Adjunctive Agents Research Articles

Isoegomaketone exhibits potential as a new Mycobacterium abscessus inhibitor.

Although the incidence of Mycobacterium abscessus infection has recently increased significantly, treatment is difficult because this bacterium is resistant to most anti-tuberculosis drugs. In particular, M. abscessus is often resistant to available macrolide antibiotics, so therapeutic options are extremely limited. Hence, there is a pressing demand to create effective drugs or therapeutic regimens for M. abscessus infections. The aim of the investigation was to assess the capability of isoegomaketone (iEMK) as a therapeutic option for treating M. abscessus infections. We determined the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of iEMK for both reference and clinically isolated M. abscessus strains. In addition to time-kill and biofilm formation assays, we evaluated iEMK's capability to inhibit M. abscessus growth in macrophages using an intracellular colony counting assay. iEMK inhibited the growth of reference and clinically isolated M. abscessus strains in macrophages and demonstrated effectiveness at lower concentrations against macrophage-infected M. abscessus than when used to treat the bacteria directly. Importantly, iEMK also exhibited anti-biofilm properties and the potential to mitigate macrolide-inducible resistance, underscoring its promise as a standalone or adjunctive therapeutic agent. Overall, our results suggest that further development of iEMK as a clinical drug candidate is promising for inhibiting M. abscessus growth, especially considering its dual action against both planktonic bacteria and biofilms.

Investigating the synergy of Shikonin and Valproic acid in inducing apoptosis of osteosarcoma cells via ROS-mediated EGR1 expression

BackgroundOsteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has been extensively studied for its notable anti-tumour effects, including for osteosarcoma. However, its application has certain limitations. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI) that has recently been employed as an adjunctive therapeutic agent that allows chromatin to assume a more relaxed state, thereby enhancing anti-tumour efficacy. PurposeThis study was aimed to investigate the synergistic anti-tumour efficacy of SHK in combination with VPA and elucidate its underlying mechanism. Methods/Study designCCK-8 assays were utilized to calculate the combination index. Additional assays, including colony formation, acridine orange/ethidium bromide double fluorescent staining, and flow cytometry, were employed to evaluate the effects on osteosarcoma cells. Wound healing and transwell assays were utilized to assess cell mobility. RNA sequencing, PCR, and Western blot analyses were conducted to uncover the underlying mechanism. Rescue experiments were performed to validate the mechanism of apoptotic induction. The impact of SHK and VPA combination treatment on primary osteosarcoma cells was also assessed. Finally, in vivo experiments were conducted to validate its anti-tumour effects and mechanism. ResultsThe combination of SHK and VPA synergistically inhibited the proliferation and migration of osteosarcoma cells in vitro and induced apoptosis in these cells. Through a comprehensive analysis involving RNA sequencing, PCR, Western blot, and rescue experiments, we have substantiated our hypothesis that the combination of SHK and VPA induced apoptosis via the ROS-EGR1-Bax axis. Importantly, our in vivo experiments corroborated these findings, demonstrating the potential of the SHK and VPA combination as a promising therapeutic approach for osteosarcoma. ConclusionThe combination of SHK and VPA exerted an anti-tumour effect by inducing apoptosis through the ROS-EGR1-Bax pathway. Repurposing the old drug VPA demonstrated its effectiveness as an adjunctive therapeutic agent for SHK, enhancing its anti-tumour efficacy and revealing its potential value. Furthermore, our study expanded the application of natural compounds in the anti-tumour field and overcame some of their limitations through combination therapy. Finally, we enhanced the understanding of the mechanistic pathways linking reactive oxygen species (ROS) accumulation and apoptosis in osteosarcoma cells. Additionally, we elucidated the role of EGR1 in osteosarcoma cells, offering novel strategies and concepts for the treatment of osteosarcoma.

Anti-inflammatory effect of luteoloside against methylglyoxal induced human dental pulp cells.

The aim of this study was to investigate whether luteoloside, a flavonoid, could protect human dental pulp cells (HDPCs) against inflammation and oxidative stress induced by methylglyoxal (MGO), one of the advanced glycated end products (AGE) substances. HDPCs were stimulated with MGO and treated with luteoloside. MTT assay was used to determine cell viability. Protein expression was measured via western blotting. Reactive oxygen species (ROS) were measured with a Muse Cell Analyzer. Alkaline phosphatase activity (ALP) and Alizarin red staining were used for mineralization assay. Luteoloside down-regulated the expression of inflammatory molecules such as ICAM-1, VCAM-1, TNF-α, IL-1β, MMP-2, MMP-9, and COX-2 in MGO-induced HDPCs without showing any cytotoxicity. It attenuated ROS formation and enhanced osteogenic differentiation such as ALP activity and Alizarin red staining in MGO-induced HDPCs. Overall, luteoloside showed protective actions against inflammation and oxidative stress in HDPCs induced by MGO through its anti-inflammatory, anti-oxidative, and osteogenic activities by down-regulating p-JNK in the MAPK pathway. These results suggest that luteoloside might be a potential adjunctive therapeutic agent for treating pulpal pathological conditions in patients with diabetes mellitus.

Preliminary Experience With Remimazolam for Procedural Sedation and as an Adjunct to General Anesthesia During Diagnostic and Interventional Cardiac Procedures.

Remimazolam is a benzodiazepine which, like midazolam, has sedative, anxiolytic, and amnestic properties. Ester metabolism results in a half-life of 5 - 10 min, a limited context sensitive half-life, and rapid recovery when the infusion is discontinued. Following the Institutional Review Board (IRB) approval, we performed a retrospective chart review of patients who received remimazolam in the cardiac catheterization, cardiac magnetic resonance imaging (MRI), and electrophysiology suites. The primary objective was to assess efficacy and safety. The secondary objective was to describe bolus and infusion dosing of remimazolam and the need for adjunctive agents to optimize procedural sedation conditions. The study cohort included 26 patients with a median age of 18 years and a total of 33 anesthetic encounters. The most common procedures were endomyocardial biopsy or isolated hemodynamic assessment (right or left heart catheterization). Remimazolam was the primary agent for sedation in 82% of the procedures. The majority of cases (25 encounters, 76%) included a bolus dose of remimazolam prior to the start of an infusion. For those patients who received a starting bolus dose, dosing typically ranged between 30 and 110 µg/kg. Continuous infusion rates of remimazolam varied from 5 to 20 µg/kg/min. No adverse hemodynamic or respiratory effects were noted. Midazolam, fentanyl, and dexmedetomidine were the most frequently used adjunctive agents. One patient required transition to general anesthesia due to the need for a surgical intervention based on the findings of the cardiac catheterization. All other patients were effectively sedated. Our preliminary experience demonstrates that remimazolam effectively provided sedation for diagnostic and therapeutic cardiovascular procedures. Future studies are needed to further define dosing parameters for both bolus dosing and continuous infusion as well as to compare remimazolam to other commonly used for procedural sedation in patients with congenital and acquired heart disease.

High Doses of ANA12 Improve Phenobarbital Efficacy in a Model of Neonatal Post-Ischemic Seizures.

Phenobarbital (PB) remains the first-line medication for neonatal seizures. Yet, seizures in many newborns, particularly those associated with perinatal ischemia, are resistant to PB. Previous animal studies have shown that in postnatal day P7 mice pups with ischemic stroke induced by unilateral carotid ligation, the tyrosine receptor kinase B (TrkB) antagonist ANA12 (N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide, 5 mg/kg) improved the efficacy of PB in reducing seizure occurrence. To meet optimal standards of effectiveness, a wider range of ANA12 doses must be tested. Here, using the unilateral carotid ligation model, we tested the effectiveness of higher doses of ANA12 (10 and 20 mg/kg) on the ability of PB to reduce seizure burden, ameliorate cell death (assessed by Fluoro-Jade staining), and affect neurodevelopment (righting reflex, negative geotaxis test, open field test). We found that a single dose of ANA12 (10 or 20 mg/kg) given 1 h after unilateral carotid ligation in P7 pups reduced seizure burden and neocortical and striatal neuron death without impairing developmental reflexes. In conclusion, ANA12 at a range of doses (10-20 mg/kg) enhanced PB effectiveness for the treatment of perinatal ischemia-related seizures, suggesting that this agent might be a clinically safe and effective adjunctive agent for the treatment of pharmacoresistant neonatal seizures.

Protective effect of a hydromethanolic extract from Fraxinus excelsior L. bark against a rat model of aluminum chloride-induced Alzheimer's disease: Relevance to its anti-inflammatory and antioxidant effects

Ethnopharmacological relevanceFraxinus excelsior L. (FE), commonly known as the ash, belongs to the Oleaceae family and has shown several pharmacological and biological properties, such as antioxidant, immunomodulatory, neuroprotective, and anti-inflammatory effects. It has also attracted the most attention toward neuroinflammation. Moreover, FE bark and leaves have been used to treat neurological disorders, aging, neuropathic pain, urinary complaints, and articular pain in traditional and ethnomedicine. Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder resulting from the involvement of amyloid-beta, metal-induced oxidative stress, and neuroinflammation. Aim of the studyThe objective of the current study was to assess the neuroprotective effects of hydromethanolic extract from FE bark in an AlCl3-induced rat model of AD. Materials and methodsThe maceration process was utilized to prepare the hydromethanolic extract of FE bark, and characterized by LC-MS/MS. To assess the anti-AD effects of the FE extract, rats were categorized into five different groups, AlCl3; normal control; FE-treated groups at 50, 100, and 200 mg/kg. Passive avoidance learning test, Y-maze, open field, and elevated plus maze behavioral tests were evaluated on days 7 and 14 to analyze the cognitive impairments. Zymography analysis, biochemical tests, and histopathological changes were also followed in different groups. ResultsLC-MS/MS analysis indicated the presence of coumarins, including isofraxidin7-O-diglucoside in the methanolic extract of FE as a new isofraxidin derivative in this genus. FE significantly improved memory and cognitive function, maintained weight, prevented neuronal damages, and preserved the hippocampus's histological features, as demonstrated by behavioral tests and histopathological analysis. FE increased anti-inflammatory MMP-2 activity, whereas it decreased that of inflammatory MMP-9. Moreover, FE increased plasma antioxidant capacity by enhancing CAT and GSH while decreasing nitrite levels in the serum of treated groups. In comparison between the treated groups, the rats that received high doses of the FE extract (200 mg/kg) showed the highest therapeutic effect. ConclusionFE rich in coumarins could be an effective anti-AD adjunct agent, passing through antioxidant and anti-inflammatory pathways. These results encourage further studies for the development of this extract as a promising agent in preventing, managing, or treating AD and related diseases.

Comparative study between topical insulin, autologous serum, and honey-based eye drops as adjunctive treatment in resistant corneal ulcer

Background Resistant keratitis is a difficult situation faced every day in ophthalmology clinics. Resistance to healing may be attributed to many factors. Many adjunctive agents are widely used in a trial to accelerate healing and to prevent resistance to eliminate the chance of development of disabling complications. Purpose The aim of this study was to compare the effectiveness of topical insulin, autologous serum, and honey-based eye drops as adjunctive therapies in resistant corneal ulcers. Patients and methods This prospective study investigated 45 eyes of infected keratitis not responding to culture-based medical treatment for 2 weeks. The eyes were divided into three groups each of 15 eyes. The insulin group was treated with topical insulin drops, the serum group with autologous serum drops, and the honey group with honey-based drops. Culture-based medical treatment was also continued in the three groups till complete healing was achieved. The results of the three groups were compared regarding the time needed for healing and best-corrected visual acuity outcome. Results Best-corrected visual acuity improved by one or more lines in 11 (73.33%) cases in the insulin group, in 10 (66.67%) cases in the serum group, and in nine (60%) cases in the honey group, with no statistically significant difference (χ 2=1.525, P=0.822). Healing occurred in 14–28 days in 12 (80%) cases in the insulin group, in 13 (86.67%) cases in the serum group, and in 10 (66.67%) cases in the honey group, with no statistically significant difference (χ 2=1.8, P=0.407). The remaining cases in each group required amniotic membrane transplantation due to thinning. Conclusion The effects of topical insulin, autologous serum, and honey-based eye drops, when used as adjunctive methods added to the culture-based medical therapy in the management of resistant corneal ulcers, were comparable. Autologous serum gave slightly higher effect than topical insulin and honey-based eye drops but the difference was statistically insignificant.

Unveiling the Antibacterial Properties of Statins: An In Vitro Study on Helicobacter pylori

Background. Helicobacter pylori (H. pylori), a widespread bacterial pathogen, is associated with various gastrointestinal diseases, including gastric cancer. Statins, widely prescribed cholesterol‐lowering agents, have demonstrated pleiotropic effects, including potential antimicrobial properties. This in vitro study investigated the direct antibacterial effects of three clinically approved statins, simvastatin, atorvastatin, and rosuvastatin, against H. pylori isolates. Methods. H. pylori strains were isolated from gastric biopsies of dyspeptic patients and identified by microbiological techniques. The minimum inhibitory concentrations (MICs) of statins were determined using the agar dilution method, and their antimicrobial activity was evaluated by the disc diffusion method using different concentrations of simvastatin, atorvastatin, rosuvastatin, tetracycline, and amoxicillin. Scanning electron microscopy (SEM) was employed to examine the morphology of H. pylori cells. Results. The minimum inhibitory concentration (MIC) values (μg/mL) of atorvastatin, rosuvastatin, simvastatin, tetracycline, and amoxicillin against H. pylori were 240 ± 20, 450 ± 20, 460 ± 15, 155 ± 30, and 140 ± 20, respectively. In the disc diffusion assay, atorvastatin and rosuvastatin produced significantly larger inhibition zones compared to simvastatin at all concentrations tested (p < 0.05). The inhibition zone diameters (mm) increased with higher statin concentrations, ranging from 9 ± 1.4 to 13 ± 1.4 for atorvastatin, 8 ± 0.9 to 11 ± 0.6 for rosuvastatin, and 5 ± 1.3 to 6 ± 1.4 for simvastatin at the highest tested concentration (1200 μg/ml). SEM analysis revealed the characteristic spiral morphology of H. pylori cells. Conclusion. Statins demonstrated varying degrees of antibacterial activity against H. pylori isolates, with atorvastatin exhibiting the highest potency. While the observed effects were lower than those of conventional antibiotics, these findings suggest the potential of statins as adjunctive agents or alternative therapeutic options, warranting further investigation through in vivo studies and clinical trials.

The efficacy of Makiang tea drinking on serum lipid profile in the treatment of dyslipidaemia: A randomized controlled trial

The purpose of this study was to investigate the effects of Makiang (MK) tea consumption on the serum lipid profile and oxidative stress biomarkers in participants with dyslipidemia. A randomized, single-blind, parallel-group, placebo-controlled study was conducted at the Outpatient Department of Phayao Hospital, Thailand. This clinical trial enrolled 64 subjects (males and females), aged between 30 and 65 years with hyperlipidemia who were randomized using simple random sampling, receiving a 12-week MK tea (3 g/250 ml hot water) taken daily or a placebo. Body mass index, lipid profile, and serum oxidative stress markers were evaluated at the baseline and the end of the study. Within-group comparisons revealed that drinking only one cup of MK tea daily caused a significant reduction (p < 0.05 all) of total cholesterol (TC), total triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C). Meanwhile, between-group differences showed that serum TC, TG, and LDL-C levels significantly decreased (p < 0.05 all), whereas the levels of high-density lipoprotein cholesterol were unchanged. This phenomenon was accompanied by decreased serum malondialdehyde and increased endogenous enzymatic defence systems (p < 0.05 all). Thus, MK tea may be useful as an adjunct agent to improve the lipid profile in patients with dyslipidemia.

Effects of Indigenous Saudi Herbals on Weight Control in High Fat Diet-fed STZ Induced Diabetic Rats

Introduction: Obesity, a critical global issue, involves the accumulation of excessive body fat, elevating the risk of diabetes, hypertension, and other severe health conditions. This widespread concern is particularly pronounced in nations like Saudi Arabia, demanding urgent and efficient management approaches. Addressing weight control necessitates comprehensive interventions encompassing education, dietary modifications, and increased physical activity. By following healthier lifestyles and fostering a supportive environment, improvement can be made on healthcare systems. Collaboration between governments, healthcare professionals, and communities is pivotal to reduce obesity's impact and fostering a healthier generations.
 Methods: Research Design and Objectives: This study aimed to fill the existing void in excessive body weight treatments by investigating viable herbal interventions that are safe, readily accessible, and economically viable. Wistar albino rats were grouped to 5 groups with 5 animals each. Diabetics were induced by intraperitoneal injection of streptozotocin for all groups except group 1. Then respective groups were fed with fat diets for 12 weeks and herbals Zingiber officinale (ginger), Nigella sativa (black seeds) and Allium sativum (Garlic) from 7th to 12th weeks along with high fat diet. Mean Body weight and Lee's obesity index were calculated for each group.
 Results and Discussion: In the realm of herbal efficacy, a striking trend surfaces. Among the diverse materials scrutinized, one distinct name rises—Garlic (Allium sativum). Its prowess in diminishing both body weight and fat content stands out prominently. Across the tested spectrum, a consistent and impressive reduction in weight prevails. Particularly, Garlic asserts its dominance as a singularly remarkable performer, showcasing unparalleled effectiveness. This herbal gem not only underscores its potency but also solidifies its position as a preeminent agent for weight and fat reduction. The findings unequivocally spotlight Garlic's exceptional role in promoting healthier body composition.
 Conclusions: Herbals as Adjunctive Therapy for Obesity The findings underscore the potential of herbal interventions, particularly Garlic, in the management of weight control. These natural remedies hold promise as adjunctive therapeutic agents. However, further rigorous human trials and animal studies with large sample size and different methodology are essential to validate their efficacy and integration into obesity / weight control treatment regimens.

Inhibition of aldo-keto reductase 1C3 overcomes gemcitabine/cisplatin resistance in bladder cancer

Systemic chemotherapy with gemcitabine and cisplatin (GC) has been used for the treatment of bladder cancer in which androgen receptor (AR) signaling is suggested to play a critical role. However, its efficacy is often limited, and the prognosis of patients who develop resistance is extremely poor. Aldo-keto reductase 1C3 (AKR1C3), which is responsible for the production of a potent androgen, 5α-dihydrotestosterone (DHT), by the reduction of 5α-androstane-3α,17β-dione (5α-Adione), has been attracting attention as a therapeutic target for prostate cancer that shows androgen-dependent growth. By contrast, the role of AKR1C3 in bladder cancer remains unclear. In this study, we examined the effect of an AKR1C3 inhibitor on androgen-dependent proliferation and GC sensitivity in bladder cancer cells. 5α-Adione treatment induced the expression of AR and its downstream factor ETS-domain transcription factor (ELK1) in both T24 cells and newly established GC-resistant T24GC cells, while it did not alter AKR1C3 expression. AKR1C3 inhibitor 2j significantly suppressed 5α-Adione-induced AR and ELK1 upregulation, as did an AR antagonist apalutamide. Moreover, the combination of GC and 2j in T24GC significantly induced apoptotic cell death, suggesting that 2j could enhance GC sensitivity. Immunohistochemical staining in surgical specimens further revealed that strong expression of AKR1C3 was associated with significantly higher risks of tumor progression and cancer-specific mortality in patients with muscle-invasive bladder cancer. These results suggest that AKR1C3 inhibitors as adjunctive agents enhance the efficacy of GC therapy for bladder cancer.

Agonistic Bivalent Human scFvs-Fcγ Fusion Antibodies to OX40 Ectodomain Enhance T Cell Activities against Cancer.

(1) Background: Understanding how advanced cancers evade host innate and adaptive immune opponents has led to cancer immunotherapy. Among several immunotherapeutic strategies, the reversal of immunosuppression mediated by regulatory T cells in the tumor microenvironment (TME) using blockers of immune-checkpoint signaling in effector T cells is the most successful treatment measure. Furthermore, agonists of T cell costimulatory molecules (CD40, 4-1BB, OX40) play an additional anti-cancer role to that of checkpoint blocking in combined therapy and serve also as adjuvant/neoadjuvant/induction therapy to conventional cancer treatments, such as tumor resection and radio- and chemo- therapies. (2) Methods and Results: In this study, novel agonistic antibodies to the OX40/CD134 ectodomain (EcOX40), i.e., fully human bivalent single-chain variable fragments (HuscFvs) linked to IgG Fc (bivalent HuscFv-Fcγ fusion antibodies) were generated by using phage-display technology and genetic engineering. The HuscFvs in the fusion antibodies bound to the cysteine-rich domain-2 of the EcOX40, which is known to be involved in OX40-OX40L signaling for NF-κB activation in T cells. The fusion antibodies caused proliferation, and increased the survival and cytokine production of CD3-CD28-activated human T cells. They showed enhancement trends for other effector T cell activities like granzyme B production and lysis of ovarian cancer cells when added to the activated T cells. (3) Conclusions: The novel OX40 agonistic fusion antibodies should be further tested step-by-step toward their safe use as an adjunctive non-immunogenic cancer immunotherapeutic agent.

The use of mirtazapine as an adjunct agent to fluoxetine and paroxetine in the treatment of canine fear-, anxiety-, and aggression-based disorders: A retrospective study of 71 cases

The use of mirtazapine as an adjunct agent to fluoxetine and paroxetine in the treatment of canine fear-, anxiety-, and aggression-based disorders: A retrospective study of 71 cases

Augmentation Strategies for Partial or Non-responders to Clozapine in Patients with Schizophrenia: A Bayesian Network Meta-analysis of Randomized Controlled Trials.

Clozapine is the only approved drug for treatment-resistant schizophrenia, but the response to the drug is often inadequate. Augmentation with other antipsychotics, anticonvulsants, and antidepressants is recommended for such patients, but there is a lack of evidence regarding the most effective therapy. This network meta-analysis was conducted to evaluate the efficacy of pharmacological agents used in the augmentation strategies in patients who were partial/ non-responders to clozapine. Relevant data were extracted from 30 randomized controlled trials through searches of electronic databases (MEDLINE/PubMed, Embase, Cochrane, clinical trial registries). PRISMA guidelines were followed for the extraction, management, analysis, and reporting of the data. The outcome measure in this study was a reduction in symptom severity according to total PANSS/BPRS and was reported as the standardized mean difference with a 95% credible interval. Bayesian network meta-analysis with random effects model and uninformative priors was conducted, and the ranking probability of each intervention was done. Meta-regression was done to assess the effect of duration on the reduction in symptom severity scores. Mirtazapine (-5.2 [95%CrI: -7.7, -2.7]) and memantine (-2.1 [95%CrI: -4.0, -0.19]] were more efficacious than placebo for augmentation of clozapine in partial/non-responders and were the most effective adjunctive agents as per SUCRA scores. Both drugs did not cause a significant increase in frequency of adverse events compared to placebo. There was a significant effect of duration on the reduction in symptom severity. There was no evident publication bias. Mirtazapine and memantine may prove beneficial for augmentation of clozapine in non/partial responders to monotherapy.

Understanding Natural History of Common Inherited Platelet Function Disorder (IPFD) Patients: An Indian Study

Background : Inherited platelet function disorders (IPFDs) are less well studied in a resource poor country in comparison to hemophilia and other bleeding disorders.With high rates of consanguinous marriages in some of the communities in India, Glanzmanns thrombasthenia (GT) and Bernard soulier syndrome (BSS) are the two platelet function disorders that are commonly diagnosed. There is no data on the nature of bleeding, mode of treatment, mortality as well as quality of life (QoL) in these conditions. Aim : To understand clinical manifestations, treatment, quality-of-life (QoL), mortality and other details in GT and BSS patients. Methods : This is a retrospective, non-interventional, observational single center data collection study.Subjects were eligible to participate, if they had confirmed reports of laboratory diagnosis of GT or BSS by both platelet aggregometry and flow cytometry studies. Data collected were demographics, medical history, co-morbidities (HIV, HCV, HBV), detailed treatment/product(s) usage, bleeding events, surgical procedures, and other adverse events. It also included patient-reported outcome questionnaires regarding health-related quality of life (HRQoL) using SF-36 and EQ-5D instruments. All data were entered into electronic case report forms by the laboratory personnel. Results : Sixty one ( GT 50, BSS 11) patients participated in the present study; 31 were males and 30 females. 43 were pediatric patients and 18 adults. Seventeen patients were diagnosed at birth and 10 patients were diagnosed beyond the age of 10 years. Forty four patients (72%) had parental consanguinity. Thirteen patients ( BSS 8, GT 5) did not have any major bleeding manifestations which required treatment. In the remaining patients, the median ABR was 10 ( range 2.5 - >75). The median ISTH BAT score was 10 (range 1-26.)The bleeding manifestations included epistaxis (61%), ecchymosis (58%) , gum bleed (48%), gastrointestinal bleed (28%), soft tissue bleed (23%), hematuria (8%), joint bleed (3%) and intracranial bleed ( 3%). Heavy menstrual bleed (HMB) was the primary bleeding manifestation in all females in the reproductive age group. Four patients were diagnosed following circumcision. Treatment strategies for bleeding events included antifibrinolytic agents alone (26%), platelet transfusion (43%), or whole blood and fresh frozen plasma (39%). Antifibrinolytic agents were also used as adjunct agents with platelet transfusion in majority of the patients. None of the patients were on recombinant activated FVIIa. Overall 8 deaths were reported due to bleeding in these 61 families during the last 10 years, the cause of death mainly being non-availability of treatment products. The self- reported median EQ-5D health score was 82.5 ( range 40-100) Figure 1 shows the detailed EQ-5D analysis in these 61 patients Conclusion : Present study provides detailed information of GT and BSS and its impact throughout life. A wide variation in clinical manifestations and disease outcomes was observed, the major attributing factor may possibly be socioeconomic factor which includes access to clinical resources and treatment products for bleed management. Unlike hemophilia, GT and BSS patients do not have the privilege of prophylactic treatment in our country, but there is a need for optimal disease management to normalize both physical and psychosocial outcomes. More such studies will add to an increased understanding of critical issues in these

175. Clindamycin versus linezolid for Group A Streptococcal bloodstream infections?: A comparative effectiveness study of adjunctive antitoxin therapy at 137 US Hospitals

Abstract Background Adjunctive clindamycin has survival benefit in invasive Group A streptococcus (GAS) infections. Like clindamycin, linezolid also leads to decreased toxin and virulence factor production. However, rising clindamycin resistance among GAS isolates and inadequate clinical data on linezolid both offer pause on which to choose. We examined the impact of adjunctive clindamycin vs. linezolid on survival among patients with GAS bloodstream infections (BSI) in the presence and absence of clindamycin resistant (clinda-R) isolates Methods Clinical characteristics, antimicrobial susceptibility testing (AST), and antibiotic therapy were examined for unique adult inpatient encounters with GAS BSIs in the PINC-AI Database. Patients treated with a β-lactam for ≥3 days ±3 days of culture who received clindamycin ±3 days of culture were overlap weighted on a propensity-score to those who received linezolid using basine patient and hospital factors. The primary outcome was odds ratio (OR) of in-hospital mortality associated with clindamycin (vs linezolid). The secondary outcome was length of stay (LOS) among survivors. Subgroups analyses were conducted excluding clindamycin receipients with clinda-R isolates (subgroup 1) and also missing clindamycin AST(including D-test; subgroup 2).Figure 1.Study Flow chart Selection of patients with Group A streptococcal blood stream infections. The database was queried for inpatients (aged ≥18 years) with blood culture displaying growth of Group A streptococcus, filtered on the basis of receiving β-lactam antibiotics within 3 days either side of culture sampling for a minimum duration of 3 days and received either adjunctive clindamycin or linezolid treatment within 3 days either side of culture sampling.Table 1:Baseline characteristics of all patients with Group A Streptococcal blood stream infections treated with β-lactam antibiotics and adjunctive clindamycin or linezolid (N=660)Abbreviations: IVIG: intravenous immunoglobulin, ICU: intensive care unit, IQR: interquartile range, SOFA: Sequential Organ Failure Assessment * This score was calculated by use of ICD-10-clinical modification codes and adapted from the methods used by Quan and colleagues ^ Calculated by use of an electronic health record-based adaption of the original Sequential Organ Failure Assessment ^^ Deteremined by clindamycin antimicrobial susceptibility and D-test results. Defined as resistant or intermediate clindamycin susceptibility results and/or a positive D-test result. † Defined as presence of ICD-10 codes coding for any of the following conditions: Human immunodeficiency virus, cancer, solid organ or hematopoietic stem cell transplantation, receipt of systemic corticosteroids, chemotherapy or other immunosuppressive therapy and immunodeficiency. ‡ Receipt of norepinephrine, epinephrine, phenylephrine, and dopamine administered within a 24-h period either side of culture sampling. Results Of 3019 β-lactam–treated inpatients with GAS BSI, 500 (17%) received clindamycin and 160 (5%) received linezolid. The prevalence of clinda-R isolates was 19%;1 isolate was linezolid resistant and excluded (Figure 1). Overlap weighting resulted in well balanced groups (Figure 2). In the overlap weighted cohort, mortality risk was similar between recipients of clindamycin (10%, [50/500]) vs linezolid (9%, [14/160]; OR 1.38 [95% CI: 0.76-2.49]). Among survivors median[interquartile range] LOS was similar between the two groups (8[9] vs. 9[8] days, p=0.45). Removing those with clinda-R isolates (N=84) and also missing AST (N=166) yielded similar results (Figure 3).Figure 2.Standardized mean differences for covariates included the propensity score calculation Standardized mean differences for covariates included in the propensity score generation averaged across exposure categories in the unweighted cohort (blue triangles) and overlap weighted cohort weight (red circles). After overlap weighting, the mean standard difference at each variable assessed was zero . Abbreviations: ICU: intensive care unit, IVIG: intravenous immunoglobulin, NSTI: necrotizing soft tissue infectionFigure 3.Odds Ratio of in-hospital mortality in patients with invasive group A streptococcal blood stream infection treated with adjunctive clindamycin versus adjunctive linezolid The ORs (95% CIs) of in-hospital mortality (including discharge to hospice) in the primary analysis and subgroup analysis with patients withclindamycin resistant isolates (subgroup 1) and those with clindamycin resistant isolates and missing clindamycin susceptibility results (subgroup 2) removed from clindamycin group. Abbreviations: CI: confidence interval Conclusion Among β-lactam-treated patients with GAS BSI, linezolid and clindamycin displayed comparable effectiveness as adjunctive antitoxin agents. Similar intrinsic effectiveness (i.e., in patients with only susceptible isolates) supports linezolid as an alternative even in low clinda-R settings. Disclosures Ahmed Babiker, MBBS, Roche: Advisor/Consultant Morgan Walker, MD, Cytovale: Advisor/Consultant

Regional anesthesia and sickle cell crisis in pediatric patients: An educational-focused review.

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy, affecting approximately 100 000 patients in United States and millions worldwide. Although the mainstay of pain management for VOC remains systemic opioids, given the potential for adverse effects including respiratory depression and hypoxemia, there remains interest in the use of regional anesthetic techniques (neuraxial or peripheral nerve blockade). A systematic search of pubMed, Scopus, and Google Scholar was conducted using the terms sickle cell disease, sickle cell crisis, pain crisis, vaso-occlusive crisis, regional anesthesia, peripheral nerve blockade, and neuraxial anesthesia. We identified 7 publications, all of which were retrospective case series or single case reports, outlining the use of neuraxial anesthesia in a total of 26 patients with SCD. Additionally, we identified 4 publications, including one retrospective case series and 3 single case reports, entailing the use of peripheral blockade in patients with VOC and SCD. The available literature, albeit all retrospective or anecdotal, suggests the potential utility of regional anesthesia to treat pain in patients with SCD. Additional benefits have included avoidance of the potential deleterious physiologic effects of systemic opioids and in one case series, an improvement in respiratory function as judged by pulse oximetry. The anecdotal and retrospective nature of the available reports with an absence of prospective trials limits the evidence based medicine available from which to develop to guidlines for the optimal local anesthetic agent to use, its concentration, the rate of infusion, and the choice of adjunctive agents.

Supra- and sub-gingival instrumentation of periodontitis with the adjunctive treatment of a chloramine – a one-year randomized clinical trial study

Periodontitis is a bacterial-induced disease and for this reason controlling the microbiota is a necessity. Therapy includes self-performed daily oral hygiene in combination with supra- and sub-gingival instrumentation. An adjunctive antimicrobial agent may improve the outcome. Aims To assess whether a chloramine (Perisolv®) has an adjunctive effect to non-surgical periodontal therapy and whether non-surgical periodontal therapy affects quality of life. Material and Methods Thirty-eight patients were randomized to a test or a control group. Clinical indices were performed at baseline and at three and twelve months. In the test group, Perisolv® was applied initially and after the sub-gingival instrumentation in pathological pockets. Oral health-related quality of life was measured with the Oral Health Impact Profile (OHIP) instrument at baseline and twelve months. Results In both groups, an initial probing pocket depth (PPD) of > 4 mm and bleeding on probing (BOP) were statistically reduced (p < 0.002 and p < 0.002 respectively) at twelve months and after adjustment for Bonferroni. There were no significant differences between the test and the control group in terms of the number of PPD, BOP or plaque index, or in the mean OHIP score. Conclusions Chloramine did not have an adjunctive effect, but the overall therapy was significantly efficacious both clinically and in terms of quality of life. Trial registration Registered at www.clinicaltrials.gov: NCT05757921.

Angiotensin-II for vasoplegia following cardiac surgery.

The objective of this study was to describe the implementation and outcomes of a protocol outlining angiotensin-II utilization for vasoplegia following cardiac surgery. This was a retrospective chart review at a single-center university hospital. Included patients received angiotensin-II for vasoplegia refractory to standard interventions, including norepinephrine 20mcg/min and vasopressin 0.04 units/min, following cardiac surgery between April 2021 and April 2022. 30 patients received angiotensin-II for refractory vasoplegia. Adjunctive agents at angiotensin-II initiation included corticosteroids (26 patients; 87%), epinephrine (26 patients; 87%), dobutamine (17 patients; 57%), dopamine (9 patients; 30%), milrinone (2 patients; 7%), and hydroxocobalamin (4 patients; 13%). At 3hours, the median mean arterial pressure increased from baseline (70 vs 61.5mmHg, p = .0006). Median norepinephrine doses at angiotensin-II initiation, 1hour, 3hours, and angiotensin-II discontinuation were 0.22, 0.16 (p = .0023), 0.10 (p < .0001), and 0.07 (p < .0001) mcg/kg/min. Median dobutamine doses decreased throughout angiotensin-II infusion from eight to six mcg/kg/min (p = .0313). Other vasoactive medication doses were unchanged. Three patients (10%) subsequently received hydroxocobalamin. Thirteen (43.3%) and five (16.7%) patients experienced mortality by day 28 and venous or arterial thrombosis events, respectively. The administration of angiotensin-II to vasoplegic patients following cardiac surgery was associated with increased mean arterial pressure, reduced norepinephrine dosages, and reduced dobutamine dosages.

SHP2 potentiates anti-PD-1 effectiveness through intervening cell pyroptosis resistance in triple-negative breast cancer

Triple negative breast cancer (TNBC) presents a formidable challenge due to the lack of effective treatment modalities. Immunotherapy stands as a promising therapeutic approach; however, the emergence of drug resistance mechanisms within tumor cells, particularly those targeting apoptosis and pyroptosis, has hampered its clinical efficacy. SHP2 is intricately involved in diverse physiological processes, including immune cell proliferation, infiltration, and tumor progression. Nevertheless, the precise contribution of SHP2 to tumor cell pyroptosis resistance remains inadequately understood. Herein, we demonstrate that SHP2 inhibition hampers the proliferative, migratory, and invasive capabilities of TNBC, accompanied by noticeable alterations in cellular membrane architecture. Mechanistically, we provide evidence that SHP2 depletion triggers the activation of Caspase-1 and GSDMD, resulting in GSDMD-dependent release of LDH, IL-1β, and IL-18. Furthermore, computational analyses and co-localization investigations substantiate the hypothesis that SHP2 may hinder pyroptosis through direct binding to JNK, thereby impeding JNK phosphorylation. Our cellular experiments further corroborate these findings by demonstrating that JNK inhibition rescues pyroptosis induced by SHP2 knockdown. Strikingly, in vivo experiments validate the suppressive impact of SHP2 knockdown on tumor progression via enhanced JNK phosphorylation. Additionally, SHP2 knockdown augments tumor sensitivity to anti-PD-1 therapy, thus reinforcing the pro-pyroptotic effects and inhibiting tumor growth. In summary, our findings elucidate the mechanism by which SHP2 governs TNBC pyroptosis, underscoring the potential of SHP2 inhibition to suppress cell pyroptosis resistance and its utility as an adjunctive agent for tumor immunotherapy.