Consistent Efficacy Research Articles

A UTILIZAÇÃO DE VALERIANA OFFICINALIS E PASSIFLORA INCARNATA EM PACIENTES COM DEPRESSÃO

Depression, a debilitating mental condition with an increasing impact on quality of life, does not always respond well to conventional treatments, which often have side effects that hinder adherence. In this context, phytotherapeutics like Valeriana officinalis and Passiflora incarnata have emerged as promising therapeutic alternatives. This study aimed to review the effectiveness of these phytotherapeutics in treating depression and anxiety. The methodology involved a systematic literature review of 16 articles published between 2014 and 2024, following PRISMA guidelines. Results indicated that both phytotherapeutics significantly reduced depressive and anxiety symptoms, with fewer adverse effects compared to conventional medications. Valeriana officinalis and Passiflora incarnata were observed to modulate the GABA system, promoting symptom relief. However, inconsistent bioactive compound standardization and preparation variability are limitations for clinical application. It is concluded that, while promising, these phytotherapeutics require further research to ensure consistent efficacy and safety.

BIOS-08. CISD: A NOVEL, USER-FRIENDLY MULTIFACETED ALGORITHM FOR DETECTING STITCHING ARTIFACTS IN LARGE-SCALE CODEX IMAGING DATASETS

Abstract BACKGROUND CODEX (CO-Detection by indEXing) imaging has emerged as a pivotal tool in cellular biology, providing unprecedented insights into cellular distributions and interactions within the tissue microenvironment, crucial for advancing computational pathology. Despite its advantages, CODEX is susceptible to stitching errors during the merging of image tiles, which can significantly distort spatial analysis by introducing artifacts that obscure true cellular architecture. METHODS Addressing this challenge, we introduce CISD (CODEX Image Stitch Detection), a novel, user-friendly algorithm optimized for the detection of stitching artifacts in large-scale CODEX datasets. Developed and validated using a comprehensive dataset from 7 matched glioblastoma patients—encompassing over 2800 images across 29 immune protein markers—CISD utilizes a combination of image preprocessing, statistical measures, and thresholding to detect stitching errors. RESULTS CISD demonstrates robust performance, achieving a median Area Under Curve (AUC) value in the gold standard dataset where 73% of markers exceed 70% AUC, and 17% surpass 90%. Further validation shows that in a secondary dataset, 45% of markers maintain AUC values over 70% with 38% exceeding 90%, validating the algorithm’s consistent efficacy across varied datasets. CONCLUSION CISD’s significance lies not only in its computational achievements but also in its accessibility, facilitating high-quality analysis of extensive datasets without complex pattern recognition requirements. This democratizes high-precision computational pathology, enabling more researchers to accurately analyze spatial data. By reducing technical barriers, CISD sets a new benchmark in CODEX imaging, enhancing data reliability and accelerating research discoveries in cellular biology. This innovation stands to substantially refine spatial analysis in digital pathology, ensuring dependable interpretation of complex biological data.

Dupilumab for Chronic Hand Eczema: A Systematic Review and Meta-Analysis.

Chronic hand eczema (CHE) is a distressing and pervasive dermatologic condition, and effective treatment can be challenging. The novel IL-4/13 inhibitor dupilumab has shown clinical efficacy for atopic dermatitis (AD) and is being studied for CHE. PubMed database was searched for terms dupilumab and chronic hand eczema/dermatitis, including CHE subtypes (dyshidrotic, hyperkeratotic, allergic, contact, atopic, occupational, vesicular). Twenty-two study publications met inclusion and exclusion criteria for evaluation. Two multicenter prospective studies, one randomized controlled trial, two prospective observational studies, one retrospective study, nine case series, and seven case reports were included in the analysis with 374 total patients. Any partial response or complete resolution of CHE occurred in 80.3% of patients treated with dupilumab within 4-16 weeks of treatment. The patient response tended to increase throughout the duration of these studies for a significant percentage of patients, and for many it lasted beyond the study duration. Significant improvement in hand eczema severity scores and quality-of-life scores were noted. Efficacy was reported in over half of the cases of hyperkeratotic hand eczema; however, efficacy was decreased compared with relatively high consistent efficacy in other CHE subtypes such as dyshidrotic, vesicular, atopic, and contact CHE. Patients with current or previous AD had increased improvement scores compared to those without. The most common adverse effects were conjunctivitis (9.9%), herpes viral infection (1.4%), and facial erythema/dermatitis (1.3%). Dupilumab shows therapeutic efficacy in treating CHE. Further randomized controlled studies of dupilumab use in CHE subtypes are needed.

Neoadjuvant cadonilimab plus FLOT chemotherapy in locally advanced gastric/gastroesophageal junction adenocarcinoma: A multicenter, phase 2 study.

Treatment with cadonilimab and chemotherapy has shown promise as a first-line treatment for gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. However, its application in neoadjuvant settings has not yet been documented. This multicenter, phase 2 trial (ChiCTR2200066893) was conducted at four hospitals across China. Treatment-naive patients with locally advanced G/GEJ adenocarcinoma (cT3/4, N+, M0) and who were human epidermal growth factor receptor 2 negative received 3-cycle or 4-cycle neoadjuvant treatment of cadonilimab plus FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy, followed by gastrectomy and 4-cycle adjuvant FLOT chemotherapy. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included major pathological response (MPR), overall response rate (ORR), disease control rate (DCR), R0 resection rate, downstaging rate, and safety. Between December 23, 2022, and December 15, 2023, 32 of 38 patients completed the scheduled treatment, achieving an R0 resection rate of 100% (32/32). The pCR rate was 21.1% (8/38, 90% confidence interval [CI]: 9.7-32.4), and the MPR rate was 44.7% (17/38, 90% CI: 30.9-58.5). Radiological evaluations wereavailable for 28 of 38 patients by blinded independent central review. The ORR was 60.7% (17/28, 90% CI: 44.7-76.7), and the DCR was 100.0% (28/28, 90% CI: 100.0-100.0). Tumor downstaging occurred in 71.9% of patients (23/32), with consistent efficacy across all populations observed in the subgroup analysis. Grade 3 adverse events occurred in 31.6% of patients without severe safety issues. Neoadjuvant cadonilimab plus FLOT chemotherapy treatment exhibits promising efficacy with manageable toxicities in locally advanced G/GEJ adenocarcinoma, providing preliminary evidence for further investigation. This study was funded by Akeso Biopharma.

Mapping active pharmaceutical ingredients Distributions in tablets using Time-of-Flight secondary ion mass spectrometry with multivariate curve resolution

This study introduces an advanced approach to identifying signals associated with indapamide, amlodipine, and perindopril in solid dosage form using time-of-flight secondary ion mass spectrometry (ToF-SIMS) combined with multivariate curve resolution (MCR). The primary objective was to obtain and characterize these signals through MCR factors, which then led to identifying unique signals specific to each active pharmaceutical ingredient (API). These unique signals were crucial for constructing detailed 2D and 3D images of the API distribution within the tablet. The results demonstrated that indapamide and amlodipine exhibited multiple unique peaks, while perindopril had only one. Additionally, the study revealed non-homogeneous distribution patterns of APIs and excipients, such as SiO2 and Mg stearate. This work highlights the significance of applying advanced analytical techniques such as ToF-SIMS and MCR in the pharmaceutical field to ensure consistent therapeutic efficacy through a better understanding of API distribution.

StressMatic: Bridging Innovation and Reliability in Animal Models of Stress

Preclinical research involving animal models of stress exposure typically rely on traditional manual protocols, which are laborious and time-consuming and may compromise reproducibility and the effective translation of findings into clinical applications. StressMatic is an automated stress exposure system (auCMS), designed to improve the standardization and reproducibility of stress-induction methodologies. The auCMS demonstrated consistent efficacy, with animals subjected to automated stressors displaying similar responses to those exposed to conventional manual methods, thus confirming its validity as a reliable tool. While some stressors still require human involvement, the automation of key processes has markedly enhanced efficiency and minimized operational time. This innovative approach reduces the introduction of human error, increases precision, and standardizes experimental workflows, resulting in a more robust preclinical research platform. By streamlining repetitive tasks, the auCMS promotes adaptability in experimental design, particularly in the study of mood disorders. Ultimately, this automated protocol not only enhances the reliability of pharmaceutical screening processes but also strengthens the drug discovery pipeline, facilitating deeper insights into behavioral outcomes and informing therapeutic strategies.

Effectiveness of empagliflozin in patients with heart failure and COPD: Results from EMPEROR-Preserved and EMPEROR-Reduced

Abstract Background Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are chronic, progressive syndromes that share numerous risk factors and clinical symptoms. We sought to analyse the relationship between COPD status and outcomes in patients receiving empagliflozin or placebo in the EMPEROR-Preserved and EMPEROR-Reduced trials. Methods and results We analyzed data of 9,718 patients, including 1,238 (12.7%) with COPD. Compared to patients without COPD, patients with COPD were more likely to be in NYHA class III (19.4 vs. 28.4%), to be male (62.4 vs. 69.0%), to have higher body mass index (29.0±5.7 vs. 29.5±6.1 kg/m2), to be white, to be smoker or ex-smoker (47.1 vs. 71.9%), to be older (69.6±10.5 vs. 72.1±8.7y, all p<0.0001), to have a longer duration of HF (5.0 vs. 5.4y, p=0.04), to have higher haemoglobin and high-sensitivity troponin T values (both p<0.01), and a trend towards more advanced kidney dysfunction. Patients with COPD exhibited a higher adjusted risk of reaching the primary endpoint of first HF hospitalization or CV death compared to those without COPD (adjusted hazard ratio [HR] 1.52, 95% confidence interval [95% CI] 1.28-1.80, p<0.0001). The favorable impact of empagliflozin on the primary outcome remained consistent regardless of COPD status at baseline (no COPD: HR 0.76, 95% CI 0.68-0.84, COPD: HR 0.82, 95% CI 0.66-1.03, p for interaction 0.50, Figure). The effects on HF hospitalizations, cardiovascular and all-cause mortality were not affected by COPD status. The Kansas City Cardiomyopathy Questionnaire showed similar improvement in patients with or without COPD treated with empagliflozin. The distribution of adverse events was comparable between patients receiving empagliflozin and those on placebo, irrespective of COPD status at baseline. Conclusions COPD is frequently encountered in patients with HF and associated with worse outcomes. Among patients with COPD, treatment with empagliflozin is associated with consistent efficacy on outcomes and improvement in quality of life as in patients without COPD.

P2X3 and P2X2/3 receptors inhibition produces a consistent analgesic efficacy: A systematic review and meta-analysis of preclinical studies

BackgroundP2X3 and P2X2/3 receptors are promising therapeutic targets for pain treatment and selective inhibitors are under evaluation in ongoing clinical trials. Here we aim to consolidate and quantitatively evaluate the preclinical evidence on P2X3 and P2X2/3 receptors inhibitors for pain treatment. MethodsA literature search was conducted in PubMed, Scopus and Web-of-Science on August 5, 2023. Data was extracted and meta-analyzed using a random-effects model to estimate the analgesic efficacy of the intervention; then several subgroup analyses were performed. Results67 articles were included. The intervention induced a consistent pain reduction (66.5 [CI95% = 58.5, 74.5]; p < 0.0001), which was highest for visceral pain (114.3), followed by muscle (79.8) and neuropathic pain (71.1), but lower for cancer (64.1), joint (57.5) and inflammatory pain (49.0). Further analysis showed a greater effect for mechanical hypersensitivity (70.4) compared to heat hypersensitivity (64.5) and pain-related behavior (54.1). Sex (male or female) or interspecies (mice or rats) differences were not appreciated (p > 0.05). The most used molecule was A-317491, but other such as gefapixant or eliapixant were also effective (p < 0.0001 for all). The analgesic effect was higher for systemic or peripheral administration than for intrathecal administration. Conversely, intracerebroventricular administration was not analgesic, but potentiated pain. ConclusionP2X3 and P2X2/3 receptor inhibitors showed a good analgesic efficacy in preclinical studies, which was dependent on the pain etiology, pain outcome measured, the drug used and its route of administration. Further research is needed to assess the clinical utility of these preclinical findings. Protocol registrationPROSPERO ID CRD42023450685.

Impact of Etiology on Efficacy Outcomes with Atezolizumab Plus Bevacizumab in Patients with Advanced Hepatocellular Carcinoma: A Multinational Retrospective Analysis in Asia-Pacific.

Atezolizumab-bevacizumab is a standard first-line treatment for unresectable hepatocellular carcinoma (uHCC). Given the diversity in HCC etiology and its potential impact on the tumor microenvironment, understanding how different liver disease etiologies affect treatment efficacy is important. We assessed the influence of liver disease etiology on the efficacy of atezolizumab-bevacizumab and evaluated changes in liver function during treatment with atezolizumab-bevacizumab. This study included 390 patients with uHCC treated with first-line atezolizumab-bevacizumab from Asan Medical Center, South Korea, and National Cancer Centre Singapore, Singapore from July 2016 to March 2023. Patients were classified to viral, metabolic dysfunction-associated liver disease (MASLD) and nonviral/non-MASLD groups. Albumin-bilirubin (ALBI) scores were recorded at baseline and every two cycles up to cycle six and at the time of disease progression. The majority of patients presented with viral etiologies (74.1%), and 17.2% had MASLD. Across etiological groups (viral versus MASLD versus nonviral/non-MASLD) no significant differences in objective response rate (23.2% versus 29.9% versus 23.5%, respectively; p = 0.515), progression-free survival (median 5.4 versus 7.7 versus 6.0 months; p = 0.320), and overall survival (18.1 versus 18.9 versus 14.4 months; p = 0.400) were observed. Among the patients with disease progression, ALBI scores at the time of progression were significantly higher than at baseline. Subsequent therapy was administered significantly less often to patients with ALBI grade 3 at disease progression compared with those with ALBI grades 1 or 2 (48.4% versus 78.8%, p = 0.002) CONCLUSIONS: Atezolizumab-bevacizumab demonstrates consistent efficacy regardless of HCC etiology, supporting its use as a first-line treatment across diverse patient populations. Liver function assessments remain crucial for managing therapy and predicting outcomes.

Ultra-low dose estradiol and dydrogesterone for the treatment of menopausal symptoms in a pooled, multi-ethnic population

ObjectivesEvidence suggests ethnicity-specific differences in postmenopausal symptoms, highlighting the need for therapies that are efficacious across different ethnicities. We evaluated the efficacy of an ultra-low dose combination of 0.5 mg estradiol and 0.25 mg dydrogesterone (E 0.5 mg/D 2.5 mg) in alleviating vasomotor symptoms across a multi-ethnic population. Study designData from two controlled trials were pooled to form a dataset of 583 postmenopausal women from across Europe and China. Participants were randomized to receive treatment with E 0.5 mg/D 2.5 mg or placebo for 12 weeks. Main outcome measuresThe main efficacy variable was absolute change in the number of hot flushes from baseline to end of treatment. Health-related quality of life and safety were also assessed. ResultsChange in the number of hot flushes per day was greater with E 0.5 mg/D 2.5 mg versus placebo (mean difference − 1.5, 95 % confidence interval − 2.1, −1.0; p < 0.001). Participants treated with E 0.5 mg/D 2.5 mg reported improvement in health-related quality of life (including psychological symptoms, vaginal dryness), and high amenorrhea rates. Combined E 0.5 mg/D 2.5 mg was well tolerated: there were no differences between groups in the percentage of participants with at least one serious adverse event or treatment-emergent serious adverse events. Analysis of change in body weight indicated no differences between groups. ConclusionsThis pooled analysis demonstrates the consistent efficacy of E 0.5 mg/D 2.5 mg in the treatment of menopause-related symptoms across a multi-ethnic population of postmenopausal women.

Effectiveness of Medhasagar Rasa® in Combating Aging-Associated Mild Neurocognitive Disorder: An Open-Label, Exploratory, Interventional Clinical Trial.

With the rising prevalence of neurocognitive disorders (NCDs) among the aging population, particularly in conditions like mild cognitive impairment (MCI), which often precedes dementia, there remains a significant gap in effective pharmacological interventions. This has generated interest in exploring alternative therapies to manage symptoms and enhance cognitive function in the aging population. The primary objective of this study was to evaluate the effect of Medhasagar Rasa® on cognitive functions, daily functioning, and quality of life in participants with aging-associated mild neurocognitive disorder using the Montreal Cognitive Assessment (MoCA) Scale, Ayurvedic Manasabhava Scale, and Brief Cognitive Rating Scale (BCRS). This open-label, interventional study at Karnatak Lingayat Education (KLE) Ayurveda Hospital, Belagavi, Karnataka, involved 32 screened participants, with 30 completing the study. Participants aged 50-70 years with MoCA scores of 18-25 received Medhasagar Rasa (2 tablets at bedtime, provided by M/s. Shree Dhootapapeshwar Limited, Mumbai, India) for 60 days. Assessments occurred at baseline and every 15 days until day 60. Thirty participants were recruited for the study after screening, all of whom completed the study. The median total MoCA score at baseline (visit one) was 20, which significantly improved to 25 by visit five (day 60±3) (p<0.001), indicating enhanced cognitive performance. The BCRS scores also showed significant improvement, with the median score decreasing from 12 to 7.5 (p<0.001) over 60 days. Anxiety symptoms were significantly reduced, with Hamilton Anxiety Rating Scale (HAM-A) scores dropping from 14 to 7 (p<0.001), while the Pittsburgh Sleep Quality Index (PSQI) scores indicated improved sleep quality, reducing from 9.5 to 7 (p<0.001). The Ayurvedic Manasabhava Scale also demonstrated a significant reduction in intensity (14 to 6; p<0.001) and frequency (13.5 to 6; p<0.001). Clinical Global Impression (CGI) scores showed stable illness severity, sustained global improvement, and consistent therapeutic efficacy. No adverse events were reported, and vital parameters remained normal throughout the study. Compliance with the medication was over 80%, and no significant changes were observed in laboratory values. Medhasagar Rasa effectively enhanced cognitive functions and alleviated anxiety and sleep disturbances in aging-related mild neurocognitive disorder, offering a promising therapeutic option.

An Exploration of the Role of Osteoclast Lineage Cells in Bone Tissue Engineering.

Bone defects because of age, trauma, and surgery, which are exacerbated by medication side effects and common diseases such as osteoporosis, diabetes, and rheumatoid arthritis, are a problem of epidemic scale. The present clinical standard for treating these defects includes autografts and allografts. Although both treatments can promote robust regenerative outcomes, they fail to strike a desirable balance of availability, side effect profile, consistent regenerative efficacy, and affordability. This difficulty has contributed to the rise of bone tissue engineering (BTE) as a potential avenue through which enhanced bone regeneration could be delivered. BTE is founded upon a paradigm of using biomaterials, bioactive factors, osteoblast lineage cells (ObLCs), and vascularization to cue deficient bone tissue into a state of regeneration. Despite promising preclinical results, BTE has had modest success in being translated into the clinical setting. One barrier has been the simplicity of its paradigm relative to the complexity of biological bone. Therefore, this paradigm must be critically examined and expanded to better account for this complexity. One potential avenue for this is a more detailed consideration of osteoclast lineage cells (OcLCs). Although these cells ostensibly oppose ObLCs and bone regeneration through their resorptive functions, a myriad of investigations have shed light on their potential to influence bone equilibrium in more complex ways through their interactions with both ObLCs and bone matrix. Most BTE research has not systematically evaluated their influence. Yet contrary to expectations associated with the paradigm, a selection of BTE investigations has demonstrated that this influence can enhance bone regeneration in certain contexts. In addition, much work has elucidated the role of many controllable scaffold parameters in both inhibiting and stimulating the activity of OcLCs in parallel to bone regeneration. Therefore, this review aims to detail and explore the implications of OcLCs in BTE and how they can be leveraged to improve upon the existing BTE paradigm.

Quantitative predictive model for screening optimal processing methods of Polygonati rhizoma

Polygonati rhizoma (Huangjing in Chinese) is a common clinical tonic with the traditional effects of tonifying Qi, nourishing Yin. However, the lack of precise control of processing parameters has led to the uneven quality of processed Huangjing. A prediction model using the CRITIC method optimizes processing by correlating method, component contents, and biological activity, ensuring consistent quality and efficacy.

Local Antibiotic Infusion in Periprosthetic Joint Infection Following Total Hip Arthroplasty.

Local antibiotic infusion has emerged as a promising adjunctive therapy, delivering high concentrations of antibiotics directly to the infection site. This approach aims to enhance eradication of pathogens while minimizing systemic side effects associated with prolonged antibiotic use. This narrative review encompassed 10 articles focused on all three procedures of surgical intervention for periprosthetic joint injection (PJI) following total hip arthroplasty (THA): debridement, antibiotics, and implant retention (DAIR), single-stage revision arthroplasty, and two-stage revision arthroplasty. Recent studies report success rates ranging from 90 to 100% in patients undergoing DAIR, 82 to 100% in single-stage revision arthroplasty, and 80% in two-stage revision arthroplasty. The adjunctive use of local antibiotic infusion alongside surgical treatment for PJI following THA provides high success rates and is associated with low systemic complications, such as renal toxicity. Further research, particularly high-quality randomized controlled trials (RCTs), is warranted to validate and refine treatment protocols, ensuring consistent efficacy and safety.

Rapid and Sustained Effect of Ixekizumab on Patient Global, Spinal Pain, Stiffness, and Fatigue in Chinese Patients with Radiographic Axial Spondyloarthritis.

Ixekizumab, an interleukin 17A (IL-17A) inhibitor, has demonstrated rapid and sustained improvement in the signs and symptoms in patients with active radiographic axial spondyloarthritis (r-axSpA) in global and Chinese populations. We studied the effect of ixekizumab on patient-reported outcomes (PROs) (including patient global, spinal pain, stiffness, and fatigue) and overall health-related quality of life (HRQoL) of ixekizumab in the phase3 study in China. In this Chinese phase3, randomized, double-blind, placebo-controlled study, patients with r-axSpA were randomized (1:1) to receive ixekizumab 80mg every 4weeks (IXEQ4W; starting dose 160mg) or placebo for 16weeks. At week16, patients receiving placebo were switched to IXEQ4W, and those receiving IXEQ4W continued, until week52. Data for patient global, spinal pain, spinal pain at night, stiffness, and fatigue were collected through week52. Minimally clinical important differences (MCIDs) were determined for spinal pain and spinal pain at night. The subgroup analyses by baseline disease duration since diagnosis and baseline C-reactive protein (CRP) level were conducted post hoc. Compared with placebo, patients treated with IXEQ4W reported significantly greater improvement with a rapid onset in changes from baseline of PROs (patient global, spinal pain, spinal pain at night, stiffness, and fatigue) through week16. Improvements were maintained through week52. A similar trend of improvement was also observed in MCID response in spinal pain and spinal pain at night. The improvement in overall HRQoL was supported by EQ-5D-5L assessment. Subgroup analyses demonstrated that IXEQ4W provided significantly greater efficacy at week16 compared with placebo, irrespective of baseline disease duration or baseline CRP level. IXEQ4W provided rapid and sustained improvement in clinically relevant PROs and overall HRQoL through 1-year treatment in Chinese patients with r-axSpA. Regardless of the baseline disease duration or baseline CRP level, consistent efficacy was observed. ClinicalTrials.gov identifier NCT04285229.

Single and combined strategies for mesenchymal stem cell exosomes alleviate liver fibrosis: a systematic review and meta-analysis of preclinical animal models.

Background: The efficacy of mesenchymal stem cells (MSCs) in treating liver fibrosis has been supported by various clinical studies. However, stem cell transplantation is limited in clinical application due to its low survival rate, low liver implantation rate, and possible carcinogenicity. Recently, there has been increasing interest in the use of MSC-exos due to their widespread availability, low immunogenicity, and non-carcinogenic properties. Numerous studies have demonstrated the potential of MSC-exos in treating liver fibrosis and preventing progression to end-stage liver disease. Objective: This study aimed to systematically investigate the efficacy of MSC-exos single administration in the treatment of hepatic fibrosis and the combined advantages of MSC-exos in combination with drug therapy (MSC-exos-drugs). Methods: Data sources included PubMed, Web of Science, Embase, and the Cochrane Library, which were built up to January 2024. The population, intervention, comparison, outcomes, and study design (PICOS) principle was used to screen the literature, and the quality of the literature was evaluated to assess the risk of bias. Finally, the data from each study's outcome indicators were extracted for a combined analysis. Results: After screening, a total of 18 papers (19 studies) were included, of which 12 involved MSC-exos single administration for the treatment of liver fibrosis and 6 involved MSC-exos-drugs for the treatment of liver fibrosis. Pooled analysis revealed that MSC-exos significantly improved liver function, promoted the repair of damaged liver tissue, and slowed the progression of hepatic fibrosis and that MSC-exos-drugs were more efficacious than MSC-exos single administration. Subgroup analyses revealed that the use of AD-MSC-exos resulted in more consistent and significant efficacy when MSC-exos was used to treat hepatic fibrosis. For MSC-exos-drugs, a more stable end result is obtained by kit extraction. Similarly, infusion through the abdominal cavity is more effective. Conclusion: The results suggest that MSC-exos can effectively treat liver fibrosis and that MSC-exos-drugs are more effective than MSC-exos single administration. Although the results of the subgroup analyses provide recommendations for clinical treatment, a large number of high-quality experimental validations are still needed. Systematic Review Registration: CRD42024516199.

The galectin-3 inhibitor selvigaltin reduces liver inflammation and fibrosis in a high fat diet rabbit model of metabolic-associated steatohepatitis.

Galectin-3 is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. Selvigaltin (previously known as GB1211) is a novel orally active galectin-3 small molecule inhibitor that has high affinity for galectin-3 (human KD = 25nM; rabbit KD = 12nM) and high oral bioavailability in rabbits and man. In this study the efficacy of selvigaltin was investigated in a high fat diet (HFD) rabbit model of metabolic-associated steatohepatitis (MASH). Male New Zealand White rabbits were individually caged under standard conditions in a temperature and humidity-controlled room on a 12h light/darkness cycle. After 1week of regular diet (RD), rabbits were randomly assigned for 8 or 12weeks to different groups: RD/vehicle, RD/selvigaltin, HFD (8weeks), HFD/vehicle and HFD/selvigaltin (0.3, 1.0, 5.0 or 30mg/kg selvigaltin with vehicle/selvigaltin p.o. dosed therapeutically q.d. 5days per week from week 9 or 12). Liver inflammation, steatosis, ballooning, and fibrosis was measured via blood metabolic markers, histomorphological evaluation [Oil Red O, Giemsa, Masson's trichome, picrosirius red (PSR) and second harmonic generation (SHG)], and mRNA and protein expression. Steatosis, inflammation, ballooning, and fibrosis were all increased from RD to HFD/vehicle groups. Selvigaltin demonstrated target engagement by significantly decreasing galectin-3 levels in the liver as measured via immunohistochemistry and mRNA analysis. Selvigaltin dose-dependently reduced biomarkers of liver function (AST, ALT, bilirubin), inflammation (cells foci), and fibrosis (PSR, SHG), as well as decreasing the mRNA and protein expression of several key inflammation and fibrosis biomarkers (e.g., IL6, TGFβ3, SNAI2, collagen). Doses of 1.0 or 5.0mg/kg demonstrated consistent efficacy across most biological endpoints supporting the current clinical doses of selvigaltin being investigated in liver disease. Selvigaltin significantly reduced hepatic inflammation and fibrosis in an HFD rabbit model of MASH following therapeutic dosing for 4 weeks in a dose-dependent manner. These data support the human selvigaltin dose of 100mg b.i.d. that has been shown to reduce key liver biomarkers during a clinical study in liver cirrhosis.

Consistency of Spleen and Symptom Reduction Regardless of Cytopenia in Patients With Myelofibrosis Treated With Pacritinib

BackgroundPacritinib is a JAK2/IRAK1/ACVR1 inhibitor that is approved in the United States for the treatment of patients with myelofibrosis who have a platelet count < 50 × 109/L. Phase 3 clinical studies of pacritinib included patients across a wide range of baseline platelet and hemoglobin levels. Patients and MethodsIn order to assess the impact of baseline blood counts on pacritinib efficacy, an analysis of efficacy outcomes by baseline platelet and hemoglobin levels was performed using data pooled from 2 Phase 3 studies of pacritinib in patients with MF (PERSIST-1 and PERSIST-2). ResultsOf 276 patients evaluable for spleen response, spleen volume reduction occurred consistently across platelet subgroups (< 100 × 109/L or ≥ 100 × 109/L) and hemoglobin subgroups (< 8 g/dL, ≥ 8 to < 10 g/dL, or > 10 g/dL), with no diminution in treatment effect in patients with severe thrombocytopenia or anemia. Among 159 patients evaluable for symptoms response, improvement in total symptom score (TTS) was similar across platelet subgroups. A ≥ 50% improvement of TSS occurred more frequently in patients with baseline hemoglobin < 8 g/dL compared with those with baseline hemoglobin ≥ 8 to < 10 g/dL or > 10 g/dL. Patients with baseline hemoglobin < 8 g/dL also experienced improved hemoglobin sustained over 24 weeks, whereas subgroups with less severe anemia had stable hemoglobin levels over time. Symptom improvement as assessed using the Patient Global Impression of Change instrument was generally consistent across platelet and hemoglobin subgroups. ConclusionPacritinib demonstrates consistent efficacy in patients with MF regardless of baseline platelet and hemoglobin counts.

Consistent efficacy and safety of sublingual immunotherapy tablets across allergens and geographic regions.

Background: The clinical development program of the SQ grass, ragweed, tree, and house dust mite (HDM) sublingual immunotherapy (SLIT)-tablets for allergic rhinitis/conjunctivitis (AR/C) included clinical trials conducted in North America, Europe, and Japan. Objective: Data from these trials were analyzed to assess efficacy, immunologic mechanisms, and safety outcomes across allergens and geographic regions. Methods: Thirteen phase III, double-blind, placebo controlled trials in the subjects with AR/C were conducted in North America, Europe (including Russia), and Japan (N = 7763 analyzed). Trials were generally similar with respect to medical practice, target population, eligibility criteria, and efficacy and safety monitoring. Data were analyzed for the approved doses in North America and Europe. Four statistical models were used to enhance comparison of the efficacy end points among the trials. Results: The SLIT-tablets demonstrated consistent efficacy across allergens and regions, regardless of the statistical analysis used. Relative improvement in the primary efficacy end point compared with placebo by using the predefined protocol analysis ranged from 17.9% to 32.8%, 17.5% to 19.3%, 20.6% to 38.3%, and 39.6% with the grass, HDM, ragweed, and tree SLIT-tablets, respectively. The kinetics of specific immunoglobulin E (IgE) and IgG4 responses were similar among the allergens and regions. Local application-site reactions were the most common adverse events for all allergens and in all regions. Most treatment-related adverse events for all allergens and in all regions were mild in severity. The rate of systemic allergic reactions was similar across regions (0%-0.54%). Conclusion: Confirmatory phase III trials for SLIT-tablets in the treatment of AR/C showed consistent efficacy, immunologic, and safety outcomes across allergens and geographic regions.

Unraveling School Adolescent Depression: Insights into Cognitive Behavioral Therapy

Adolescent depression presents a significant global mental health concern, exerting profound impacts on various facets of young people's lives. Cognitive Behavioral Therapy (CBT) has emerged as a leading intervention for tackling adolescent depression, grounded in principles derived from cognitive theory. This review delves into the effectiveness, mechanisms, and outcomes of CBT in addressing adolescent depression, synthesizing findings from a range of empirical studies including randomized controlled trials, meta-analyses, and systematic reviews. The review underscores the consistent efficacy of CBT in diminishing depressive symptoms among adolescents, elucidating mechanisms such as cognitive restructuring and behavioral activation that underpin its therapeutic effects. Additionally, CBT yields favorable outcomes beyond mere symptom reduction, encompassing enhancements in social connections and academic performance. Nonetheless, challenges such as limited accessibility and hurdles in engaging adolescents persist in CBT implementation. To surmount these obstacles, forthcoming research ought to concentrate on devising innovative delivery approaches, such as internet-based interventions and school-centered programs. In essence, CBT stands as a pivotal component in the treatment of adolescent depression, furnishing a holistic framework to address the intricate interplay of cognitive, emotional, and behavioral elements, thereby fostering the mental well-being of adolescents on a global scale.