Epilepsy is a neural disorder that occurs because of a disruption in neural conductions in various parts of the brain and is mainly characterized by seizures, pensive gaze, involuntary mimics, contractions, meaningless speeches, repetitive movements, and loss of consciousness. The serious side effects of conventional drug delivery systems due to high applied doses, low transition rates to the brain, and limitations of drug application during seizures result in the urgent need for novel drug delivery systems for the enhanced treatment of epilepsy.

In this study, Lacosamide was selected because of its high therapeutic dose, which is due to its low transition to the target site. Microneedle patches were formulated by micromolding of polymers of carboxymethyl cellulose (CMC) and Eudragit S 100 (ES100) for a unique route for applications to reduce the applied dose to minimize the severe side effects. This strategy enhanced brain transition via the nasal route and overcame the blood-brain barrier (BBB) to minimize the applied dose. Characterization studies were performed in detail.

The results revealed that the releases of Lacosamide extended to 96 h with ES100 microneedle patches. In contrast, CMC microneedles released almost all the active ingredients within 1 h due to the hydrophilic nature of the polymer. Stability studies indicated that the formulations were stable at 25 ± 2°C (60 ± 5% Relative Humidity; RH), 40 ± 2°C (75 ± 5% RH) and 5 ± 3°C for 6 months.

By considering the film like structures, polymeric microneedle patches have the potential for Lacosamide delivery through the unconventional nasal route for the improved treatment of epilepsy.

High Mobility Group A2 gene (HMGA2), an oncofetal protein, is normally expressed in fetal development and completely shuts down in almost all organs and tissue types during adulthood. It is upregulated or overexpressed again in certain mesenchymal neoplasms due to chromosomal translocations and in malignant epithelial tumors through transcription regulation. HMGA2 overexpression can either drive tumor development or promote the aggressiveness of tumor growth. Many gynecologic neoplasms, including uterine smooth muscle tumors and ovarian cancer, are associated with HMGA2 overexpression. In this article, we review recent developments in the study of HMGA2 and its expression as a potential biomarker for gynecologic neoplasms and clinic application.

Novel biological agents including cytokines and recombinant fusion proteins are increasingly prescribed for cancer, rheumatologic, autoimmune, and inflammatory diseases, and are currently being evaluated in hepatocellular carcinoma (HCC). They are classified by their mechanism of action and include tumor necrosis factor-alpha (TNF-α) antagonists, T cell mediated antitumor inhibitors, interleukin receptor antagonists, and immune checkpoint inhibitors (ICIs). Some ICIs cause frequent hepatotoxicity with a variable clinical, biochemical, and serological presentation, especially in patients receiving another immunomodulatory agent. Half of the cases of liver damage induced by biological agents spontaneously regress after drug withdrawal, but the others require steroid therapy. Unfortunately, there are no widely accepted recommendation for the use of corticosteroids in these patients, even though international cancer societies have their own guidelines. Differentiating drug-induced autoimmune hepatitis (DIAIH) from classic AIH is challenging for pathologists, but liver biopsy is valuable, particularly in cases with unclear clinical presentation. Interesting, novel histological patterns have been described in liver damage induced by these agents (i.e., endothelitis, ring granuloma and secundary sclerosing cholangitis associated with lymphocytic infiltration of cytotoxic CD8+T cells). Here, we describe the clinical and biochemical characteristics of patients with hepatotoxicity induced by TNF-α antagonists and ICIs. Controversial issues involved in the administration of corticosteroid therapy, and hepatitis B virus (HBV) reactivation induced by immunosuppressive therapy are also discussed.

COVID-19 is a worldwide pandemic. Currently, there are a few approved effective antiviral drugs against COVID-19. Therefore, an effective way to treat an emerging disease is to use existing medicines, which usually have a safety profile. A large number of compounds are produced from traditional medicinal plants and some of them that have antiviral activity could be used as therapeutics, such as Artemisia annua L (A. annua L.). Here, we update the information on the therapeutic effects and possible antiviral mechanisms of A. annua L. and their derivatives against severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection will be updated. The A. annua L. derivatives might be effective alternatives for COVID-19 treatment. A. annua L. might act against the SARS-CoV-2 infection by inhibiting its invasion, angiotensin-converting enzyme2, cluster of differentiation 147, and transmembrane protease serine 2 expression, virus replication, reducing oxidative stress and inflammation by attenuating Nrf2 and NF-kB signaling, and mitigating lung damage in patients with COVID-19. However, clinical effectiveness needs to be demonstrated.

Primary sclerosing cholangitis is a disease affecting around 0.006–0.016% of the population. Of these, around 75% have concomitant inflammatory bowel disease (IBD) according to the most recent epidemiological studies. Several theories have been proposed regarding the pathogenesis of primary sclerosing cholangitis (PSC). These include changes in the function of cholangiocytes, effects of the gut microbiome, association with specific human leukocyte antigen haplotypes and dysregulation of the immune system. However, these do not explain the observed association with IBD. Moreover, there are considerable differences in the frequency and outcomes between patients with PSC and ulcerative colitis compared with PSC and Crohn’s disease. The aim of this review is to appraise the most recent studies that have contributed to the epidemiology, advances in the pathophysiology, and characterization of important clinical aspects of the association of PSC and IBD.

Wound healing and tumor progression share some common biological features; however, how variations in wound healing patterns affect hepatocellular carcinoma (HCC) prognosis remains unclear.

We analyzed the wound healing patterns of 594 HCC samples from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) and correlated them with immune infiltration and the expression levels of immune checkpoint genes. A risk score, which we named the “heal.immune” score, was established via stepwise Cox estimation. We constructed a nomogram based on age, sex, TNM stage, and heal.immune score and explored its predictive value for HCC prognosis. Seventy-four clinical patients were enrolled in this study, and all were from Huashan Hospital of Fudan University between 2015 and 2017 to serve as an independent validation group.

We identified two distinct wound healing patterns in HCC. The biological processes of healing cluster 1 (C1) are related to metabolism, while those of healing cluster 2 (C2) are related to the inflammatory response and immune cell accumulation. A total of 565 wound healing-related genes (based on Gene Ontology) and 25 immune checkpoint genes were considered. By analyzing differentially expressed genes and implementing a stepwise Cox estimation analysis, six genes with p values less than 0.02 in a multivariate Cox estimation were chosen as the “heal.immune” gene set (FCER1G, PLAT, ITGA5, CCNB1, CD86 and CD40). The “heal.immune” gene set, as an OS risk factor, was further validated in Fudan cohort. We constructed a nomogram to predict the 1-, 3- and 5-year overall survival (OS) in the TCGA cohort. The area under curve vales of the receiver characteristic operator curves were 0.82, 0.76 and 0.73 in the training group and 0.84, 0.76 and 0.72 in the test group.

We established a prognostic nomogram based on the heal.immune gene signature, which includes six wound healing- and immunity-related genes. This nomogram accurately predicts the OS of HCC patients.

The coronavirus disease 2019 (COVID-19) pandemic has killed millions of people globally and severely affected quality of life and the global economy. The present randomized survey aimed to collect information based on vaccination, symptoms, treatments, and post-COVID-19 complications from participants who recovered from COVID-19 to find out the disease pattern, trends, and effective treatment protocols.

The information from participants was collected by an online questionnaire that was circulated among the population of India through emails and social media.

A total of 706 responses were recorded from participants who recovered from COVID-19 from 20 Indian states. Males and females from all age groups took part in the online survey. Among them, 77% of the participants were not vaccinated, 17% were vaccinated with a single dose and 6% with a booster dose. An average of 27% of the total vaccinated participants had a comorbidity that included diabetes, hypertension, and pulmonary disease. Most of the patients with moderate to severe symptoms preferred allopathic treatment. The adoption level of allopathic treatment was significantly higher (p = 0.001) than that of other treatment options. The results showed that 12% of the patients adopted the Ayurvedic treatment and 14% preferred a mixed treatment. Approximately one-third of the participants had various post-COVID-19 complications that were related to breathing and anxiety.

The survey concluded that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected almost the whole population irrespective of gender, age, and region. The study further concluded that vaccination is the main protection against SARS-CoV-2 infection.

Acute-on-chronic liver failure (ACLF) tends to progress rapidly with high short-term mortality. We aimed to create a widely applicable, simple prognostic (WASP) score for ACLF patients.

A retrospective cohort of ACLF cases recruited from three centers in China were divided into training and validation sets to develop the new score. A prospective longitudinal cohort was recruited for further validation.

A total of 541 cases were included in the training set, and seven independent ACLF prognostic factors were screened to construct a new quantitative WASP-ACLF table. In the validation set of 671 cases, WASP-ACLF showed better predictive ability for 28-day and 90-day mortality than the currently used prognostic scores at baseline, day 3, week 1, and week 2. The predictive efficacy and clinical validity of the model improved over time. Patients were assigned to low-, intermediate-, and high-risk groups by their WASP-ACLF scores. Compared with the other two groups, intermediate-risk patients had a more uncertain prognosis, with a 90-day mortality of 44.4–50.6%. Sequential assessments at weeks 1 and 2 found the 90-day mortality of intermediate-risk groups was <20% for patients with a ≥2 point decrease in WASP-ACLF and was up to 56% for patients with a ≥2 points increase. Similar results were observed in prospective data.

The new ACLF prognostic score was simple, widely applicable, and had good predictive efficacy. Continuous assessments and trend of change in WASP-ACLF need to be considered, especially for intermediate-risk patients.

Previous meta-analyses have shown that aspirin use may reduce the risk of hepatocellular carcinoma (HCC). However, the optimal dose, frequency, and duration of aspirin use or the safety and efficacy of aspirin in target populations for HCC prevention remain unclear. The study aim was to investigate the efficacy and safety of aspirin for prevention of HCC.

Publications were retrieved by a comprehensive literature research of several databases. Based on a random-effects model, hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to assess the pooled risk. The dose-response relationship between aspirin use and HCC risk was assessed with a restricted cubic spline model.

Twenty-two studies were included in the meta-analysis. Aspirin use was associated with a reduced risk of HCC (HR=0.64, 95% CI: 0.56–0.75). The effect was robust across sex and age; however, women and the non-elderly had the greatest benefit from aspirin use. The preventive effect was well reproduced in those with comorbidities. Daily use and long-term use of aspirin appeared to offer greater benefits. Aspirin 100 mg/d was associated with maximum reduction of HCC risk. Aspirin use did slightly increase the risk of bleeding (HR=1.14, 95% CI: 1.02–1.27).

Our meta-analysis confirmed that use of aspirin significantly reduced the incident risk of HCC. Regular and long-term aspirin use offers a greater advantage. Aspirin use was associated with an increased risk of bleeding. We recommend 100 mg/d aspirin as a feasible dose for further research on primary prevention of HCC in a broad at-risk population.

The concurrence of nonalcoholic steatohepatitis (NASH) and ulcerative colitis (UC) is increasingly seen in clinical practice, but the underlying mechanisms remain unclear. This study aimed to develop a mouse model of the phenomenon by combining high-fat high-cholesterol diet (HFHCD)-induced NASH and dextran sulfate sodium (DSS)-induced UC, that would support mechanistic studies.

Male C57BL/6 mice were randomly assigned to two groups receiving either a chow diet or HFHCD for 12 weeks of NASH modeling. The mice were the divided into four subgroups for UC modeling: (1) A control group given a chow diet with normal drinking water; (2) A colitis group given chow diet with 2% DSS in drinking water; (3) A steatohepatitis group given HFHCD with normal drinking water; and (4) A steatohepatitis + colitis group given HFHCD with 2% DSS in drinking water.

NASH plus UC had high mortality (58.3%). Neither NASH nor UC alone were fatal. Although DSS-induced colitis did not exacerbate histological liver injury in HFHCD-fed mice, premorbid NASH significantly increased UC-related gut injury compared with UC alone. It was characterized by a significantly shorter colon, more colonic congestion, and a higher histopathological score (p<0.05). Inflammatory (tumor necrosis factor-alpha, interleukin 1 beta, C-C motif chemokine ligand 2, and nuclear factor kappa B) and apoptotic (Bcl2, Bad, Bim, and Bax) signaling pathways were significantly altered in distal colon tissues collected from mice with steatohepatitis + colitis compared with the other experimental groups.

Premorbid steatohepatitis significantly aggravated DSS-induced colitis and brought about a lethal phenotype. Potential links between NASH and UC pathogeneses can be investigated using this model.

Patients with severe fever with thrombocytopenia syndrome (SFTS) commonly show liver function impairment. This study aimed to characterize the liver function indices in SFTS patients and investigate their association with mortality.

Clinical information and laboratory results of 459 laboratory-confirmed SFTS patients, including 78 deceased and 381 surviving patients, were retrospectively analyzed. To explore the infectivity of SFTS caused by novel Bunyavirus (SFTSV) in hepatocytes, Huh7 human hepatoma cells were infected with various concentrations of SFTSV in vitro.

The proportion of SFTS patients developing liver injury during hospitalization was 73.2% (336/459); the hepatocellular injury was the predominant type. The median time to occurrence of liver injury from disease onset was 8 d. Liver injury in the deceased group occurred earlier than that in the surviving group. Alanine aminotransferase (ALT) level between 2–5 times upper limit of normal (ULN) at 4–6 d and between 5–15 ULN at 7–12 d of disease course were independent predictors of mortality. Alkaline phosphatase (ALP) >2 ULN at 7–9 d and elevated ALP at 10–12 days after disease onset were risk factors for death. ALT and aspartate transaminase (AST) levels were correlated with lymphocyte count and platelet-to-lymphocyte ratio (PLR). Total bilirubin (TB), ALT, AST levels showed positive correlation with viral load. In the in vitro experiment, SFTSV infected and replicated inside Huh7 cells.

Liver injury is common in SFTS patients. ALT and ALP were independent predictors of SFTS-related mortality. Frequent monitoring and evaluation of liver function indices are needed for SFTS patients.

Acute-on-chronic liver failure (ACLF) is associated with very high mortality. Accurate prediction of prognosis is critical in navigating optimal treatment decisions to improve patient survival. This study was aimed to develop a new nomogram integrating two-dimensional shear wave elastography (2D-SWE) values with other independent prognostic factors to improve the precision of predicting ACLF patient outcomes.

A total of 449 consecutive patients with ACLF were recruited and randomly allocated to a training cohort (n=315) or a test cohort (n=134). 2D-SWE values, conventional ultrasound features, laboratory tests, and other clinical characteristics were included in univariate and multivariate analysis. Factors with prognostic value were then used to construct a novel prognostic nomogram. Receiver operating curves (ROCs) were generated to evaluate and compare the performance of the novel and published models including the Model for End-Stage Liver Disease (MELD), MELD combined with sodium (MELD-Na), and Jin’s model. The model was validated in a prospective cohort (n=102).

A ACLF prognostic nomogram was developed with independent prognostic factors, including 2D-SWE, age, total bilirubin (TB), neutrophils (Neu), and the international normalized ratio (INR). The area under the ROC curve (AUC) was 0.849 for the new model in the training cohort and 0.861 in the prospective validation cohort, which were significantly greater than those for MELD (0.758), MELD-Na (0.750), and Jin’s model (0.777, all p <0.05). Calibration curve analysis revealed good agreement between the predicted and observed probabilities. The new nomogram had superior overall net benefit and clinical utility.

We established and validated a 2D-SWE-based noninvasive nomogram to predict the prognosis of ACLF patients that was more accurate than other prognostic models.

Non-alcoholic fatty liver disease (NAFLD) is closely related to insulin resistance, type 2 diabetes mellitus and obesity. It is considered a multisystem disease and there is a strong association with cardiovascular disease and arterial hypertension, which interfere with changes in the coagulation system. Coagulation disorders are common in patients with hepatic impairment and are dependent on the degree of liver damage. Through a review of the literature, we consider and discuss possible disorders in the coagulation cascade and fibrinolysis, endothelial dysfunction and platelet abnormalities in patients with NAFLD.

Plantar heel pain (PHP) is a common musculoskeletal disorder that is effectively treated with extracorporeal shockwave therapy (ESWT) and exercise. This review aimed to evaluate the effectiveness of combined ESWT and exercise versus other interventions in treating PHP. A systematic review of effectiveness was conducted, adhering to the PRISMA guidelines. Five databases were searched for studies published between January 2000 and September 2021 with 12 studies (n = 861) meeting the inclusion criteria, which compared ESWT and stretching to various other treatments. High-quality evidence indicates that combined ESWT and stretching interventions are more effective than their individual use or botulinum toxin injections, and low-quality evidence of superiority versus ultrasound and stretching. There was moderate quality evidence that combined ESWT and stretching is no more effective than corticosteroid injection, and high-quality evidence that the combination is no more effective than blood-derived injection therapies, custom orthotics, or low-level laser therapy combined with stretching. There is high-quality evidence that topical corticosteroid or laser therapy in combination with ESWT and stretching increases its effectiveness and moderate-quality evidence for the additive effectiveness of dry needling. Overall, combined ESWT and stretching treatments are effective and may be recommended where they are available and practical to implement. Further high-quality studies comparing combined interventions for PHP, including different exercise activities like resistance training, are required. PROSPERO registration number: CRD42020213286

Metabolic-associated fatty liver disease (MAFLD) is a newly proposed terminology from 2020; yet, the applicability of conventional noninvasive fibrosis models is still unknown for it. We aimed to evaluate the performance of conventional noninvasive fibrosis scores in MAFLD.

The NHANES 2017-2018 datasets were used to compare the performances of different noninvasive fibrosis scores in MAFLD, including the aspartate aminotransferase (AST) to platelet ratio index (APRI), body mass index (BMI)-AST/alanine aminotransferase (ALT) ratio and diabetes score (BARD), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS). Moreover, Asian patients with biopsy-proven MAFLD were enrolled to further validate the findings.

A total of 2,622 participants in the National Health and Nutrition Examination Survey (NHANES) cohort and 293 patients with MAFLD in the Asian cohort were included. Patients in the Asian cohort had a lower BMI and higher liver enzymes (p<0.001). The area under the receiver operating characteristic curve (AUROC) of NFS was the largest in the NHANES cohort and Asian cohorts (0.679 and 0.699, respectively). The AUROC of NFS was followed by APRI, FIB-4, and BARD in the NHANES cohort (0.616, 0.601, and 0.589, respectively). In the Asian cohort, the AUROC of APRI, FIB-4, and BARD for predicting advanced fibrosis were 0.625, 0.683, and 0.615, respectively. The performance of FIB-4 was better in the Asian cohort than that in the NHANES cohort.

NFS is better for predicting advanced fibrosis in MAFLD. FIB-4 can be an alternative choice for MAFLD with high liver enzymes when NFS is unavailable. Novel efficient noninvasive fibrosis scoring systems are highly required for patients with MAFLD.

PTEN-induced putative kinase 1 (PINK1) is a mitochondrial kinase that regulates mitophagy. PINK1-deficient mAPP mice display low LC3B levels, and PINK1 overexpression enhances autophagy and increases the expression level of lysosome-associated membrane protein 1 (LAMP1). The present study evaluated whether altered PINK1 expression could modulate β-amyloid (Aβ)-treated mitophagy in PC12 cells, a simple cellular model to simulate pathological changes in neurodegenerative diseases in vitro.

PC12 cells were transfected with PINK1 siRNA for 48 h, and then incubated with 20 µM Aβ25–35 for 24 h. The relevant protein expression was determined by immunofluorescence, immunoelectron microscopy, and Western blot. Mitochondrial membrane potential (MMP) was tested by JC-1-based confocal fluorescent imaging.

Following Aβ25–35 treatment, PINK1 silencing significantly decreased the levels of LC3B, Parkin, and LAMP1 as well as Parkin in mitochondria, p62 degradation, but increased OPTN and Parkin expression in PC12 cells, relative to that of the control PC12 cells. Furthermore, PINK1 silencing decreased MMP in PC12 cells.

PINK1 deficiency deteriorated the blockade of the Aβ25–35-induced mitophagy-lysosome pathway in PC12 cells. Aβ-treated PC12 cells might be a valuable cellular model to evaluate PINK1-mediated mitophagy and bioactive compound screening.

Sphincter of Oddi dysfunction (SOD) encompasses a spectrum of clinical syndromes that are not fully understood, and various diagnostic and therapeutic methods have had varying results depending on the type of dysfunction. This review explored various mechanisms that might play a role in SOD and methods of diagnosis and management. It is important to rule out other causes of abdominal pain with laboratory testing, imaging studies, and endoscopic procedures. Medications that affect sphincter motility should be identified as well. Manometry is the gold standard for diagnosis but it is not always required. For example, patients with type I SOD may have symptomatic improvement with sphincterotomy without need for a diagnostic manometry. Hepatobiliary scintigraphy and fatty meal sonography may also have diagnostic utility. Sphincterotomy is not always effective for symptomatic improvement in type II and III SOD. Alternate therapies with calcium channel blockers and botulinum toxin have been studied and might be considered as options after discussing the risks and benefits with the patients.

Since their introduction in 1987, hydroxymethyl glutaryl coenzyme A reductase (HMG-CoA) inhibitors, more commonly known as statins, have become some of the most widely prescribed medications in the world. Though generally considered to be safe and well tolerated, statins have been associated with several side effects including mild liver dysfunction manifested by increases in aminotransferases. Rarely, statins have been noted to induce more serious hepatic injury, including liver injury with autoimmune features. Current literature supports statin induced liver injury presenting in either hepatocellular or cholestatic patterns, though with the former being the prevailing pattern of injury. Fortunately, severe liver injury is uncommon with statin use and is generally reversible without any intervention other than offending statin cessation. When evaluating cases of suspected statin-induced liver injury, a complete medical history, laboratory tests including a complete metabolic panel, autoimmune markers, and viral panel, as well as hepatic imaging, are crucial for a complete causality analysis with validated tools such as Roussel Uclaf Causality Assessment Method. The aim of this review is to review the current evidence for statin-induced liver injury and cholestasis.