Several first-line immune checkpoint inhibitor (ICI)-based combination therapies have been identified for unresectable hepatocellular carcinoma (uHCC). This network meta-analysis (NMA) aimed to provide the most updated evidence about the preferred first-line ICI-based regimens for uHCC.

A comprehensive literature search was performed in various databases from database inception to May 2022. The phase 3 trials evaluating first-line single-agent ICIs, molecular-target agents (MTAs), or their combinations in uHCC were included. The main endpoints were overall survival (OS) and progression-free survival (PFS). Pooled effect estimates were calculated using a random effects model within the frequentist framework. Subgroup analyses based on etiology were also conducted.

Twelve trials at low risk of bias with 8,275 patients comparing 13 treatments were included. OS with atezolizumab plus bevacizumab was comparable to sintilimab plus IBI305 [hazard ratio (HR): 1.16; 95% confidence interval (CI): 0.80–1.68] and camrelizumab plus apatinib (HR: 1.06; 95% CI: 0.75–1.51). The combination therapies, apart from atezolizumab plus cabozantinib in OS and durvalumab plus tremelimumab in PFS, had higher P-score than single-agent MTAs or ICIs. The survival benefits were associated with a high risk of adverse events leading to treatment discontinuation. The proportion of patients with hepatitis B virus-related HCC receiving ICIs combinations might positively correlate with survival advantages (R2=0.8039, p=0.0155).

This NMA demonstrated that atezolizumab plus bevacizumab remains the stand of care and confers comparable survival benefits to sintilimab plus IBI305 and camrelizumab plus apatinib in first-line therapy for uHCC. The optimal treatment algorithms should consider efficacy, safety, and etiology.

SARS-CoV-2 vaccines-associated autoimmune liver diseases have been reported in several case reports. However, the safety and immunogenicity after primary and booster inactivated SARS-CoV-2 vaccination in patients with autoimmune liver diseases (AILD) is still unknown.

Eighty-four patients with AILD were prospectively followed up after the second dose (primary) of inactivated SARS-CoV-2 vaccine. Some of them received the third dose (booster) of inactivated vaccine. Adverse events (AEs), autoimmune activation, and liver inflammation exacerbation after primary and booster vaccination were recorded. Meanwhile, dynamics of antireceptor-binding-domain IgG (anti-RBD-IgG), neutralizing antibodies (NAbs) and RBD-specific B cells responses were evaluated.

The overall AEs in AILD patients after primary and booster vaccination were 26.2% and 13.3%, respectively. The decrease of C3 level and increase of immunoglobulin light chain κ and λ levels were observed in AILD patients after primary vaccination, however, liver inflammation was not exacerbated, even after booster vaccination. Both the seroprevalence and titers of anti-RBD-IgG and NAbs were decreased over time in AILD patients after primary vaccination. Notably, the antibody titers were significantly elevated after booster vaccination (10-fold in anti-RBD-IgG and 7.4-fold in NAbs, respectively), which was as high as in healthy controls. Unfortunately, the inferior antibody response was not enhanced after booster vaccination in patients with immunosuppressants. Changes of atypical memory B cells were inversely related to antibody levels, which indicate that the impaired immune memory was partially restored partly by the booster vaccination.

The well tolerability and enhanced humoral immune response of inactivated vaccine supports an additional booster vaccination in AILD patients without immunosuppressants.

Vaccine development has come center stage in the public domain given the extensive exposure it received during the COVID-19 pandemic. Although messenger RNA (mRNA) technology has been the focus of research and development efforts, particularly for oncology, for over three decades, its recent impact has enhanced the trajectory of vaccine development. mRNA technology is now at the forefront of enormous efforts focused on developing new vaccines against infectious diseases and cancer. This review outlines the current status of cancer vaccination and discusses its potential as a therapeutic modality.

The current paradigm presumes the higher the triglyceride level, the greater the probability of acne vulgaris (AV) occurrence or severity. However, this prevailing view lacks the necessary premises required to prove causality—for which the reverse should hold true: that low TG levels are predictive of less AV occurrence or severity. A low TG concentration in patients with AV has not yet been addressed, probably because of (i) the lack of any hypothesis connecting low TG levels to AV, and (ii) a lower prevalence of hypotriglyceridemia compared to hypertriglyceridemia in societies, which may lead to missing or misdiagnosis of other types of AV. Therefore, a formal or causal position statement cannot be issued. My observations on the high prevalence of severe cases of AV in a subgroup of individuals with extremely low levels of either serum TG or TC levels (between 40–60 mg/dl) encouraged me to share this experience. I suggest that studies investigating AV calculate—retrospectively or prospectively—the odds ratio of finding AV in people with extremely low levels of TG and/or TC. I further propose that researchers investigating different therapeutic approaches and medications in patients with AV measure relevant parameters/variables (such as those described in this paper) to yield necessary data for contemporary and future trials. The prevailing view, i.e., hyperlipidemia theory, lacks the necessary premises required to prove causality and should be revisited.

Because of its extraordinary phytomedicinal potential and numerous potential health benefits, lemongrass (Cymbopogon citratus), a well-known medicinal and aromatic plant, is of paramount significance. It is typically used as a drug replacement.

The present study was comprised of drying lemongrass into powder and determining the proximate and mineral composition, and then developing ethanolic extracts of powder to determine total phenolic contents (TPC), total flavonoid contents (TFC), total carotenoids (TC), and DPPH free radical scavenging activity. Next, lemongrass powder (LGP) was replaced at 0, 2.5, 5, 7.5, and 10% levels to develop nutritional biscuits.

The results revealed that lemongrass powder contained higher fiber (8.34 ± 0.04%) and ash (7.26 ± 0.06%) quantities, than wheat flour. Similarly, essential minerals Ca, Mg, K, Fe, and Zn contents in LGP were 36.80 ± 0.12, 64.89 ± 0.13, 54.65 ± 0.18, 12.68 ± 0.05, and 8.46 ± 0.07 mg/100 g dry weight, respectively, which were significantly higher than that calculated in wheat flour. Phytochemical analyses of lemongrass ethanolic extracts documented TPC as 240.46 ± 0.20 mg gallic acid equivalent/100 g, TFC as 98.45 ± 0.15 mg catechin equivalent/100 g, TC as 62.36 ± 0.12 mg/100 g, and DPPH activity as 60.18 ± 0.14 mg AAE/100 g, with such values being significantly higher than those in wheat flour.

Incorporation of LGP at different levels in wheat flour resulted in boosted phytochemical profiles of nutritional biscuits, but upon sensory evaluation of biscuits 2.5% level of LGP provided good scores for taste, flavor and overall acceptability, while for color and flavor 5% LGP was also found to be suitable with highest sensory scores.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern has been the dominant cause of worldwide COVID-19 cases since 2022. All Omicron sub-lineage viruses have demonstrated high transmissibility and an ability to escape vaccine-induced immunity. While first-generation vaccines, including monovalent vaccines, continue to provide protection against severe disease, hospitalization, and mortality, their efficacy against Omicron subvariants remains sparse. These vaccines have also been associated with rapidly waning protection against primary COVID-19 and COVID-19 reinfections conferred by evolving Omicron sub-lineages. This led to the development and deployment of updated vaccines and the introduction of the bivalent booster. Through this review, we highlight the brief journey of the variants of concern leading to the dominance of Omicron and the effectiveness of the key vaccines against these variants, including the updated (bivalent) boosters.

Plasma cell neoplasms are well-known for having diverse morphological and phenotype presentations and less commonly unusual immunophenotypical profiles. Such unexpected immunophenotypical variability could lead to inaccurate impressions upon initial assessment, thus delaying an accurate diagnosis. Here, the authors report seven plasma cell neoplasm cases with unusual morphology, immunophenotype, or unusual anatomic locations from the archives of Montefiore Medical Center Hematopathology department to highlight key considerations involved in diagnosing plasma cell neoplasms.

The authors reviewed the 2015 to 2022 electronic medical records at Montefiore Medical Center and identified seven plasma cell neoplasm cases with unusual immunophenotypes as well as anatomic localization. Clinical information including demographics, patient history, clinical presentation, and treatment was retrieved along with pertinent laboratory data. Cell morphology and immunohistochemistry were evaluated from formalin-fixed, paraffin-embedded biopsy specimens stained with hematoxylin and eosin (H&E). Morphologic features and immunophenotype determined by flow cytometry and immunohistochemistry were reviewed, along with molecular and cytogenetic studies.

The analysis of the cases underscores the diagnostic complexity associated with the diverse array of morphological and immunophenotypic features of plasma cell neoplasms and offers insight into overcoming diagnostic challenges while avoiding potential pitfalls.

Awareness of the spectrum of morphological and immunophenotypic variability in plasma cell neoplasms is key to avoiding misdiagnosing variants and delaying clinical workup. Correlation with clinical and laboratory findings and evaluation by immunostaining to confirm plasma cell origin is necessary to reach a correct diagnosis.

The liver is the largest glandular organ in the body and has a unique distribution of cells and biomolecules. However, the treatment outcome of end-stage liver disease is extremely poor. Single-cell sequencing is a new advanced and powerful technique for identifying rare cell populations and biomolecules by analyzing the characteristics of gene expression between individual cells. These cells and biomolecules might be used as potential targets for immunotherapy of liver diseases and contribute to the development of precise individualized treatment. Compared to whole-tissue RNA sequencing, single-cell RNA sequencing (scRNA-seq) or other single-cell histological techniques have solved the problem of cell population heterogeneity and characterize molecular changes associated with liver diseases with higher accuracy and resolution. In this review, we comprehensively summarized single-cell approaches including transcriptomic, spatial transcriptomic, immunomic, proteomic, epigenomic, and multiomic technologies, and described their application in liver physiology and pathology. We also discussed advanced techniques and recent studies in the field of single-cell; our review might provide new insights into the pathophysiological mechanisms of the liver to achieve precise and individualized treatment of liver diseases.

Liposomes are a potential drug delivery system involving encapsulation into a phospholipid-based vesicular carrier system. In comparison with conventional delivery systems, liposomes may be advantageous due to site-specific targeting, controlled release patterns, enhanced stability, and reduced associated toxicity, among other processes. Several researchers in the last decade have attempted to develop simple or modified forms of liposomes for the effective delivery of various types of therapeutic agents. This review is focused on a discussion about some of the recent literature on the medical application of liposomes. An account of the mode of action of different types of liposomes as a supporting basis for their superior therapeutic efficiency was provided. The application of liposomes in the delivery of anticancer, anti-bacterial, and anti-fungal drugs, among others, was discussed. Along with this discussion, liposomal carriers for the management of diseases related to the respiratory and nervous system were included along with a special emphasis on the outcomes of current literature. The information gathered through this review will be useful in furnishing ideas about the current status of research studies conducted on the formulation and development of liposomal carriers.

Functional bowel disorders (FBDs) afflict millions of people worldwide. The pathogenesis of FBDs remains unclear and there are no effective treatments currently available. The intestinal microbiota is deemed a critical etiological factor in FBDs, and microbiota-targeted treatment strategies have promising therapeutic value. However, no comprehensive scientometric analyses related to FBDs and the intestinal microbiota have been performed. This study aimed to employ scientometrics to thoroughly analyze the knowledge base and the viable frontier between the intestinal microbiota and FBDs research fields.

Scientometrics was used to analyze the global research trends and hotspots in the overlapping fields of FBDs and the intestinal microbiota. The Web of Science database was selected as the research tool, and documents written in English and published from database inception to June 26th, 2023, were investigated.

There was a growth in publications from 2007 to 2022, with a total of 2,924 articles identified. China (n = 685, 23.43%) made the greatest contribution, followed by the United States (n = 672, 22.98%) and United Kingdom (n = 276, 9.44%). Co-citation analysis of references reflected the knowledge base in the past 16 years, including updating the understanding of FBDs, unveiling the relationship between the intestinal microbiota and FBDs, and preliminary research on the effects of microbiota-targeted treatment on FBDs.

By utilizing scientometrics, we identified three main research frontiers including microbiome-metabolites-mechanisms in FBDs, microbiota-related biomarkers for FBDs, and mechanism of microbiota-targeted treatments towards FBDs for precise medicine. These findings could provide valuable guidance for future research.

Major depressive disorder (MDD) continues to be a prevalent disease worldwide. While selective serotonin reuptake inhibitors and other medications continue to be prescribed, further research has been conducted toward other treatment modalities. Within the past decade, ketamine, an N-methyl-d-aspartate receptor antagonist, has been extensively studied as a new treatment for MDD. Recent studies show that ketamine at subanesthetic doses provides antidepressant effects. An extensive overview of the latest statistics of MDD and treatment plans are emphasized, with a review of current medications and their subsequent side effects. However, an important factor to consider with ketamine is dissociation, and given ketamine’s psychotomimetic side effects, it must be reviewed further. Despite such side effects of hallucinations and depersonalization, studies have shown administration achieves rapid and lasting antidepressant effects. The synergistic effects of ketamine are also analyzed with recent studies to summarize the effects of different treatment modalities. A summary of the latest research studies of ketamine as a possible treatment for MDD is provided. By focusing on the evolution of ketamine as a treatment for MDD, physicians can now utilize newer techniques for depression, with better short-term and long-term outcomes for the patients.

Our aim was to determine the immune efficacy of a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) booster vaccination in cirrhotic patients who had received the primary series.

We performed a longitudinal assessment in 48 patients with cirrhosis, 57 patients with chronic hepatitis B (CHB) and 68 healthy controls (HCs) to continuously track the dynamics of SARS-CoV-2 specific antibodies and memory B cells after receiving the primary series and booster dose at different times. A pseudovirus neutralization assay was used to determine neutralization against Omicron subvariants BA.2.12.1, BA.4 and BA.5 from serum samples collected from three cohorts.

Serum anti-receptor-binding domain (RBD) immunoglobulin (Ig)G and neutralizing antibody (NAb) levels in cirrhotic patients were elevated within 15–45 days after completing the primary series before rapidly declining and reaching a valley at around 165–195 days. After receiving the booster dose, both antibody levels were significantly increased to levels comparable to patients with CHB and HCs. Subgroup analysis showed that booster vaccination induced weaker antibody responses in patients with decompensated cirrhosis than in those with compensated cirrhosis. The SARS-CoV-2 memory B-cell response in cirrhotic patients was durable during follow-up regardless of the hepatic fibro-cirrhosis grade. However, compared with the primary series, the booster dose did not result in an evident improvement of neutralization activity against the Omicron subvariants BA.2.12.1 and BA.4, and was followed by a significant decrease in the titer against BA.5.

A booster dose elicited a robust and durable humoral response to the wild-type strain in cirrhotic patients but not the Omicron subvariants. Repeated vaccination of inactivated SARS-CoV-2 vaccine may not benefit cirrhotic patients in neutralization against newly circulating strains.

Direct evidence on the outcomes of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients with normal alanine transaminase after long-term antiviral treatment is lacking.

HBeAg-negative patients with normal ALT and positive HBV DNA (≥20 IU/mL) were retrospectively enrolled. The endpoints included virological response (HBV DNA<100 IU/mL), changes in aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 index (FIB-4), and the incidence of liver nodules, cirrhosis, and hepatocellular carcinoma (HCC).

This cohort (n=194) was divided into three subgroups, untreated (n=67), treatment-continued (n=87), and treatment-discontinued patients (n=40), with a median follow-up of 54 months. The treatment-continued group achieved 100% (95% CI: 94.7–100) virological response, and significantly reduced APRI and FIB-4 scores (both p<0.001). The risk of liver nodules and cirrhosis in that group was reduced by 76% (HR: 0.24, 95% CI: 0.11–0.54, p<0.001) and 89% (HR: 0.11, 95% CI: 0.14–0.91, p=0.041) vs. the untreated group and by 77% (HR: 0.23, 95% CI: 0.10–0.49, p<0.001) and 95% (HR: 0.05, 95% CI: 0.01–0.44, p=0.006) vs. the treatment-discontinued group. For patients with HBV DNA≥2,000 IU/mL, adherence to treatment lowered the risks of liver cirrhosis by 92% (95% CI: 0.01–0.67) and 93% (95% CI: 0.01–0.53) vs. the untreated and treatment-discontinued patients, respectively. No patient adhering to treatment developed HCC, but one in each of the remaining groups did.

Continuous nucleos(t)ide analog (NA) treatment has a satisfactory effectiveness and helps to lower the risk of liver cirrhosis in HBeAg-negative CHB patients with normal alanine transaminase, especially in those with HBV DNA≥2,000 IU/mL.

Non-alcoholic fatty liver disease (NAFLD) affects 25% of the global population. About 20% have a normal body mass index (BMI) and a variant known as lean NAFLD. Unlike typical NAFLD cases associated with obesity and diabetes, lean NAFLD causes liver disease by mechanisms not related to excess weight or insulin resistance. Genetic disorders are among the major factors in developing lean NAFLD, and genome-wide association studies have identified several genes associated with the condition. This review aims to increase awareness by describing the genetic markers linked to NAFLD and the defects involved in developing lean NAFLD.

Development of fibrosis in chronic liver disease requires activation of hepatic stellate cells (HSCs) and leads to a poor outcome. Artesunate (Art) is an ester derivative of artemisinin that can induce ferroptosis in HSCs, and activated transcriptional factor 3 (ATF3) is an ATF/CREB transcription factor that is induced in response to stress. In this study, we examined the role of the Rho-associated protein kinase 1 (ROCK1)/ATF3 axis in Art-induced ferroptosis in HSCs.

HSC activation and ferroptosis were studied in vitro by western blotting, polymerase chain reaction, immunofluorescence, and other assays. ATF3 electrophoretic mobility and ROCK1 protein stability were assayed by western blotting. Immunoprecipitation was used to detect the interaction of ROCK1 and ATF3, as well as ATF3 phosphorylation. A ubiquitination assay was used to verify ROCK1 degradation. Atf3-interfering and Rock1-overexpressing mice were constructed to validate the anti-hepatic fibrosis activity of Art in vivo.

Art induced ferroptosis in HSCs following glutathione-dependent antioxidant system inactivation resulting from nuclear accumulation of unphosphorylated ATF3 mediated by ROCK1-ubiquitination in vitro. Art also decreased carbon tetrachloride-induced liver fibrosis in mice, which was reversed by interfering with Atf3 or overexpressing Rock1.

The ROCK1/ATF3 axis was involved in liver fibrosis and regulation of ferroptosis, which provides an experimental basis for further study of Art for the treatment of liver fibrosis.

Coronavirus disease (COVID-19) exhibits a range of clinical symptoms, including viral pneumonia, which can progress to acute respiratory distress syndrome, substantial alveolar destruction, and even multi-organ failure in severe cases. Disease pathology is greatly influenced by the host immune response. Several studies reported the perturbation of T-cell responses in COVID-19 patients. Activation and differentiation of CD4+ T cells into various subsets depend on the expression of lineage-specific transcription factors and overall cytokine milieu. Hence, a thorough evaluation of T helper cell lineage-specific transcription factors and pro-inflammatory cytokines can provide crucial insight into COVID-19 pathogenesis and may aid in developing strategies to prevent disease severity. Here, we performed a cross-sectional study to delineate the dysfunctional T helper cell subset immune response associated with COVID-19 disease severity.

We assessed T helper cell responses in SARS-CoV-2 infected individuals who presented with either asymptomatic, mild, or severe disease. mRNA profiling of lineage specific transcription factors and associated cytokines was done using real-time qPCR. Cytokine profiling was done using ELISA.

mRNA levels of FOXP-3 were significantly decreased in patients with severe COVID-19. No significant difference was observed for T-bet and GATA-3 among all of the groups. Bcl-6, the transcription factor for Tfh cell subsets, showed an increased trend in its association with disease progression. Furthermore, mRNA levels of IL-21 were significantly increased with disease severity. We also observed a significant increase in the concentration of pro-inflammatory cytokines IL-6 and IL-1β in patients with severe COVID-19.

These findings provide new insight into COVID-19 disease pathology and may aid in developing effective strategies to manage/control disease severity.

Semisolid oral preparations (Avaleha) are used in Ayurvedic therapeutics. The problems with these preparations include a bitter taste and the use of a sugar base. Here, we aimed to modify the semisolid Vasavaleha (VA) preparation to an oral solution (syrup) and to observe the efficacy of the VA syrup on patients with bronchial asthma.

VA syrup was prepared by dissolving the water-soluble extracts of Adhatoda vasica leaves and Piper longum fruits in purified water; sorbitol solution and honey were used as sweeteners. Organoleptic tests as well as pH, specific gravity, and viscosity measurements were performed. Liquid chromatography-mass spectrometry analysis of the VA syrup was carried out using an Agilent UHPLC-MS/Q-TOF (6545) system coupled with a Dual AJS ESI source. An open-label clinical trial of the VA syrup was performed on 13 patients with bronchial asthma at a dose of 10 mL (oral, twice a day) for 30 days.

The prepared VA syrup was brown in color and sweet in taste. The pH, specific gravity, and viscosity of the prepared VA syrup were 7.52, 1.10, and 1.922, respectively. Piperine, piperdardine, vasicine, vasicol, vasicinol, and vasicinone were determined to be the major phytochemical compounds. This preparation significantly improved all clinical symptoms of asthma and lung function test results in patients with bronchial asthma. It had mucolytic, bronchodilator, and anti-allergic properties. It had no adverse effects at the indicated dose.

The oral solution (syrup) might be an effective alternative for Ayurvedic semisolid preparations. The VA syrup may be taken as an alternative for VA as it was found to be an effective formulation for the management of bronchial asthma.

Increasing utilization of extended criteria donor leads to an increasing rate of early allograft failure after liver transplantation. However, consensus of definition of early allograft failure is lacking.

A retrospective, multicenter study was performed to validate the Liver Graft Assessment Following Transplantation (L-GrAFT) risk model in a Chinese cohort of 942 adult patients undergoing primary liver transplantation at three Chinese centers. L-GrAFT (L-GrAFT7 and L-GrAFT10) was compared with existing models: the Early Allograft Failure Simplified Estimation (EASE) score, the model of early allograft function (MEAF), and the Early Allograft Dysfunction (EAD) model. Univariate and multivariate logistic regression were used to find risk factors of L-GrAFT high-risk group.

L-GrAFT7 had an area under the curve of 0.85 in predicting 90-day graft survival, significantly superior to MEAF [area under the curve (AUC=0.78, p=0.044)] and EAD (AUC=0.78, p=0.006), while there was no statistical significance between the predicting abilities of L-GrAFT7 and EASE (AUC=0.84, p>0.05). Furthermore, L-GrAFT7 maintains good predicting ability in the subgroup of high-donor risk index (DRI) cases (AUC=0.83 vs. MEAF, p=0.007 vs. EAD, p=0.014) and recipients of donors after cardiac death (AUC=0.92 vs. EAD, p<0.001). Through multivariate analysis, pretransplant bilirubin level, units of packed red blood cells, and the DRI score were selected as independent risk factors of a L-GrAFT7 high-risk group.

The accuracy of L-GrAFT7 in predicting early allograft failure was validated in a Chinese multicenter cohort, indicating that it has the potential to become an accurate endpoint of clinical practice and transitional study of machine perfusion.