review aims to inform clinicians and researchers about the current advancements in biomarker research and therapeutic approaches for IIs, emphasizing the importance of integrating these biomarkers and treatments into clinical practice to improve the management and prognosis of the disease.

A study of the comparative effectiveness of dual antiplatelet therapy and a combination of acetylsalicylic acid with colchicine in patients in the acute period of “minor” ischemic atherothrombotic stroke during hospitalization. Interim analysis of data from the «COLCHIDA» study

Influence on inflammation is currently becoming a priority target for the prevention of recurrent atherothrombotic events, including stroke. In 2022, we planned the KOLCHIDA study, a two-center, prospective, randomized, open-label, controlled clinical trial with endpoint assessment (ClinicalTrials.gov identifier: NCT06102720). The purpose of this study is to conduct a comparative assessment of the clinical effectiveness of dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel and the combination of ASA with colchicine in patients in the acute period of “minor” ischemic atherothrombotic stroke. The purpose of this publication is to present the basic concept of the protocol, its design and the first intermediate results. Material and methods. The intervention consisted of colchicine 0.5 mg/day in addition to ASA versus dual antiplatelet therapy (DAPT) in patients with non-severe ischemic stroke. 31 patients were included in the colchicine and ASA group, and 34 patients were included in the DAPT group. Results. In the comparison group, 7 (20.6%) recurrent non-fatal strokes were recorded, in contrast to the colchicine group, where acute vascular events were recorded in only two patients (6.5%) [RRR 2.2, NNT = 7, χ2 = 2, 9, p = 0.09]. There were no clinically significant bleeding or other adverse events in both groups. Conclusion. Interim results of the study indicate possible confirmation of the hypothesis that anti-inflammatory therapy with low doses of colchicine in combination with standard therapy is not inferior to the combination of ASA and clopidogrel, and perhaps more effectively reduces the number of early neurological deteriorations and recurrent ischemic strokes in patients in the acute period of mild atherothrombotic stroke with equal security profile.

Acute pancreatitis following asparaginase treatment in pediatric acute lymphoblastic leukemia with a heterozygous SPINK1 c.194 + 2T>C intronic variant: a case report

BackgroundAsparaginase is a critical component of chemotherapy for pediatric acute lymphoblastic leukemia (ALL), but its use is often complicated by asparaginase-associated pancreatitis (AAP). Genetic predispositions, such as variants in the SPINK1 gene, have been linked to an increased risk of pancreatitis. However, the role of genetic factors in relation to asparaginase treatment remains incompletely understood, partly because mutations in pancreatitis-causing genes are rarely found in pediatric ALL.Case descriptionA four-year and three-month-old Chinese girl was admitted to our hospital due to fever for half a day, with no history of significant prior medical history. Initial blood tests revealed hematological abnormalities, including leukopenia, anemia, and thrombocytosis. Bone marrow aspiration identified 81.5% blast cells with B-lymphocyte morphology and immunophenotype, leading to a diagnosis of B-cell acute lymphoblastic leukemia (B-ALL). The patient began treatment under the CCCG-ALL-2015 protocol, which included PEG-asparaginase (PEG-asp). On day 10 of induction, she developed AAP, which was primarily characterized by severe epigastric pain and elevated serum amylase. Despite effective symptom management with analgesics and anti-inflammatory therapy, AAP recurred following administration of L-asparaginase (L-asp). Genetic analysis revealed a heterozygous SPINK1 c.194 + 2T>C variant (rs148954387), a well-known pathogenic variant associated with increased susceptibility to pancreatitis. Sanger sequencing confirmed that the SPINK1 variant was inherited from her asymptomatic mother. The patient's AAP was managed conservatively, and an asparaginase-free regimen ultimately achieved complete remission without recurrence of pancreatitis.ConclusionsThe identification of the SPINK1 c.194 + 2T>C variant, which is recognized as pathogenic, provides valuable information for understanding the heightened risk of AAP in our pediatric ALL patient. Our case underscores the potential role of genetic predisposition in the development of AAP and highlights the importance of considering genetic screening prior to asparaginase therapy in pediatric ALL patients to identify those at increased risk.

Selective PPARδ Agonist GW501516 Protects Against LPS-Induced Macrophage Inflammation and Acute Liver Failure in Mice via Suppressing Inflammatory Mediators

Inflammation is critical in the development of acute liver failure (ALF). Peroxisome proliferator-activated receptor delta (PPARδ) regulates anti-inflammatory responses and is protective in several diseases such as obesity and cancer. However, the beneficial effects and underlying mechanisms of PPARδ agonist GW501516 in ALF remain unclear. This study investigated the molecular mechanisms underlying the anti-inflammatory effects of GW501516 in macrophages and assessed its protective potential against lipopolysaccharide (LPS)/galactosamine (GalN)-induced ALF. In vivo administration of GW501516 significantly reduced LPS/GalN-induced hepatotoxicity, as evidenced by lower mortality, decreased liver damage, and attenuated secretion of IL-1β, IL-6, and TNF-α. GW501516 treatment also decreased LPS-induced nitric oxide synthase 2 (NOS2) expression and nitric oxide (NO) production in RAW264.7 cells, an effect reversed by PPARδ siRNA. Additionally, GW501516 inhibited LPS-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), suggesting that inactivation of these MAPKs contributes to its effects. The secretion of IL-6, TNF-α, and NF-κB DNA-binding activity were also suppressed by GW501516, while the nuclear translocation of the NF-κB p65 subunit was unaffected. In conclusion, our findings suggest that GW501516 exerts protective effects in ALF by inhibiting the production of inflammatory mediators. Therefore, GW501516 may act as a potential agent for developing anti-inflammatory therapies for ALF.

Five principles and protocols for the clinician based on the 2021 ERS and BTS statements for treating sarcoidosis.

The European Respiratory Society (ERS) and the British Thoracic Society (BTS) have recently published their statements on the treatment of sarcoidosis. There are five key questions in sarcoidosis treatment that need to be addressed: when to treat, how to initiate treatment, how long to treat, when and how to change treatment, and how to treat relapses. Herein, we describe the principles and protocols to answer these questions based on the ERS and BTS statements and other expert reviews. Pulmonary or extrapulmonary sarcoidosis should be treated with anti-inflammatory therapy if it significantly impairs the quality of life (QoL), causes significant organ dysfunction, or threatens to cause organ damage, disability, or death. If treatment is initiated for improving the QoL alone, low-dose (10 mg/day) prednisone is a good initial treatment that can be tapered and stopped over 3 months. Disease that causes significant organ dysfunction needs to be treated with medium-dose glucocorticoids (initial daily dose, 20 mg of prednisone equivalent) tapered over a minimum duration of 6 months. Worsening of disease while tapering treatment indicates that longer (9-24 months) treatment may be necessary. If a daily prednisone dose of >10 mg is required for >6 months to maintain remission, it is best to use a second-line drug such as methotrexate or azathioprine. Anti-tumor necrosis factor agents, such as infliximab or adalimumab, may be used to treat inflammatory disease that persists on combination treatment with glucocorticoids and a second-line agent.

The Impact of Anti-inflammatory Therapy on Parkinson's Disease Incidence: A Retrospective Cohort Study

BackgroundPrevious research suggests shared pathophysiology between Parkinson's Disease (PD) and autoimmune disorders, with inflammation reduction as a potential PD intervention. The impact of anti-tumor necrosis factor (anti-TNF) and anti-interleukin (IL)-17 drugs on PD development has yielded conflicting results. ObjectivesThe study investigated the association between PD incidence and immunosuppressive anti-inflammatory drugs in patients with autoimmune diseases (rheumatoid arthritis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, psoriasis/psoriatic arthritis). MethodsA retrospective study was conducted using data from 2014-2022 from the US Komodo Health claims database. Two cohorts of patients diagnosed with autoimmune diseases were designed: 1) exposed to biologic disease-modifying antirheumatic drugs (bDMARDS e.g., anti-TNF/anti-IL-17 drugs) and 2) absent such exposure. Person-time incidence rates of PD per 100 person-years (PY) and incidence rate ratios (IRRs) were calculated and covariate adjusted via Poisson regressions. ResultsAmong 2,105,677 identified patients with autoimmune disease, 114,082 were treated with anti-TNF/anti-IL-17 and 1,991,595 were not. Unadjusted analyses indicated lower PD incidence in those treated with bDMARDscompared to the not treated (0.661 vs 0.949 per 100-PY; IRR 0.696 [95% CI: 0.669-0.724]). Multivariate Poisson models comparing cohorts exposed to bDMARDs vs those lacking exposure resulted in significantly lower risk of PD (adjusted IRR 0.77 [95% CI 0.74-0.80], p-value <.0001). For patients exposed to anti-TNF or anti-IL-17 therapies, the IRRs were 0.77 (95% CI 0.74-0.81) and 0.64 (95% CI 0.52-0.80), respectively (p-values<0.001). ConclusionsThe results suggest that reduced systemic inflammation via anti-TNF or anti-IL-17 treatment may decrease PD risk in patients with autoimmune diseases.

Design, Synthesis, and Anti-Inflammatory Activity Evaluation of Novel Indanone Derivatives for the Treatment of Vascular Dementia.

Vascular dementia (VaD) is a neurodegenerative disease resulting from cerebral vascular obstruction, leading to cognitive impairment, and currently lacks effective treatment options.Due to its complex pathogenesis, multi-target drug design (MTDLs) strategies are considered among the most promising therapeutic approaches. In this study, we designed and synthesized a series of novel indanone derivatives targeting targets related to vascular health and dementia. The results indicated that compound C5exhibited excellent acetylcholinesterase inhibitory activity (IC50= 1.16 ± 0.41 μM) and anti-platelet aggregation activity (IC50= 4.92 ± 0.10 μM) within ranges of 0.1-1000 μM and 0.03-300 μM, respectively, possibly mediated by molecular docking interactions. Furthermore, compound C5demonstrated protective effects on cells at concentrations ≤50 μM, significantly reducing the release of nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) in a concentration-dependent manner, showcasing its potent neuroinflammatory inhibitory effects. Anti-inflammatory therapies are regarded as effective strategies for treating VaD. Therefore, compound C5holds promise as a novel candidate drug for further investigation into the treatment of vascular dementia.

Interleukin-6, C-Reactive Protein, and Recurrence After Stroke: A Time-Course Analysis of Individual-Participant Data.

Inflammation promotes atherogenesis. Randomized controlled trials of anti-inflammatory therapies for prevention after stroke have not yet demonstrated clear benefit. IL-6 (interleukin-6) and hsCRP (high-sensitivity C-reactive protein) are independently associated with major adverse cardiovascular events poststroke and may guide patient selection in future randomized controlled trials. Optimal timing of hsCRP/IL-6 measurement poststroke is unknown, as early blood levels may be confounded by the inflammatory response to brain infarction. Using individual-participant data from a systematic review, we performed a time-course analysis to investigate the association between hsCRP/IL-6 and recurrent events stratified by timing of sampling. The prespecified coprimary end points after sample measurement were: (1) recurrent major adverse cardiovascular events (first major coronary event, recurrent stroke, or vascular death) and (2) recurrent stroke (ischemic, hemorrhagic, or unspecified). The poststroke dynamics of IL-6/hsCRP were analyzed by plotting their median (interquartile interval) concentrations within each tenth of the sampling timeframe. Acute/postacute phases were defined for each biomarker according to the shape of this relationship. There were data for 9798 patients from 11 studies (19 891 person-years follow-up, 10 observational cohorts, and 1 randomized trial). Each marker was measured once. IL-6 was markedly elevated <24 hours poststroke compared with postacute levels (≥24 hours; 11.6 versus 3.02 pg/mL; P<0.001). HsCRP was elevated for 10 days. IL-6 was associated with recurrent major adverse cardiovascular events in the postacute phase (≥24 hours; risk ratio, 1.30 [CI, 1.19-1.41], per unit logeIL-6), but not in the acute phase (<24 hours; risk ratio, 1.10 [CI, 0.98-1.25]; Pinteraction=0.03). After adjustment for risk factors/medication, the association remained for postacute IL-6 when analyzed per logeunit (risk ratio, 1.16 [CI, 1.05-1.66]) and per quarter increase (risk ratio, 1.55 [CI, 1.19-2.02]; Q4 versus Q1), but not if measured acutely. Similar findings were observed for recurrent stroke. There was no evidence of time-dependent interaction with hsCRP. Timing of sample measurement after stroke modifies the association with recurrent major adverse cardiovascular events for IL-6 but not hsCRP. These data inform future randomized controlled trial designs incorporating biomarker-based selection of patients for anti-inflammatory therapies.

Optic Neuritis and its Prevalence in Immunocompromised Patients: A Review Article

Optic neuritis is an inflammation that affects the optic nerve, causing vision loss, eye pain, and changes in color perception. The condition can be associated with autoimmune diseases such as multiple sclerosis (MS) or infections, especially in immunocompromised individuals such as HIV/AIDS patients or those undergoing chemotherapy. In these individuals, optic neuritis usually results from opportunistic infections like toxoplasmosis and syphilis, complicating diagnosis and treatment. In immunocompetent patients, optic neuritis may indicate autoimmune diseases like MS or neuromyelitis optica (NMO), with better prognoses when treated early with corticosteroids. However, in immunocompromised individuals, the prognosis tends to be worse due to underlying infections and a limited response to immunosuppressive treatment. The management of optic neuritis involves anti-inflammatory therapies and, in cases of infections, specific antimicrobials. Continuous clinical and visual follow-up is also crucial. Studies suggest that clinical outcomes vary depending on the etiology and the patient's immune status, highlighting the need for personalized therapeutic strategies. Early diagnosis is critical to improving vision and quality of life for patients.

Oxygen-Bonded Amorphous Transition Metal Dichalcogenides with pH-Responsive Reactive Oxygen Biocatalysis for Combined Antibacterial and Anti-inflammatory Therapies in Diabetic Wound Healing.

Diabetic wound healing is a formidable challenge, often complicated by biofilms, immune dysregulation, and hindered vascularization within the wound environments. The intricate interplay of these microenvironmental factors has been a significant oversight in the evolution of therapeutic strategies. Herein, the design of an efficient and versatile oxygen-bonded amorphous transition metal dichalcogenide biocatalyst (aRuS-Or) with pH-responsive reactive oxygen biocatalysis for combined antibacterial and anti-inflammatory therapies in promoting diabetic wound healing is reported. Leveraging the incorporation of Ru─O bonds, aRuS-Or exhibits optimized adsorption/desorption behavior of oxygen intermediates, thereby enhancing both the reactive oxygen species (ROS) generation activity in acidic conditions and ROS scavenging performance in neutral environments. Remarkably, aRuS-Or demonstrates exceptional bactericidal potency within infected milieus through biocatalytic ROS generation. Beyond its antimicrobial capability, post-eradication, aRuS-Or serves a dual role in mitigating oxidative stress in inflammatory wounds, providing robust cellular protection and fostering an M2-phenotype polarization of macrophages, which is pivotal for accelerating the wound repair process. The findings underscore the multifaceted efficacy of aRuS-Or, which harmoniously integrates high antibacterial action with anti-inflammatory and pro-angiogenic properties. This triad of functionalities positions aRuS-Or as a promising candidate for the comprehensive management of complex diabetic ulcers, addressing the unmet needs in the current therapeutics.

A novel risk-stratification model that predicts long-term clinical outcomes in patients with recurrent pericarditis

Abstract Background Recurrent Pericarditis (RP) is condition associated with significant debility and morbidity. Previous studies have identified variables such as elevated C-Reactive protein, corticosteroid usage, and presence of delayed hyper-enhancement (DHE) on cardiac magnetic resonance imaging are associated with recurrence. To date however, there is no established model for risk stratifying outcomes in these patients, therefore we attempted to develop a model that could predict long-term outcomes in patients with RP and stratify them into groups based on risk. Methods A total of 365 consecutive patients with RP from 2012-2019 were retrospectively examined. Our primary outcome was clinical remission (CR) defined as symptom resolution in addition to complete cessation of all anti-inflammatory therapy. We employed 5 survival models: CoxPH, RSF, SSVM, GBSA and XGBoost with Cox loss function to determine the likelihood of achieving CR within 5 years and to stratify patients into specific risk groups. We divided the dataset into training (70%) and test (30%) sets. Model training and optimization of the training set occurred via 5-fold cross validation. Model evaluation and selection was based on C-index. Finally, we employed an explainable artificial intelligence approach, SHapley Additive exPlanations to generate both individual and global explanation of the models decision. Results Amongst the cohort, the mean age was 46 ± 15 years, 205 (56%) were female, and the main etiology was idiopathic in 223 (61%). CR was achieved in 118 (32%) patients. The final model included steroid dependency, total number of recurrences, pericardial DHE, age, etiology, gender, ejection fraction and heart rate as its most important parameters. We observed similar CR rates across three risk score ranges and accordingly stratified patients into low (n=62), intermediate (n=154), and high-risk (n=149) groups. Scores of 3 or lower were categorized as low risk, with CR rates exceeding 90%. Scores of 4 to 7 were associated with CR rates of 50%. Scores of 8 or higher were deemed high-risk, with CR rates notably below 10%. Overall, the model predicted the outcome with C-index of 0.800 on the test set and exhibited a significant ability in stratification of patients into low-, intermediate-, and high-risk groups (log-rank test; P &amp;lt;0.0001). Conclusion We created a novel risk prediction model that can aid in predicting rates clinical remission in patients with recurrent pericarditis as well as aid in stratification into low, medium, and high risk groups. This risk prediction model may be helpful in diagnosis and management of these complicated patients.Figure 1

Therapeutic potential of d-limonene in rheumatoid arthritis: Modulation of inflammatory, anti-inflammatory cytokines, and prostaglandin E2.

Rheumatoid arthritis (RA) is a persistent autoimmune disorder predominantly affecting the joint structures, eliciting inflammatory responses, and ultimately leading to degenerative changes without proper medical intervention. Ultimately, this can severely impair joint function and impact the patient's quality of life. Current treatment approaches include disease-modifying anti-rheumatic drugs, non-steroidal anti-inflammatory drug, corticosteroids, and biologic therapies for RA management. The current study contributes to the ongoing advancements in RA treatment. d-Limonene is a monocyclic monoterpene. It is present in essential oils of various aromatic plants, such as Lippia alba and Artemisia dracunculus, and in citrus fruits such as lemon and orange. It has reported anti-inflammatory and anti-nociceptive properties and was selected for the current study as a potential anti-arthritic candidate. It was administered at three dosages (25, 50, 100 mg/kg, b.w., p.o) in Complete Freund's adjuvant-induced arthritic rats over 28 days. The efficacy of the compound was compared to piroxicam, a widely used standard drug for treating RA. The anti-arthritic activity of the compound was assessed by measuring arthritic scoring and plethysmometry at both baseline and post-intervention stages. Additional confirmation of the investigation was sought by performing biochemical and hematological activities. Moreover, quantitative polymerase chain reaction was employed to determine the levels of messenger RNA expression for transcription factors such as tumor necrosis factor-α, interleukin (IL)-1β, nuclear factor-κB, matrix metalloproteinase-3, IL-6, and IL-4 in the blood. The levels of PGE2 were evaluated by enzyme-linked immunosorbent assay. The histopathological and radiographic studies were also carried out for further confirmation. The results of these findings supported our assertion regarding the anti-arthritic potential of the compound.

Ovarian carcinosarcoma with lung metastasis characterized by persistent fever: A case report and literature review.

Ovarian carcinosarcoma (OCS) is a rare malignant tumor prone to distant metastasis. Primary manifestations include pelvic and/or abdominal pain, bloating, and compression. Nevertheless, it is uncommon for OCS to present primarily with persistent fever. This is the first reported case of OCS with lung metastasis characterized by persistent fever. A 61-year-old female patient complaining of abdominal pain and fever was admitted to our hospital. Computed tomography showed an irregular, slightly low-density mass on the left side of the uterus and multiple solid nodules in both lungs. She underwent cytoreductive surgery for pathologically confirmed stage IVB OCS. She was administered chemotherapy after cytoreductive surgery. Given the patient's history of persistent fever and progressively enlarged pulmonary nodules, a pulmonary abscess was considered as a possible diagnosis. Following antibiotic therapy, the patient's high body temperature did not decrease; however, following nonsteroidal anti-inflammatory drug therapy, it quickly decreased. These symptoms were eventually considered the consequence of neoplastic fever caused by lung metastases. Owing to the rapid progression of the disease, the patient ultimately died. This study suggests that, for patients with pelvic and/or abdominal pain, bloating, and pelvic masses, especially those with suspicious lesions in other organs accompanied by fever of unknown origin, a diagnosis of cancer or sarcoma with metastasis should be considered after ruling out infectious fever.

A derivative of tanshinone IIA and salviadione, 15a, inhibits inflammation and alleviates DSS-induced colitis in mice by direct binding and inhibition of RIPK2.

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions primarily affecting the gastrointestinal tract. Previous studies established the role of the NF-κB signaling pathway in the development of IBDs, suggesting that anti-inflammatory therapies might offer a viable treatment strategy. Tanshinone IIA and salviadione, both derived from Salviae Miltiorrhizae Radix et Rhizoma, possess anti-inflammatory and anti-oxidative activities. A series of new compounds were synthesized by hybridizing salviadione with tanshinone. Among these compounds, 15a showed beneficial effects in LPS-induced acute lung injury and diabetes-induced renal injury mouse models. The current study explored the therapeutic efficacy of 15a using both acute and chronic colitis models and elucidated the underlying mechanisms. DSS-induced colitis models were established in mice, where acute colitis was treated with compound 15a (5 or 10 mg·kg-1·d-1) for 8 days, while chronic colitis mice received compound 15a (5 or 10 mg·kg-1·d-1, i.g.) during 2.5% DSS administration. The 15a treatment significantly alleviated DSS-induced pathological and inflammatory damages in both acute and chronic colitis mouse models. In mouse intestinal epithelial cell line MODE-K, pretreatment with compound 15a (5 or 10 μM) significantly suppressed LPS + L18-MDP-induced inflammatory responses. The receptor-interacting serine/threonine kinase 2 (RIPK2) was identified as a direct binding target of compound 15a using microarrays and recombinant human proteins. Moreover, 15a could directly bind to and inhibit the phosphorylation of RIPK2, leading to the suppression of the NF-κB and MAPK signaling pathways. Furthermore, LEU153 and VAL32 were identified within the KD domain of RIPK2 as critical amino residues for the binding of 15a. Briefly, the current findings demonstrate that compound 15a holds promise as a therapeutic agent for managing acute and chronic colitis.

Treatment of OSA beyond adenotonsillectomy.

Pediatric obstructive sleep apnea (OSA) is a common syndrome in children. While an adenotonsillectomy is effective for most, it may not be the treatment of choice for all, and possible alternative treatment options are briefly discussed herein. In obese children, in whom OSA is more prevalent, and has high rates of persistence after surgery, weight loss interventions may be recommended. Anti-inflammatory therapies, such as nasal steroids and montelukast, reduce the size of the adenoids and tonsils and are considered part of the stepwise treatment approach. Functional orthodontic therapies may improve OSA as well as orthopedic interventions in children in whom orthodontic indications exist. Positive airway pressure and high flow nasal cannula, stent the airway open and alleviate the obstruction, but adherence may be challenging. Tongue surgery, as well as several additional interventions are further discussed. In conclusion, multiple therapeutic options are available for pediatric OSA. Further studies are required to better identify the children most likely to benefit from these therapies.