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Chimeric antigen receptor (CAR) T-cell therapy is a human gene therapy product where T cells from a patient are genetically modified to enable them to recognize desired target antigen(s) more effectively. In recent years, promising antitumor activity has been seen with autologous CAR T cells. Since 2017, six CAR T-cell therapies for the treatment of hematological malignancies have been approved by the Food and Drug Administration (FDA). Despite the rapid progress of CAR T-cell therapies, considerable statistical challenges still exist for this category of products across all phases of clinical development that need to be addressed. These include (but not limited to) dose finding strategy, implementation of the estimand framework, use of real-world data in contextualizing single-arm CAR T trials, analysis of safety data and long-term follow-up studies. This paper is the first step in summarizing and addressing these statistical hurdles based on the development of the six approved CAR T-cell products. [ABSTRACT FROM AUTHOR]

The digital revolution in healthcare, amplified by the COVID-19 pandemic and artificial intelligence (AI) advances, has led to a surge in the development of digital technologies. However, integrating digital health solutions, especially AI-based ones, in rare diseases like Waldenström macroglobulinemia (WM) remains challenging due to limited data, among other factors. CURATE.AI, a clinical decision support system, offers an alternative to big data approaches by calibrating individual treatment profiles based on that individual's data alone. We present a case study from the PRECISE CURATE.AI trial with a WM patient, where, over two years, CURATE.AI provided dynamic Ibrutinib dose recommendations to clinicians (users) aimed at achieving optimal IgM levels. An 80-year-old male with newly diagnosed WM requiring treatment due to anemia was recruited to the trial for CURATE.AI-based dosing of the Bruton tyrosine kinase inhibitor Ibrutinib. The primary and secondary outcome measures were focused on scientific and logistical feasibility. Preliminary results underscore the platform's potential in enhancing user and patient engagement, in addition to clinical efficacy. Based on a two-year-long patient enrollment into the CURATE.AI-augmented treatment, this study showcases how AI-enabled tools can support the management of rare diseases, emphasizing the integration of AI to enhance personalized therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Early-stage hepatocellular carcinoma (HCC) is notorious for its high recurrence rate even after curative treatment. Several studies have suggested the association between diabetes mellitus (DM) and the risk of HCC. However, current evidence regarding the impact of glycemic burden on the outcomes of HCC is still limited. The present study provides an important insight into the relationship between glycemic burden and outcomes of early-stage HCC. Lower glycemic burden was an independent factor associated with better overall survival as well as lower recurrence in early-stage HCC. Moreover, there was a dose–response relationship between recurrence/overall survival and glycemic burden. Good glycemic control should be considered as a significant part of HCC management. Early-stage hepatocellular carcinoma (HCC) is still difficult to cure for its high recurrence rate. This study aimed to examine whether glycemic burden management could be one way to improve outcomes of early-stage HCC. A total of 137 very early or early-stage HCC patients who underwent resection or ablation at Samsung Medical Center and had glycemic burden assessment were analyzed. Glycemic burden was assessed using hemoglobin A1c (HbA1c) level. Outcomes were recurrence and overall survival. Risks of recurrence and overall survival were compared according to glycemic burden using a cut-off point of 6.5% or two cut-off points of 6.0% and 7.5%. Overall, 51 (37.2%) patients experienced HCC recurrence. The adjusted hazard ratio (aHR) for recurrence comparing patients with HbA1c > 6.5% to those with HbA1c ≤ 6.5% was 2.66 (95% CI: 1.26–5.78). The risk of recurrence increased in a dose-dependent manner by glycemic burden; aHR for 6.0 < HbA1c ≤ 7.5%: 2.00 (95% CI: 0.78–5.55); aHR for HbA1c > 7.5%: 6.05 (95% CI: 2.31–17.5). Mortality was observed in 16 (11.7%) patients. The risk of mortality was higher for HbA1c > 6.5% than for HbA1c ≤ 6.5% (aHR: 2.33; 95% CI: 1.10–5.08). There was also a dose–response relationship between overall survival and glycemic burden. Glycemic burden assessed using HbA1c level was significantly associated with outcomes of early-stage HCC patients. Good glycemic control could be a therapeutic goal to improve clinical outcomes in these populations. [ABSTRACT FROM AUTHOR]

Phytolacca dodecandra (L' Herit), or 'Endod', is one of the widely known medicinal plants in Ethiopia. Berries of the endod have been used as a detergent for centuries. The present study was aimed to test the hepatoprotective effects of the plant against acetaminophen (APAP)-induced liver injury in rats. Mice of either sex were used for oral acute toxicity tests and APAP-induced lethality tests. Hepatoprotective experiments were done on male rats using 2 g/kg of APAP to induce liver damage. Liver enzymes, total bilirubin (TB), and lipid profile were determined. Liver tissues were also examined histopathologically to see a morphologic change in the control and experiment groups. The protective effect of the plant extract was also tested through sodium pentobarbital (SPB)-induced sleeping time. A significant increase in serum levels of liver enzymes, TB, low-density lipoprotein (LDL), and triglycerides (TGs) was seen from oral administration of 2 g/kg APAP. Total cholesterol (TC) and high-density lipoprotein (HDL) levels were decreased. Serum levels of all parameters were reversed to normal after administration of silymarin 100 mg/kg and, 100, 200, and 400 mg/kg doses of the extract. A significant dose-dependent hepatoprotective effect of Phytolacca dodecandra Methanol Root Extract (PDME) was seen in terms of LDL. Histopathological investigations and SPB-induced sleeping time confirmed the findings of biochemical analysis. The findings of the present study indicate that PDME protected the liver from APAP injury. [ABSTRACT FROM AUTHOR]

Simple Summary: High-dose post-transplant cyclophosphamide is effective in preventing graft-versus-host disease (GVHD) but is associated with adverse outcomes such as delayed engraftment, infections, and cardiac issues. This pilot study evaluated the efficacy and toxicity of reduced-dose PTCY (40 mg/kg/day) in patients undergoing HLA-matched allogeneic hematopoietic stem cell transplantation (alloHSCT). Neutrophil and platelet engraftment occurred at medians of 15 and 16 days, respectively. At day 100, the incidences of grade II–IV and III–IV acute GVHD were 18.2% and 4.5%, respectively, with no cases of grade IV acute GVHD or steroid-refractory disease. One-year incidence of moderate-severe chronic GVHD was 6.4%. Both incidences, acute GVHD and chronic GVHD, are similar to our previous experience with higher doses of PTCY. Two-year overall survival and relapse-free survival were 77.1% and 58.3%. There were low incidences of infections and only one early cardiac event. These results suggest that reduced-dose PTCY provides adequate immunosuppression with a low toxicity profile. PTCY 50 mg/kg/day on days +3/+4 is an excellent strategy to prevent GVHD. However, its use is associated with adverse outcomes such as delayed engraftment, increased risk of infection, and cardiac complications. This pilot study evaluates the efficacy and toxicity of a reduced dose of PTCY (40 mg/kg/day) combined with tacrolimus in 22 peripheral blood HLA-matched alloHSCT patients. At day +100, the cumulative incidences of grade II–IV and III–IV acute GVHD were 18.2% and 4.5%, respectively. No grade IV acute GVHD or steroid-refractory disease was observed. The cumulative incidences of all-grade and moderate-severe chronic GVHD at 1-year were 11.4% and 6.4%, respectively. No patient died from transplant-related complications. Two-year OS and RFS were 77.1% and 58.3%, respectively. All patients engrafted, with neutrophil and platelet recovery occurring at a median of 15 (IQR 14–16) and 16 days (IQR 12–23), respectively. The cumulative incidences of bloodstream bacterial infections, polyomavirus BK hemorrhagic cystitis, HHV6 reactivation, CMV reactivation, and fungal infections were 13.6%, 9.1%, 9.1%, 4.6%, and 6%, respectively. Only one early cardiac event was observed. These results suggest that PTCY 40 mg/kg/day on a +3/+4 schedule provides adequate immunosuppression to allow for engraftment and prevent clinically significant GVHD with a low toxicity profile. [ABSTRACT FROM AUTHOR]

Background: Silver nanoparticles (AgNPs) are receiving a lot of attention as a prospective antibacterial agent for use in caries prevention. The objective of this study was to investigate the bioactivity and antibacterial effect of silver nanoparticles biosynthesized using Star Anise against Streptococcus mutans (S.mutans). Methods: The bioactive components of the Star Anise were assessed by employing the gas chromatography-mass spectrometry technique. The antibacterial activities of Star Anise Biosynthesized Silver Nanoparticles against S.mutans bacteria were evaluated using Bauer and Kirby's disc diffusion mechanism and the minimum inhibitory concentration. Results: Silver nanoparticles biosynthesized using Star Anise revealed high antioxidant activity. AgNPs inhibited S. mutans with a 16 mm inhibition zone diameter and demonstrated an 80 µg/ml minimum inhibitory concentration. Conclusions: Biologically synthesized AgNPs made from aqueous extract of Star anise appear to be a potential and effective bactericidal agent against S.mutans that can be used to prevent dental caries. [ABSTRACT FROM AUTHOR]

Background: This study investigated the optimal concentration of ropivacaine epidural anesthesia for clinical use in percutaneous transforaminal endoscopic discectomy (PTED) by comparing the effects of different concentrations. Methods: Seventy patients scheduled for their first PTED procedure were enrolled in this randomized controlled trial. Patients were randomized to receive ropivacaine at varying concentrations (0.3% or 0.4%). Primary outcome measures included the numeric rating scale (NRS) and hip extension level (HEL). Secondary outcome measures included intraoperative fentanyl dosage and postoperative complications. Results: One patient withdrew due to severe postoperative complications. The remaining 69 patients were allocated to the 0.3% (n = 34) and 0.4% (n = 35) groups, respectively. Baseline characteristics showed no significant differences between the two groups (P > 0.05). The NRS score was significantly lower in the 0.4% group than in the 0.3% group (P < 0.01), whereas the HEL score was significantly higher (P < 0.001). The average fentanyl dose in the 0.4% group was significantly lower than that in the 0.3% group (P < 0.01). Postoperative complications occurred in five and two patients in the 0.3% and 0.4% groups, respectively. Conclusion: Although 0.4% ropivacaine (20 mL) impacts muscle strength, it does not impede PTED surgery. Given its effective analgesic properties and few postoperative complications, 0.4% ropivacaine can be considered a preferred dose for PTED. Trial registration: This study was registered with the Chinese Clinical Trials Registry (Registration number: ChiCTR2200060364; Registration Date: 29/5/2022) and on chictr.org.cn (https://www.chictr.org.cn/showproj.html?proj=171002). [ABSTRACT FROM AUTHOR]

Simple Summary: In contrast to external beam radiation therapy, our understanding of the dose–response relationship in radiopharmaceutical therapy (RPT) remains limited. Given that the estimation of radiation-induced deoxyribonucleic acid (DNA) damage can correlate with various biological responses, nanoscale dosimetry emerges as a critical tool in lighting this intricate relationship. In this study, we developed a novel simulation-based nanoscale dosimetry platform by identifying optimal DNA physics models and benchmarking against existing data. Leveraging this platform, we conducted a case study to estimate DNA damage, thereby enhancing our comprehension of RPT effects at nanoscales. This research serves as a foundation for future studies on how RPT affects DNA at the nano-level, potentially improving cancer treatment strategies. Radiopharmaceutical therapy (RPT) is evolving as a promising strategy for treating cancer. As interest grows in short-range particles, like Auger electrons, understanding the dose–response relationship at the deoxyribonucleic acid (DNA) level has become essential. In this study, we used the Geant4-DNA toolkit to evaluate DNA damage caused by the Auger-electron-emitting isotope I-125. We compared the energy deposition and single strand break (SSB) yield at each base pair location in a short B-form DNA (B-DNA) geometry with existing simulation and experimental data, considering both physical direct and chemical indirect hits. Additionally, we evaluated dosimetric differences between our high-resolution B-DNA target and a previously published simple B-DNA geometry. Overall, our benchmarking results for SSB yield from I-125 decay exhibited good agreement with both simulation and experimental data. Using this simulation, we then evaluated the SSB and double strand break (DSB) yields caused by a theranostic Br-77-labeled poly ADP ribose polymerase (PARP) inhibitor radiopharmaceutical. The results indicated a predominant contribution of chemical indirect hits over physical direct hits in generating SSB and DSB. This study lays the foundation for future investigations into the nano-dosimetric properties of RPT. [ABSTRACT FROM AUTHOR]

Background: Rising resistance to antimicrobials, particularly in the case of methicillin-resistant Staphylococcus aureus (MRSA), represents a formidable global health challenge. Consequently, it is imperative to develop new antimicrobial solutions. This study evaluated 68 Chinese medicinal plants renowned for their historical applications in treating infectious diseases. Methods: The antimicrobial efficacy of medicinal plants were evaluated by determining their minimum inhibitory concentration (MIC) against MRSA. Safety profiles were assessed on human colorectal adenocarcinoma (Caco-2) and hepatocellular carcinoma (HepG2) cells. Mechanistic insights were obtained through fluorescence and transmission electron microscopy (FM and TEM). Synergistic effects with vancomycin were investigated using the Fractional Inhibitory Concentration Index (FICI). Results: Rheum palmatum L., Arctium lappa L. and Paeonia suffructicosaas Andr. have emerged as potential candidates with potent anti-MRSA properties, with an impressive low MIC of 7.8 µg/mL, comparable to the 2 µg/mL MIC of vancomycin served as the antibiotic control. Crucially, these candidates demonstrated significant safety profiles when evaluated on Caco-2 and HepG2 cells. Even at 16 times the MIC, the cell viability ranged from 83.3% to 95.7%, highlighting their potential safety. FM and TEM revealed a diverse array of actions against MRSA, such as disrupting the cell wall and membrane, interference with nucleoids, and inducing morphological alterations resembling pseudo-multicellular structures in MRSA. Additionally, the synergy between vancomycin and these three plant extracts was evident against MRSA (FICI < 0.5). Notably, aqueous extract of R. palmatum at 1/4 MIC significantly reduced the vancomycin MIC from 2 µg/mL to 0.03 µg/mL, making a remarkable 67-fold decrease. Conclusions: This study unveil new insights into the mechanistic actions and pleiotropic antibacterial effectiveness of these medicinal plants against resistant bacteria, providing robust evidence for their potential use as standalone or in conjunction with antibiotics, to effectively combat antimicrobial resistance, particularly against MRSA. [ABSTRACT FROM AUTHOR]

Iron nanoparticles comprise a significant class of inorganic nanoparticles, which discover applications in various zones by prudence of their few exciting properties. This study achieved the green synthesis of iron oxide nanoparticles (IONPs) by black cumin seed (Nigella sativa) extract, which acts as a reducing and capping agent. The iron nanoparticles and black cumin extract were synthesized in three different concentrations: (01:01, 02:04,01:04). UV-visible spectroscopy, XRD, FTIR, and AFM characterized the synthesized iron oxide nanoparticles. UV-visible spectra show the maximum absorbance peak of 01:01 concentration at 380 nm. The other concentrations, such as 02:04, peaked at 400 nm and 01:04 at 680 nm, confirming the formation of iron oxide nanoparticles. AFM analysis reveals the spherical shape of iron oxide nanoparticles. The XRD spectra reveal the (fcc) cubic crystal structure of the iron oxide nanoparticles. The FTIR analysis's peaks at 457.13, 455.20, and 457.13 cm-1 depict the characteristic iron nanoparticle synthesis. The black cumin extract-mediated iron oxide nanoparticles show substantial antibacterial, antifungal, antioxidant and anti-inflammatory activity in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

The present study aimed to assess the anti-leishmanial effects of curcumin nanoemulsion (CUR-NE) against Leishmania major (MRHO/IR/75/ER) in both in vitro and in vivo experiments. CUR-NE was successfully prepared via the spontaneous emulsification method. The in vitro effect of various concentrations of CUR-NE against L. major promastigotes was assessed using the flow cytometry method. In vivo experiments were carried out in BALB/c mice inoculated subcutaneously with 2 × 106 L. major promastigotes. Mice were treated with topical CUR-NE (2.5 mg/ml), intra-lesion injection of CUR-NE (2.5 mg/ml), topical CUR suspension (CUR-S, 2.5 mg/ml), topical NE without CUR (NE-no CUR), amphotericin B as the positive control group, and infected untreated mice as the negative control group. In vitro exposure of promastigotes to CUR-NE showed a dose-dependent anti-leishmanial effect, with a 67.52 ± 0.35% mortality rate at a concentration of 1250 µg/ml and an IC50 of 643.56 µg/ml. In vivo experiments showed that topical CUR-NE and CUR-S significantly decreased the mean lesion size in mice after four weeks from 4.73 ± 1.28 to 2.78 ± 1.28 mm and 4.45 ± 0.88 to 3.23 ± 0.59 mm, respectively (p = 0.001). Furthermore, CUR-NE significantly decreased the parasite load in treated mice compared with the negative control group (p = 0.001). Results from the current study demonstrated the promising activity of CUR-NE against L. major in both in vitro and in vivo experiments. Moreover, CUR-NE was more efficient than CUR-S in healing and reducing parasite burden in mouse models. Future studies should aim to identify molecular mechanisms as well as the pharmacologic and pharmacokinetic aspects of CUR-NE. [ABSTRACT FROM AUTHOR]

Simple Summary: In this work, we evaluated the need for frequent laboratory assessments in patients with metastatic renal cell carcinoma treated with nivolumab and nivolumab+ipilimumab during the TITAN-RCC clinical trial. We analysed how often reached criteria for dose delay or permanent discontinuation of therapy would have been missed if the frequency of laboratory testing had been reduced, in order to avoid over-sampling patients and to optimise clinical workflow and staffing. Our study showed that if the frequency of laboratory tests had been reduced, reached dose delay criteria would hardly have been missed. This would have affected up to 1% (2/207) of patients. An exception was dose delay due to the elevation of lipase blood levels which would have been missed in up to 7% (15/207) of patients. However, these patients presented with symptoms and would have been identified based thereupon. Discontinuation criteria would have only been overlooked for lipase (2% [4/207] of patients) and amylase (0.5% [1/207] of patients). Again, these patients would have been identified, since only symptomatic patients would have needed to discontinue treatment due to amylase or lipase laboratory values. In conclusion, in asymptomatic patients in our setting, laboratory analyses do not seem to be necessary before every treatment application. In clinical trials, laboratory values are assessed with high frequency. This can be stressful for patients, resource intensive, and difficult to implement, for example in office-based settings. In the prospective, multicentre phase 2 TITAN-RCC trial (NCT02917772), we investigated how many relevant changes in laboratory values would have been missed if laboratory values had been assessed less frequently. Patients with metastatic renal cell carcinoma (n = 207) received a response-based approach with nivolumab and nivolumab+ipilimumab boosts for non-response. We simulated that laboratory values were obtained before every second dose instead of every dose of the study drug(s). We assessed elevated leukocyte counts, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, amylase, lipase, and thyroid-stimulating hormone. Dose delay and discontinuation criteria were defined according to the study protocol. With the reduced frequency of laboratory analyses, dose delay criteria were rarely missed: in a maximum of <0.1% (3/4382) of assessments (1% [2/207] of patients) during nivolumab monotherapy and in a maximum of 0.2% (1/465) of assessments (1% [1/132] of patients) during nivolumab+ipilimumab boosts. An exception was lipase-related dose delay which would have been missed in 0.6% (25/4204) of assessments (7% [15/207] of patients) during nivolumab monotherapy and in 0.8% (4/480) of assessments (3% [4/134] of patients) during nivolumab+ipilimumab boosts, but would have required the presence of symptoms. Discontinuation criteria would have only been missed for amylase (<0.1% [1/3965] of assessments [0.5% (1/207) of patients] during nivolumab monotherapy, none during nivolumab+ipilimumab boosts) and lipase (0.1% [5/4204] of assessments [2% (4/207) of patients] during nivolumab monotherapy; 0.2% [1/480] of assessments [0.7% (1/134) of patients] during nivolumab+ipilimumab boosts). However, only symptomatic patients would have had to discontinue treatment due to amylase or lipase laboratory values. In conclusion, a reduced frequency of laboratory testing appears to be acceptable in asymptomatic patients with metastatic renal cell carcinoma treated with nivolumab or nivolumab+ipilimumab. [ABSTRACT FROM AUTHOR]

Simple Summary: Gorlin syndrome (GS) is a genetic disorder characterized by multiple basal cell carcinomas (BCCs) due to mutations in the hedgehog signaling pathway. Patients with GS may need dozens or even hundreds of surgical procedures in their lifetime, which can leave them severely scarred, deformed, and disfigured. In 16 patients with GS, we examined the effectiveness, safety, and length of response to oral hedgehog inhibitors. According to our retrospective study, sonidegib inhibited the growth of both newly diagnosed and pre-existing basal cell carcinomas more successfully and safely than vismodegib. Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome (GS), is a genetic disorder characterized by the development of multiple cutaneous BCCs due to mutations in the hedgehog signaling pathway. The use of hedgehog pathway inhibitors—vismodegib and sonidegib—has emerged as a promising therapeutic strategy for managing BCCs in individuals with GS. In a retrospective study conducted between March 2012 and January 2024, a cohort of 16 Gorlin syndrome patients who received treatment with either sonidegib or vismodegib were analyzed. The primary objectives of the study were to evaluate the efficacy, safety profile, and duration of response to oral hedgehog inhibitors in this patient population. The study assessed various parameters, including the number of new BCCs that developed before and after treatment initiation, the duration and sustainability of treatment responses, as well as the incidence of adverse effects associated with hedgehog inhibitor therapy. The findings of the study revealed that sustained treatment with hedgehog inhibitors could effectively suppress the progression of both new and existing BCCs. Furthermore, the results indicated that sonidegib exhibited superior efficacy and safety compared to vismodegib in the treatment of BCCs in individuals with GS. Notably, adjustments to the administration schedule of sonidegib were found to improve tolerability without compromising therapeutic efficacy, potentially leading to prolonged durations of treatment response and disease control. [ABSTRACT FROM AUTHOR]

In the past few decades, there has been a notable rise in the occurrence of several types of candidiasis. Candida albicans is the most common cause of superficial fungal infections in humans. In this study, plumieride, one of the major iridoids from Plumeria obtusa L. leaves, was isolated and investigated for its potential against Candida albicans (CA)-induced dermatitis in mice. qRT-PCR was done to assess the impact of plumieride on the expression of the major virulence genes of CA. Five groups (n = 7) of adult male BALB/c mice were categorized into: group I: non-infected mice; group II: mice infected intradermally with 107–108 CFU/mL of CA; group III: CA-infected mice treated with standard fluconazole (50 mg/kg bwt.); group IV and V: CA-infected mice treated with plumieride (25- and 50 mg/kg. bwt., respectively). All the treatments were subcutaneously injected once a day for 3 days. Skin samples were collected on the 4th day post-inoculation to perform pathological, microbial, and molecular studies. The results of the in vitro study proved that plumieride has better antifungal activity than fluconazole, manifested by a wider zone of inhibition and a lower MIC. Plumieride also downregulated the expression of CA virulence genes (ALS1, Plb1, and Hyr1). CA-infected mice showed extensive dermatitis, confirmed by strong iNOS, TNF-α, IL-1β, and NF-κB genes or immune expressions. Whereas the treatment of CA-infected mice with plumieride significantly reduced the microscopic skin lesions and modulated the expression of all measured proinflammatory cytokines and inflammatory markers in a dose-dependent manner. Plumieride interfered with the expression of C. albicans virulence factors and modulated the inflammatory response in the skin of mice infected with CA. [ABSTRACT FROM AUTHOR]

A novel regression model, monotonic inner relation-based non-linear partial least squares (MIR-PLS), is proposed to address complex issues like limited observations, multicollinearity, and nonlinearity in Chinese Medicine (CM) dose-effect relationship experimental data. MIR-PLS uses a piecewise mapping function based on monotonic cubic splines to model the non-linear inner relations between input and output score vectors. Additionally, a new weight updating strategy (WUS) is developed by leveraging the properties of monotonic functions. The proposed MIR-PLS method was compared with five well-known PLS variants: standard PLS, quadratic PLS (QPLS), error-based QPLS (EB-QPLS), neural network PLS (NNPLS), and spline PLS (SPL-PLS), using CM dose-effect relationship datasets and near-infrared (NIR) spectroscopy datasets. Experimental results demonstrate that MIR-PLS exhibits general applicability, achieving excellent predictive performances in the presence or absence of significant non-linear relationships. Furthermore, the model is not limited to CM dose-effect relationship research and can be applied to other regression tasks. [ABSTRACT FROM AUTHOR]

Background: Despite the growing realization regarding the importance of adverse childhood experiences (ACEs) in adult health outcomes, this area of research has received little scientific attention in low- and middle-income countries, including India. Aims: To understand the overall and domain-specific association of exposure to ACEs with current depression, anxiety, stress, and well-being among young adults of Delhi-NCR. Methods: This cross-sectional study was carried out among 1,812 young adults (aged 18–25 years) of both sexes (68.7% females). Fieldwork was conducted on the campuses of the University of Delhi, Delhi, and Amity University, Noida, India. ACEs, depression, anxiety, stress, and well-being were screened using the Adverse Childhood Experiences International Questionnaire, Beck Depression Inventory-II, Beck Anxiety Inventory, Perceived Stress Scale, and WHO-5 Well-Being Index, respectively. Results: Exposure to ACEs was found to increase the odds of moderate/severe depression, moderate/severe anxiety, and high stress and decreased the odds of good well-being in a dose-response manner. Being bullied, followed by emotional abuse, was associated with the highest odds of current moderate/severe depression, moderate/severe anxiety, and high stress and the lowest odds of good well-being. Further, while several domains of household dysfunction showed poor association with studied mental health outcomes, domains of abuse and violence were more consistently associated. Conclusions: The present study revealed the detrimental impact of ACEs on mental health outcomes among young adults of Delhi-NCR, India, and underscored the relevance of ACEs in the Indian context. Considering the lack of trauma awareness in Indian societies, there is an urgent need to create widespread awareness regarding ACEs and associated health implications. [ABSTRACT FROM AUTHOR]

Background: Opioids such as sufentanil are used as anaesthetics due to their rapid action and superior analgesic effect. However, sufentanil induces a huge cough in paediatric patients. In contrast, intravenous (IV) lidocaine suppresses opioid-induced cough in children, but its use is limited due to anaesthetists' concern about its toxicity. Therefore, this study aimed to evaluate the effect of dose-dependent IV lidocaine on sufentanil-induced cough (SIC) in paediatric patients. Methods: A total of 188 patients aged 3–12 years scheduled for elective tonsillectomy with or without adenoidectomy were enrolled and divided into four groups depending on different dose of lidocaine: A (0 mg.kg-1), B (1 mg.kg-1), C (1.5 mg.kg-1), and D (2 mg.kg-1). The primary outcome was the SIC grade observed during the induction of general anaesthesia. The secondary outcomes were the incidence of SIC, mean arterial pressure, and heart rate at T0, T1, T2, T3, T4, and T5. Results: The SIC grade was significantly different between groups A and D (P = 0.04) and between groups B and D (P = 0.03). Moreover, the incidence of SIC in groups A, B, C, and D was 81%, 87%, 68%, and 64%, respectively, and the difference between groups B and C (P = 0.03) and between groups B and D (P = 0.0083) was statistically significant. No statistical differences were observed in the hemodynamic parameters between the groups. The incidence of severe cough was statistically different between group D and group A (P < 0.0001), between group D and group B (P < 0.0001), and between group D and group C (P < 0.0001) respectively. Conclusions: Lidocaine suppresses SIC in a dose-dependent manner without severe adverse events. IV lidocaine can be used in paediatric patients safely and efficiently, and the median effective dose was 1.75 mg/kg. Trial registration: This study was approved by the Institutional Review Board of Yichang Central People's Hospital (HEC-KYJJ-2020-038-02), The trial was registered at www.chictr.org.cn (ChiCTR2100053006). [ABSTRACT FROM AUTHOR]

Background Depression is one of the most common psychological disorders that can affect a person’s mood and change his/her perception of the self and environment. Melilotus officinalis L. plant contains effective substances and antioxidant compounds. Objective The present study aims to investigate the antidepressant effects of alcoholic extract of Melilotus officinalis L. in male rats. Methods In this experimental research, 42 male rats were divided into six groups of 7 including control (normal saline), negative control (reserpine), positive control (reserpine+fluoxetine) and three reserpine groups treated by intraperitoneal injection of 100, 200, 400 mg/kg doses of alcoholic extract of Melilotus officinalis L. Behavioral tests including forced swim test (FST) and tail suspension test (TST) were used to evaluate depression, and the antioxidant capacity and malondialdehyde level were also measured. The data were analyzed in SPSS software, version 20 using one-way analysis of variance. The significance level was set at P<0.05. Results The 200 mg/kg and 400 mg/kg doses of alcoholic extract significantly reduced the duration of immobility in the FST compared to the negative control. In the TST, the doses of 200 and 400 mg/kg showed a significant increase compared to the negative control. The doses of 200 and 400 mg/kg significantly increased the antioxidant capacity of the brain compared to the negative control. The doses of 200 and 400 mg/kg significantly reduced the antioxidant capacity of the brain compared to the negative control. Conclusion The alcoholic extract of Melilotus officinalis L has antidepressant effects similar to fluoxetine probably due to its antioxidant compounds. [ABSTRACT FROM AUTHOR]

BACKGROUND: The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to 0.2ng/kg body weight (BW)/day. BPA is an extensively studied high production volume endocrine disrupting chemical (EDC) associated with a vast array of diseases. Prior risk assessments of BPA by EFSA as well as the US Food and Drug Administration (FDA) have relied on industry-funded studies conducted under good laboratory practice protocols (GLP) requiring guideline end points and detailed record keeping, while also claiming to examine (but rejecting) thousands of published findings by academic scientists. Guideline protocols initially formalized in the mid-twentieth century are still used by many regulatory agencies. EFSA used a 21st century approach in its reassessment of BPA and conducted a transparent, but time-limited, systematic review that included both guideline and academic research. The German Federal Institute for Risk Assessment (BfR) opposed EFSA's revision of the TDI for BPA. OBJECTIVES: We identify the flaws in the assumptions that the German BfR, as well as the FDA, have used to justify maintaining the TDI for BPA at levels above what a vast amount of academic research shows to cause harm. We argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications using the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) nonguideline academic studies in a collaborative government–academic program model. DISCUSSION: We strongly endorse EFSA’s revised TDI for BPA and support the European Commission’s (EC) apparent acceptance of this updated BPA risk assessment. We discuss challenges to current chemical risk assessment assumptions about EDCs that need to be addressed by regulatory agencies to, in our opinion, become truly protective of public health. Addressing these challenges will hopefully result in BPA, and eventually other structurally similar bisphenols (called regrettable substitutions) for which there are known adverse effects, being eliminated from all food-related and many other uses in the EU and elsewhere. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) in neonates is associated with increased morbidity and mortality. Theophylline (a methylxanthine) has been shown to prevent neonatal AKI but is seldom used due to its unfavorable profile. Caffeine, another methylxanthine, is utilized ubiquitously to treat apnea of prematurity, but there are no randomized trials evaluating its efficacy in preventing neonatal AKI. This literature review aims to summarize the existing research pertaining to the relationship between caffeine and neonatal AKI. The review was conducted using Pubmed, Embase, Google Scholar, and Cochrane. Inclusion criteria incorporated empirical studies, being published in English, and being available electronically. All eight studies identified were included. Seven studies found caffeine-exposed premature neonates had lower rates of AKI than caffeine-unexposed neonates. Four found reduced AKI severity with caffeine exposure. One study included term neonates and did not find a difference in the AKI rate between caffeine-exposed and non-exposed babies. Limitations include exclusively observational studies, short study periods, heterogenous definitions of prematurity, and a lack of assessment of dose–effect relationships. In conclusion, premature neonates exposed to caffeine appear to have lower rates and potentially less severe AKI. Further research is needed before caffeine can be considered for use in the primary prevention of neonatal AKI. [ABSTRACT FROM AUTHOR]

Objectives. This study aimed to investigate the effects of different triazole antifungal agents on the blood concentration and dosage of cyclosporine (CsA) in patients with aplastic anaemia (AA). Methods. This retrospective study enrolled AA patients who received CsA and triazole antifungal agents simultaneously between January 2018 and December 2022. The ratio of CsA blood concentration (ng/mL) to dosage (mg/day) (C/D) co-administration with and without azoles was compared. The effects of different triazole antifungal agents on blood concentrations and dosages of CsA were analysed. Results. The mean C/D ratio of CsA increased 1.97 times when co-administered with posaconazole (POS), while the mean C/D ratio of CsA increased 1.76 times when co-administered with fluconazole (FCZ). Compared with CsA monotherapy, there was a significant difference in CsA concentrations among patients with azoles (P < 0.05). The mean dose of CsA decreased was 0.26 (−0.25—1.05) mg/kg/day and 0.18 (−0.50—0.69) mg/kg/day when co-administered with POS and FCZ, respectively. There is a wide interindividual variability in the magnitude of drug interaction between azoles and CsA. Conclusions. Although azoles increased CsA concentration, a wide individual variability was found in the patients with CsA C/D ratio. Therefore, the CsA dose should be adjusted by closely monitoring the blood levels of CsA co-administered with triazole antifungal agents. In addition, we observed that POS had a greater effect on the blood concentration of CsA than FCZ. When adjusting the dose of CsA in clinical practice, the blood concentration of CsA and the type of co-administered triazole antifungal agents should be considered. [ABSTRACT FROM AUTHOR]

Background: Butea superba Roxb. (B. superba), is an herbal plant traditionally used for rejuvenation. Additionally, there have been reports on its antioxidant properties. Low-density lipoproteins (LDL) oxidation is the leading cause of cardiovascular diseases (CVDs). Natural products with antioxidant properties have the potential to inhibit LDL oxidation. However, no work has been done about the anti-isolated human LDL oxidation of B. superba extract (BSE). This study aimed to investigate the antioxidant potential of BSE and its ability to prevent isolated human (LDL) oxidation induced by free radical agents. Methods: The antioxidant properties were investigated by antioxidant assays, including 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azinobis-(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS), ferric reducing ability power (FRAP), nitric oxide (NO) and peroxynitrite scavenging assay. More so, anti-isolated human LDL oxidation activities were evaluated by 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) and 3-morpholinosydnonimine hydrochloride (SIN-1) induced LDL oxidation assay. Results: BSE exhibited a significant (p < 0.05) antioxidant activity in all the test systems, demonstrating its potential as a potent free radical scavenger. It displayed scavenging effects on DPPH (p < 0.05; IC50 = 487.67 ± 21.94 µg/ml), ABTS (p < 0.05; IC50 = 30.83 ± 1.29 µg/ml). Furthermore, it generated significantly (p < 0.05) increased antioxidant capacity in a dose-dependent manner in FRAP assay and exhibited significantly (p < 0.01) higher percent NO scavenging activity than gallic acid. Besides, BSE at 62.5 µg/ml exhibited a considerable percent peroxynitrite scavenging of 71.40 ± 6.59% after a 2 h period. Moreover, BSE demonstrated anti-isolated human LDL oxidation activity induced by AAPH and SIN-1 (p < 0.05) and revealed scavenging activity similar to ascorbic acid (p > 0.05). Identifying the main constituents of BSE revealed the presence of genistein, daidzein, and biochanin A through Liquid Chromatography-Mass Spectrometer/Mass Spectrometer (LC–MS/MS) analysis. Conclusion: This is the first report that the presence of isoflavones in BSE could play an important role in its antioxidation and isolated human LDL oxidation scavenging properties. These findings suggest the potential for developing antioxidant herbal supplements. However, further studies must be investigated, including efficacious and safe human dosages. [ABSTRACT FROM AUTHOR]

Background: Osteoking has been used for fracture therapy with a satisfying clinical efficacy. However, its therapeutic properties and the underlying mechanisms remain elusive. Method: A bone defect rat model was established to evaluate the pharmacological effects of Osteoking by the dynamic observation of X-ray, micro-CT and histopathologic examination. Transcriptome profiling was performed to identify bone defect-related genes and Osteoking effective targets. Then, a "disease-related gene–drug target" interaction network was constructed and a list of key network targets were screened, which were experimentally verified. Results: Osteoking effectively promoted bone defect repair in rats by accelerating the repair of cortical bone and the growth of trabeculae. Histopathologically, the bone defect rats displayed lower histopathologic scores in cortical bone, cancellous bone and bone connection than normal controls. In contrast, Osteoking exerted a favorable effect with a dose-dependent manner. The abnormal serum levels of bone turnover markers, bone growth factors and bone metabolism-related biochemical indexes in bone defect rats were also reversed by Osteoking treatment. Following the transcriptome-based network investigation, we hypothesized that osteoking might attenuate the levels of ZBP1–STAT1–PKR–MLKL-mediated necroptosis involved into bone defect. Experimentally, the expression levels of ZBP1, STAT1, PKR and the hallmark inflammatory cytokines for the end of necroptosis were distinctly elevated in bone defect rats, but were all effectively reversed by Osteoking treatment, which were also suppressed the activities of RIPK1, RIPK3 and MLKL in bone tissue supernatants. Conclusions: Osteoking may promote bone formation and bone defect repair by regulating ZBP1–STAT1–PKR axis, leading to inhibit RIPK1/RIPK3/MLKL activation-mediated necroptosis. [ABSTRACT FROM AUTHOR]

Background: This meta-analysis aimed to explore the correlation between the different doses of remifentanil-based anaesthesia and postoperative pain in randomised trials. Methods: The electronic databases including PubMed, Cochrane, clinical trial registries, and Google Scholar were searched up to November 2022 for randomised controlled trials (RCTs) that assessed the dose dependent efficacy of remifentanil for postoperative pain intensity and hyperalgesia. Results: 31 studies involving 2019 patients were included for analysis. Compared with the high remifentanil dose administration, patients in low doses showed less postoperative pain intensity at 1-2 h (weighted mean differences (WMD): 0.60, 95% CI, 0.05 to 1.15), 3-8 h (WMD: 0.38, 95% CI, 0.00 to 0.75), 24 h (WMD: 0.26, 95% CI, 0.04 to 0.48) and 48 h (WMD: 0.32, 95% CI, 0.09 to 0.55). Remifentanil-free regimen failed to decrease the pain score at 24 h (WMD: 0.10, 95% CI, -0.10 to 0.30) and 48 h (WMD: 0.15, 95% CI, -0.22 to 0.52) in comparison with remifentanil-based anaesthesia. After excluding trials with high heterogeneity, the dose of the remifentanil regimen was closely correlated with the postoperative pain score (P=0.03). In addition, the dose of the remifentanil regimen was not associated with the incidence of postoperative nausea and vomiting (PONV) (P=0.37). Conclusions: Our meta-analysis reveals that the low dose of remifentanil infusion is recommendable for general anaesthesia maintenance. No evidence suggests that remifentanil-free regimen has superiority in reducing postoperative pain. Moreover, remifentanil doesn't have a dose dependent effect in initiating PONV. Trial registration: The protocol of present study was registered with PROSPERO (CRD42022378360). [ABSTRACT FROM AUTHOR]

In biomedical research, high-throughput screening is often applied as it comes with automatization, higher-efficiency, and more and faster results. High-throughput screening experiments encompass drug, drug combination, genetic perturbagen or a combination of genetic and chemical perturbagen screens. These experiments are conducted in real-time assays over time or in an endpoint assay. The data analysis consists of data cleaning and structuring, as well as further data processing and visualisation, which, due to the amount of data, can easily become laborious, time-consuming and error-prone. Therefore, several tools have been developed to aid researchers in this process, but these typically focus on specific experimental set-ups and are unable to process data of several time points and genetic-chemical perturbagen screens. To meet these needs, we developed HTSplotter, a web tool and Python module that performs automatic data analysis and visualization of visualization of eitherendpoint or real-time assays from different high-throughput screening experiments: drug, drug combination, genetic perturbagen and genetic-chemical perturbagen screens. HTSplotter implements an algorithm based on conditional statements to identify experiment types and controls. After appropriate data normalization, including growth rate normalization, HTSplotter executes downstream analyses such as dose-response relationship and drug synergism assessment by the Bliss independence (BI), Zero Interaction Potency (ZIP) and Highest Single Agent (HSA) methods. All results are exported as a text file and plots are saved in a PDF file. The main advantage of HTSplotter over other available tools is the automatic analysis of genetic-chemical perturbagen screens and real-time assays where growth rate and perturbagen effect results are plotted over time. In conclusion, HTSplotter allows for the automatic end-to-end data processing, analysis and visualisation of various high-throughput in vitro cell culture screens, offering major improvements in terms of versatility, efficiency and time over existing tools. [ABSTRACT FROM AUTHOR]

Background: Shikonin, a natural naphthoquinone compound extracted from the Chinese traditional herbal medicine "Lithospermum erythrorhizon", possesses antitumor activity against various cancer types. Tumor-suppressor genes (TSGs) negatively regulate cell growth, proliferation, and differentiation, thereby inhibiting tumor formation. However, the molecular mechanism of action of shikonin on TSGs in non–small-cell lung cancer (NSCLC) remains unclear. Methods: The inhibitory effect of shikonin on the proliferation and migration abilities of lung cancer cells were measured by Cell Counting Kit 8 (CCK8) and wound healing assays. The alteration of genes by shikonin treatment was detected by mRNA high-throughput sequencing and further confirmed by qPCR and western blotting experiments. The dominant functions of the upregulated genes were analyzed by GO and KEGG profiling. Results: Shikonin inhibited the proliferation and migration of A549 and H1299 NSCLC cells in a dose-dependent manner. mRNA high-throughput sequencing revealed a total of 1794 upregulated genes in shikonin-treated NSCLC cells. Moreover, bioinformatic analysis of GO and KEGG profiling revealed that the up-regulated genes were mostly involved in the JNK/P38/MAPK signaling pathway, among which the expression of GADD45B and PPP3CC was significantly enhanced. Finally, we confirmed that GADD45B and PPP3CC were indeed upregulated in JNK/P38/MAPK pathway. Conclusions: Taken together, these results suggested that shikonin might affect the expression of GADD45B and PPP3CC through the JNK/P38/MAPK pathway, therefore exerting an inhibitory effect on the proliferation and migration of cancer cells. To our knowledge, this is the first study reporting the role of shikonin in upregulating TSGs to activate the JNK/P38/MAPK signaling pathways in NSCLC. [ABSTRACT FROM AUTHOR]

Objective : Anthracycline administration in children is associated with cardiac dysfunction. Speckle-tracking echocardiography (STE) can detect subclinical cardiac damage that may go undetected by conventional two-dimensional (2D) echocardiography. This study aims to investigate medium-term anthracycline cardiotoxicity using STE and determine a safer administrable level of anthracyclines (ACs). Methods : This observational case-control study enrolled 37 healthy controls and 78 pediatric cancer survivors who received chemotherapy. The patients were divided into two groups: cardiotoxic received (CR) and cardiotoxic free (CF). Data on segmental longitudinal strain (LS), global LS (GLS), and 2D echocardiographic parameters were collected after a drug-free period of at least one year. Results : A total of 115 children with a mean age of 108 ± 55 months, of whom 66% were males, were included in the study. Both the groups of cancer survivors exhibited significantly reduced GLS compared to healthy controls (CR vs. controls, P = 0.001; CF vs. controls, P = 0.013), but no significant difference in left ventricular ejection fraction (LVEF) was observed (P = 0.75). Overall, cancer survivors treated with ACs demonstrated a significant reduction in strain in 10 left ventricular segments, particularly in the basal segments (P < 0.05). Among CR patients, those with impaired GLS (n = 43, GLS worse than -21.9) had significantly higher mean age and cumulative anthracycline dose compared to CR patients with normal GLS (age, P = 0.024; anthracycline dosage, P = 0.036). Using an anthracycline cutoff of 223 mg/m² resulted in a higher detection rate (49% vs. 25%) and fewer missed cases (51% vs. 74%) compared to the 360 mg/m² anthracycline cutoff. Conclusion : Childhood cancer survivors demonstrate significantly reduced GLS while preserving a normal LVEF, which does not differ significantly from reference values of healthy children. The reduction in strain appears to be associated with higher anthracycline doses and older age. Lowering the anthracycline threshold to 223 mg/m² may improve the predictability of a decline in cardiac function using strain imaging at medium-term follow-up. [ABSTRACT FROM AUTHOR]

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The objective of the study was to systematically assess whether the oral probiotic Lactobacillus rhamnosus (LGG) improves symptoms of irritable bowel syndrome in children. Four randomised clinical trials met the inclusion criteria, a total of 252 patients. Success of treatment was reported in 50 out of 82 patients (58.82%) from the LGG group, compared with 28 from 82 (34.14%) in the placebo group (p = 0.05). The number of pain episodes was lower in the LGG group compared with the placebo group (n = 117, 95% CI: 1.50 [-2.03; -0.97], p < 0.05). The use of LGG resulted in a decrease in the perception of pain intensity in the study population overall (n = 219, 95% CI: -0.61 [-1.13; -0.09], p < 0.05). A higher dosage of LGG was less effective than a lower dosage in improving the overall treatment success (p = 0.05). The dosage of LGG was not statistically significant in improving pain severity (p = 0.12). [ABSTRACT FROM AUTHOR]

The article comments on a study which investigated a type of nonmonotonic dose-response curve (NMDRC), an inverted U-risk trend between total effective xenoestrogen (TEXB) levels in serum and endometrial cancer, and the health effects of exposure to endocrine disruptors. It suggests the potential therapeutic use of high doses of estrogen for breast cancer and calls for epidemiologists to stop expecting monotonic dose-response curves as the norm.