Disease Progression Research Articles

Non-invasive Scores and Serum Biomarkers for Fatty Liver in the Era of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD): A Comprehensive Review From NAFLD to MAFLD and MASLD.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide, making it the leading cause of liver related morbidity and mortality. Currently, liver biopsy is the gold standard for assessing individuals with steatohepatitis and fibrosis. However, its invasiveness, sampling variability, and impracticality for large-scale screening has driven the search for non-invasive methods for early diagnosis and staging. In this review, we comprehensively summarise the evidence on the diagnostic performance and limitations of existing non-invasive serum biomarkers and scores in the diagnosis and evaluation of steatosis, steatohepatitis, and fibrosis. Several non-invasive serum biomarkers and scores have been developed over the last decade, although none has successfully been able to replace liver biopsy. The introduction of new NAFLD terminology, namely metabolic dysfunction-associated fatty liver disease (MAFLD) and more recently metabolic dysfunction-associated steatotic liver disease (MASLD), has initiated a debate on the interchangeability of these terminologies. Indeed, there is a need for more research on the variability of the performance of non-invasive serum biomarkers and scores across the diagnostic entities of NAFLD, MAFLD and MASLD. There remains a significant need for finding valid and reliable non-invasive methods for early diagnosis and assessment of steatohepatitis and fibrosis to facilitate prompt risk stratification and management to prevent disease progression and complications. Further exploration of the landscape of MASLD under the newly defined disease subtypes is warranted, with the need for more robust evidence to support the use of commonly used serum scores against the new MASLD criteria and validation of previously developed scores.

Cost-effectiveness analysis of tislelizumab vs. camrelizumab for the treatment of second-line locally advanced or metastatic esophageal squamous cell carcinoma

BackgroundEsophageal carcinoma is a type of cancer that occurs in the esophagus. For patients with locally advanced or metastatic esophageal squamous cell carcinoma who have either experienced disease progression following first-line standard chemotherapy or are intolerant to it, the prognosis is typically poor. Additionally, these patients often bear a substantial economic burden during the course of their treatment. Tislelizumab is a selective PD-1 inhibitor with efficacy proven in locally advanced or metastatic esophageal squamous cell carcinoma. The study aims to evaluate the cost-effectiveness of tislelizumab versus camrelizumab as the second-line treatment in locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) patients in China.MethodsFrom the perspective of China’s healthcare system, the partitioned survival model with three health states was established in a 3-week cycle and a lifetime horizon. Anchored matching adjusted indirect comparison was used for survival analyses based on individual patient data from RATIONALE 302 trial and the published ESCORT study due to the lack of head-to-head clinical trials. Only direct medical costs were included. Costs and utility values were derived from local charges, the published literature, and related databases. Sensitivity analyses and a scenario analysis were also performed to verify the robustness of the model results.ResultsCompared with camrelizumab monotherapy, tislelizumab monotherapy incurred a lower lifetime cost ($8,346 vs. $8,851) and yielded higher quality-adjusted life-years (QALYs) (0.87 vs. 0.63), which resulted in an incremental cost-effectiveness ratio (ICER) of -$2,051/QALY. Tislelizumab monotherapy is a dominant option over camrelizumab monotherapy in China. The three primary parameters upon which this result was most sensitive were the unit cost of camrelizumab, the unit cost of tislelizumab, and the duration of reactive cutaneous capillary endothelial proliferation (RCCEP). According to the probabilistic sensitivity analysis (PSA), tislelizumab monotherapy was 100% cost-effective when the WTP was 1–3 times GDP per capita in China($11,207/QALY∼$33,621/QALY). Scenario analysis showed that the result was consistent.ConclusionTislelizumab monotherapy is a dominant option compared with camrelizumab monotherapy as the second-line treatment for locally advanced or metastatic ESCC in China.

MIIP downregulates PD-L1 expression through HDAC6 in cutaneous melanoma

PurposeImmune checkpoint inhibitors have improved the objective response rate and survival of melanoma patients. However, there are still many melanoma patients suffering from disease progression due to primary or secondary immune checkpoint inhibitor resistance, as is observed in the failure of anti-PD1/PD-L1 therapy. While the expression of valuable markers, such as TMB, MSI, and PD-L1, could serve as effective predictors of anti-checkpoint inhibitor therapies, tumor cell PD-L1 expression and its regulating mechanism would significantly affect the anti-PD-1 immunotherapy response and efficacy. Therefore, it is urgent to determine the function of PD-1/PD-L1 expression in melanoma and its associated pathways to enhance the efficacy of anti-PD-1 therapies.MethodsA cohort of 133 patients with histologically confirmed melanoma from Tianjin Medical University Cancer Institute & Hospital were included in this study. We performed immunohistochemical staining to detect the expression of Migration and invasion inhibitory protein (MIIP), HDAC6 and PD-L1. Kaplan–Meier and log-rank test were used for survival analysis. As for vitro, Western blot was used in melanoma cell lines to verify the signaling pathway that MIIP regulates PD-L1 expression.ResultsMIIP expression was decreased in melanoma and that the negative expression of MIIP was correlated with worse overall survival. The positive expression of HDAC6, a molecule that is downstream of MIIP, had a positive trend with decreased overall survival. At the same time, the positive expression of PD-L1, a crucial costimulatory molecule, was associated with decreased overall survival. Furthermore, there was a positive association between HDAC6 and PD-L1 protein expression (p < 0.01), and this correlation is more prominent in cutaneous melanoma than acral melanoma. In cutaneous melanoma cell lines, we found that increasing MIIP led to decreased HDAC6, pSTAT3, and PD-L1 expression. Knocking down MIIP led to increased HDAC6, pSTAT3, and PD-L1 expression. Combining the published results, showing that HDAC6 can regulate PD-L1 expression through STAT3, our present data suggest that MIIP inhibits the expression of PD-L1 by downregulating HDAC6 in melanoma. Most importantly, methods for targeting MIIP-HDAC6-PD-L1 pathways, such as treatment with HDAC6 inhibitors, might indicate a new therapeutic approach for enhancing immune checkpoint inhibitor therapies in melanoma.ConclusionsOur findings highlight the immunomodulatory effects of MIIP in the inhibition of PD-L1 expression by downregulating HDAC6 in melanoma. Methods for targeting MIIP-HDAC6-PD-L1 pathways might be new therapeutic approaches for enhancing immune checkpoint inhibitor therapies in melanoma.

Lenvatinib rechallenge after failure of lenvatinib and sorafenib in metastatic thyroid cancer.

The oral multikinase inhibitors sorafenib and lenvatinib are currently available as first-line treatment for patients with unresectable or metastatic thyroid cancer. However, treatment options for patients who are refractory to these multikinase inhibitors are limited. This study aimed to evaluate the safety and efficacy of rechallenged lenvatinib after failure of both lenvatinib and sorafenib in patients with metastatic thyroid cancer in the real-world clinical practice. We retrospectively reviewed the data of consecutive 16 patients with metastatic thyroid cancer who received lenvatinib as a rechallenge after failure of initial lenvatinib and sorafenib treatment at Shizuoka Cancer Center between 2016 and 2023. Of these, the initial lenvatinib was discontinued in 12 patients owing to progressive disease, in 3 patients owing to adverse events, and in 1 patient owing to both. The overall response rate was 6.7%, and disease control was achieved by rechallenge with lenvatinib in all patients with the target lesions. The median progression free survival after rechallenging with lenvatinib was 15.0 months. No new signs of toxicity were observed after rechallenging with lenvatinib. Our findings suggest that rechallenge with lenvatinib after failure of both lenvatinib and sorafenib showed manageable safety and modest efficacy in patients with metastatic thyroid cancer in clinical practice. The strategy of lenvatinib rechallenge may provide an alternative option for patients with no targetable driver genes or when selective kinase inhibitors are not indicated.

Unraveling progression subtypes in people with Huntington’s disease

Abstract Background Huntington’s disease (HD) is a progressive neurodegenerative disease caused by a CAG trinucleotide expansion in the huntingtin gene. The length of the CAG repeat is inversely correlated with disease onset. HD is characterized by hyperkinetic movement disorder, psychiatric symptoms, and cognitive deficits, which greatly impact patient’s quality of life. Despite this clear genetic course, high variability of HD patients’ symptoms can be observed. Current clinical diagnosis of HD solely relies on the presence of motor signs, disregarding the other important aspects of the disease. By incorporating a broader approach that encompasses motor as well as non-motor aspects of HD, predictive, preventive, and personalized (3P) medicine can enhance diagnostic accuracy and improve patient care. Methods Multisymptom disease trajectories of HD patients collected from the Enroll-HD study were first aligned on a common disease timescale to account for heterogeneity in disease symptom onset and diagnosis. Following this, the aligned disease trajectories were clustered using the previously published Variational Deep Embedding with Recurrence (VaDER) algorithm and resulting progression subtypes were clinically characterized. Lastly, an AI/ML model was learned to predict the progression subtype from only first visit data or with data from additional follow-up visits. Results Results demonstrate two distinct subtypes, one large cluster (n = 7122) showing a relative stable disease progression and a second, smaller cluster (n = 411) showing a dramatically more progressive disease trajectory. Clinical characterization of the two subtypes correlates with CAG repeat length, as well as several neurobehavioral, psychiatric, and cognitive scores. In fact, cognitive impairment was found to be the major difference between the two subtypes. Additionally, a prognostic model shows the ability to predict HD subtypes from patients’ first visit only. Conclusion In summary, this study aims towards the paradigm shift from reactive to preventive and personalized medicine by showing that non-motor symptoms are of vital importance for predicting and categorizing each patients’ disease progression pattern, as cognitive decline is oftentimes more reflective of HD progression than its motor aspects. Considering these aspects while counseling and therapy definition will personalize each individuals’ treatment. The ability to provide patients with an objective assessment of their disease progression and thus a perspective for their life with HD is the key to improving their quality of life. By conducting additional analysis on biological data from both subtypes, it is possible to gain a deeper understanding of these subtypes and uncover the underlying biological factors of the disease. This greatly aligns with the goal of shifting towards 3P medicine.

Microbiota and Gut-Liver Axis: An Unbreakable Bond?

The gut microbiota, amounting to approximately 100 trillion (1014) microbes represents a genetic repertoire that is bigger than the human genome itself. Evidence on bidirectional interplay between human and microbial genes is mounting. Microbiota probably play vital roles in diverse aspects of normal human metabolism, such as digestion, immune modulation, and gut endocrine function, as well as in the genesis and progression of many human diseases. Indeed, the gut microbiota has been most closely linked to various chronic ailments affecting the liver, although concrete scientific data are sparse. In this narrative review, we initially discuss the basic epidemiology of gut microbiota and the factors influencing their initial formation in the gut. Subsequently, we delve into the gut-liver axis and the evidence regarding the link between gut microbiota and the genesis or progression of various liver diseases. Finally, we summarise the recent research on plausible ways to modulate the gut microbiota to alter the natural history of liver disease.

The amyloid precursor protein and its derived fragments concomitantly contribute to the alterations of mitochondrial transport machinery in Alzheimer’s disease

Mitochondria dysfunctions and mitophagy failure have been associated with several Alzheimer’s disease (AD) related molecular actors including amyloid beta (Aβ) and recently the amyloid precursor protein-C terminal fragments (APP-CTFs). The efficacy of the mitophagy process in neurons relies on regulated mitochondrial transport along axons involving a complex molecular machinery. The contribution of the amyloid precursor protein (APP) and its derived fragments to the mitochondrial transport machinery alterations in AD have not been investigated before. We report herein a change of the expression of mitochondrial transport proteins (SNPH and Miro1), motor adapters (TRANK1 and TRAK2), and components of the dynein and kinesin motors (i.e., IC1,2 and Kif5 (A, B, C) isoforms) by endogenous APP and by overexpression of APP carrying the familial Swedish mutation (APPswe). We show that APP-CTFs and Aβ concomitantly regulate the expression of a set of transport proteins as demonstrated in APPswe cells treated with β- and γ-secretase inhibitors and in cells Knock-down for presenilin 1 and 2. We further report the impact of APP-CTFs on the expression of transport proteins in AAV-injected C99 mice brains. Our data also indicate that both Aβ oligomers (Aβo) and APP-CTFs impair the colocalization of mitochondria and transport proteins. This has been demonstrated in differentiated SH-SY5Y naive cells treated with Aβo and in differentiated SH-SY5Y and murine primary neurons expressing APPswe and treated with the γ-secretase inhibitor. Importantly, we uncover that the expression of a set of transport proteins is modulated in a disease-dependent manner in 3xTgAD mice and in human sporadic AD brains. This study highlights molecular mechanisms underlying mitochondrial transport defects in AD that likely contribute to mitophagy failure and disease progression.

Machine learning for prediction of chronic kidney disease progression: Validation of the Klinrisk model in the CANVAS Program and CREDENCE trial.

To validate the Klinrisk machine learning model for prediction of chronic kidney disease (CKD) progression in patients with type 2 diabetes in the pooled CANVAS/CREDENCE trials. We externally validated the Klinrisk model for prediction of CKD progression, defined as 40% or higher decline in estimated glomerular filtration rate (eGFR) or kidney failure. Model performance was assessed for prediction up to 3 years with the area under the receiver operating characteristic curve (AUC), Brier scores and calibration plots of observed and predicted risks. We compared performance of the model with standard of care using eGFR (G1-G4) and urine albumin-creatinine ratio (A1-A3) Kidney Disease Improving Global Outcomes (KDIGO) heatmap categories. The Klinrisk model achieved an AUC of 0.81 (95% confidence interval [CI] 0.78-0.83) at 1 year, and 0.88 (95% CI 0.86-0.89) at 3 years. The Brier scores were 0.020 (0.018-0.022) and 0.056 (0.052-0.059) at 1 and 3 years, respectively. Compared with the KDIGO heatmap, the Klinrisk model had improved performance at every interval (P < .01). The Klinrisk machine learning model, using routinely collected laboratory data, was highly accurate in its prediction of CKD progression in the CANVAS/CREDENCE trials. Integration of the model in electronic medical records or laboratory information systems can facilitate risk-based care.

Learning semi-supervised enrichment of longitudinal imaging-genetic data for improved prediction of cognitive decline

BackgroundAlzheimer’s Disease (AD) is a progressive memory disorder that causes irreversible cognitive decline. Given that there is currently no cure, it is critical to detect AD in its early stage during the disease progression. Recently, many statistical learning methods have been presented to identify cognitive decline with temporal data, but few of these methods integrate heterogeneous phenotype and genetic information together to improve the accuracy of prediction. In addition, many of these models are often unable to handle incomplete temporal data; this often manifests itself in the removal of records to ensure consistency in the number of records across participants.ResultsTo address these issues, in this work we propose a novel approach to integrate the genetic data and the longitudinal phenotype data to learn a fixed-length “enriched” biomarker representation derived from the temporal heterogeneous neuroimaging records. Armed with this enriched representation, as a fixed-length vector per participant, conventional machine learning models can be used to predict clinical outcomes associated with AD.ConclusionThe proposed method shows improved prediction performance when applied to data derived from Alzheimer’s Disease Neruoimaging Initiative cohort. In addition, our approach can be easily interpreted to allow for the identification and validation of biomarkers associated with cognitive decline.

Oropharyngeal Dysphagia Phenotypes Across Huntington’s Disease Stages: Endoscopic Findings and Tongue Pressure Analysis

Background: Oropharyngeal dysphagia (OD) is a common symptom in Huntington’s disease (HD) and is associated with severe health and psychosocial consequences. Different OD phenotypes are defined on the basis of characteristic patterns at fiberoptic endoscopic evaluation of swallowing (FEES), and they may vary during disease progression. Objective: To describe OD phenotypes in different HD stages and to analyze their association with neurological data and tongue pressure measurements. Methods: Twenty-four patients with HD at different stages of disease progression underwent a FEES. Data on penetration/aspiration, pharyngeal residue, and OD phenotypes were gained. Neurological examination was performed with the Unified Huntington’s Disease Rating Scale (UHDRS). Patient Maximum tongue pressure (MTP) and tongue endurance were measured. Results: We confirmed that the occurrence of penetration/aspiration increased with disease duration and pharyngeal residue increased from 16.7% to 100% , respectively. The most common OD phenotypes were oropharyngeal dyspraxia (91.7% ), posterior oral incontinence (87.5% ), and delayed pharyngeal phase (87.5% ). These types of dysfunctions are already detectable in &gt;80% of patients in the early disease stages. In more advanced stages, we also observed propulsion deficit (66.7% ), resistive issue (54.2% ), and protective deficit (37.5% ). Propulsion deficit was associated with higher disease stage, greater motor dysfunction (UHDRS-I), and lower MTP and tongue endurance (p &lt; 0.05). Conclusions: OD in HD results from a combination of different swallowing phenotypes. Early assessment of swallowing and periodical follow-ups are necessary to monitor OD severity and phenotypes and to revise diet recommendations.

Association of NOTCH3 Variant Risk Category With 2-Year Clinical and Radiologic Small Vessel Disease Progression in Patients With CADASIL.

Pathogenic variants in NOTCH3 are the main cause of hereditary cerebral small vessel disease (SVD). SVD-associated NOTCH3 variants have recently been categorized into high risk (HR), moderate risk (MR), or low risk (LR) for developing early-onset severe SVD. The most severe NOTCH3-associated SVD phenotype is also known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to investigate whether NOTCH3 variant risk category is associated with 2-year progression rate of SVD clinical and neuroimaging outcomes in CADASIL. A single-center prospective 2-year follow-up study was performed of patients with CADASIL. Clinical outcomes were incident stroke, disability (modified Rankin Scale), and executive function (Trail Making Test B given A t-scores). Neuroimaging outcomes were mean skeletonized mean diffusivity (MSMD), normalized white matter hyperintensity volume (nWMHv), normalized lacune volume (nLV), and brain parenchymal fraction (BPF). Cox regression and mixed-effect models, adjusted for age, sex, and cardiovascular risk factors, were used to study 2-year changes in outcomes and differences in disease progression between patients with HR-NOTCH3 and MR-NOTCH3 variants. One hundred sixty-two patients with HR (n = 90), MR (n = 67), and LR (n = 5) NOTCH3 variants were included. For the entire cohort, there was 2-year mean progression for MSMD (β = 0.20, 95% CI 0.17-0.23, p = 7.0 × 10-24), nLV (β = 0.13, 95% CI 0.080-0.19, p = 2.1 × 10-6), nWMHv (β = 0.092, 95% CI 0.075-0.11, p = 8.8 × 10-20), and BPF (β = -0.22, 95% CI -0.26 to -0.19, p = 3.2 × 10-22), as well as an increase in disability (p = 0.002) and decline of executive function (β = -0.15, 95% CI -0.30 to -3.4 × 10-5, p = 0.05). The HR-NOTCH3 group had a higher probability of 2-year incident stroke (hazard ratio 4.3, 95% CI 1.4-13.5, p = 0.011), and a higher increase in MSMD (β = 0.074, 95% CI 0.013-0.14, p = 0.017) and nLV (β = 0.14, 95% CI 0.034-0.24, p = 0.0089) than the MR-NOTCH3 group. Subgroup analyses showed significant 2-year progression of MSMD in young (n = 17, β = 0.014, 95% CI 0.0093-0.019, p = 1.4 × 10-5) and premanifest (n = 24, β = 0.012, 95% CI 0.0082-0.016, p = 1.1 × 10-6) individuals. In a trial-sensitive time span of 2 years, we found that patients with HR-NOTCH3 variants have a significantly faster progression of major clinical and neuroimaging outcomes, compared with patients with MR-NOTCH3 variants. This has important implications for clinical trial design and disease prediction and monitoring in the clinic. Moreover, we show that MSMD is a promising outcome measure for trials enrolling premanifest individuals.

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial

ObjectiveTo evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy.DesignRandomised, double blind,...

Non-small cell lung cancer and metabolism research from 2013 to 2023: a visual analysis and bibliometric study

BackgroundAs one of the most prevalent primary lung tumors, non-small cell lung cancer (NSCLC) has garnered considerable research interest due to its high metastasis rates and poor prognosis outcomes. Across different cancer types, metabolic processes are required for tumors progression and growth, thus interfering with such processes in NSCLC may therapeutically viable for limiting/halting disease progression. Therefore, comprehending how metabolic processes contribute to growth and survival mechanisms in cancers, including NSCLC, may elucidate key functions underpinning tumor cell metabolism. However, no bibliometric analyses have been published in this field, therefore we address this knowledge gap here.MethodsBetween 2013 and 2023 (December 28th), articles related to the NSCLC and metabolism (NSCLC-Met) field were retrieved from the Web of Science Core Collection (WoSCC). To fully dissect NSCLC-Met research directions and articles, we used the Bibliometrix package in R, VOSviewer and CiteSpace software to visually represent global trends and hotspots.ResultsBetween 2013 and 2023, 2,246 NSCLC-Met articles were retrieved, with a continuous upward trend and rapid development observed year on year. Cancers published the most articles, with Cancer Research recording the highest average citation numbers. Zhang Li from China was the most prolific author, but the highest number of authors came from the USA. China, USA, and Italy were the top three countries with the highest number of published articles, with close cooperation identified between countries. Recent hotspots and research directions were reflected by “lung adenocarcinoma”, “immunotherapy”, “nivolumab”, “checkpoint inhibitors”, “blockade”, and “pembrolizumab”, while “gut microbiome”, “egfr” and “dose painting” were important topics for researchers.ConclusionFrom our analyses, scientists can now explore new hotspots and research directions in the NSCLC-Met field. Further in-depth research in this field will undoubtedly provide more new insights on disease diagnostics, treatment, and prognostics.

The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease in which chronic membrane potential (Em) depolarisation of the pulmonary arterial smooth muscle cells (PASMCs) causes calcium overload, a key pathological alteration. Under resting conditions, the negative Em is mainly set by two pore domain potassium (K2P) channels, of which the TASK-1 has been extensively investigated. Ion channel currents and membrane potential of primary cultured human(h) PASMCs were measured using the voltage- and current clamp methods. Intracellular [Ca2+] was monitored using fluorescent microscopy. Pulmonary BP and vascular tone measurements were also performed ex vivo using a rat PAH model. TREK-1 was the most abundantly expressed K2P in hPASMCs of healthy donors and idiopathic(I) PAH patients. Background K+-current was similar in hPASMCs for both groups and significantly enhanced by the TREK activator ML-335. In donor hPASMCs, siRNA silencing or pharmacological inhibition of TREK-1 caused depolarisation, reminiscent of the electrophysiological phenotype of idiopathic PAH. ML-335 hyperpolarised donor hPASMCs and normalised the Em of IPAH hPASMCs. A close link was found between TREK-1 activity and intracellular Ca2+-signalling using a channel activator, ML-335, and an inhibitor, spadin. In the rat, ML-335 relaxed isolated pre-constricted pulmonary arteries and significantly decreased pulmonary arterial pressure in the isolated perfused lung. These data suggest that TREK-1is a key factor in Em setting and Ca2+ homeostasis of hPASMC, and therefore, essential for maintenance of a low resting pulmonary vascular tone. Thus TREK-1 may represent a new therapeutic target for PAH.

Association between atherosclerotic cardiovascular disease score and skin carotenoid levels estimated via refraction spectroscopy in the Japanese population: a cross-sectional study

Carotenoids play a role in preventing and impeding the progression of atherosclerotic cardiovascular diseases (ASCVDs) through their anti-oxidative effects. This study evaluated associations between ASCVD risk and skin carotenoid (SC) levels, reflecting dietary carotenoid intake. Participants’ ASCVD risk was assessed using the Hisayama ASCVD risk prediction model, and SC levels were measured through a reflection spectroscope (Veggie Meter). The associations between high ASCVD risk and SC levels were analyzed using logistic regression analysis and a restricted cubic spline (RCS) model. A total of 1130 men and women (mean age: 56 years) from participants who underwent a health examination in Seirei Center for Health Promotion and Prevention Medicine in 2019 and 2022 were analyzed. Of these, 4.6% had moderate or high ASCVD risk. Mean SC values were 236, 315, 376, 447, and 606 in quintile Q1 to Q5, respectively. The adjusted odds ratios (95% confidence intervals) of SC quintile for moderate- or high-risk ASCVD was 0.24 (0.12–0.51) in Q5 (495 ≤), 0.42 (0.23–0.77) in Q4, 0.50 (0.29–0.88) in Q3, and 0.68 (0.41–1.12) in Q2 compared to Q1 (< 281). High SC values continuously showed non-linear inverse association with moderate- or high-risk for ASCVD in Japanese adults. Non-invasive SC measurements may be a good indicator for recommending carotenoids to prevent cardiovascular disease.

Nonspecific therapy for Eisenmenger syndrome

Eisenmenger syndrome (ES) is systemic pulmonary hypertension with venoarterial or bidirectional shunting of blood between the ventricles, atria or great arteries due to the progression of pulmonary vascular disease in the natural course of “simple” and “complex” congenital heart defects.Patients with ES require constant attention from a multidisciplinary team of specialists. One of the main tasks is not to destabilize the fragile pathological physiology, which relies on the balance of pulmonary and peripheral vascular resistance. Surgical interventions with anesthesia, if they cannot be avoided, should be performed in specialized centers. Pregnancy is contraindicated in patients with ES. Clinical symptoms of blood hyperviscosity in ES are rare.The anachronistic practice of venesections, which leads to a decrease in the oxygen transport function of the blood, iron deficiency and an increased risk of cerebrovascular complications, should be avoided. Oral and intravenous replenishment of iron deficiency improves exercise tolerance and quality of life. Routine administration of anticoagulants for ES is not indicated. In most cases, endovascular embolization of pathological collateral arteries can eliminate hemoptysis. The use of venous access requires careful prevention of embolism. Therapeutic tactics for ES are discussed in detail in this review

Exploring Phenolic Compounds in Crop By-Products for Cosmetic Efficacy

Phenolic compounds represent a group of secondary metabolites that serve essential functions in plants. Beyond their positive impact on plants, these phenolic metabolites, often referred to as polyphenols, possess a range of biological properties that can promote skin health. Scientific research indicates that topically using phenolics derived from plants can be advantageous, but their activity and stability highly depend on storage of the source material and the extraction method. These compounds have the ability to relieve symptoms and hinder the progression of different skin diseases. Because they come from natural sources and have minimal toxicity, phenolic compounds show potential in addressing the causes and effects of skin aging, skin diseases, and various types of skin damage, such as wounds and burns. Hence, this review provides extensive information on the particular crops from which by-product phenolic compounds can be sourced, also emphasizing the need to conduct research according to proper plant material storage practices and the choice of the best extracting method, along with an examination of their specific functions and the mechanisms by which they act to protect skin.

Epigenetics and environmental health.

Epigenetic modifications including DNA methylation, histone modifications, chromatin remodeling, and RNA modifications complicate gene regulation and heredity and profoundly impact various physiological and pathological processes. In recent years, accumulating evidence indicates that epigenetics is vulnerable to environmental changes and regulates the growth, development, and diseases of individuals by affecting chromatin activity and regulating gene expression. Environmental exposure or induced epigenetic changes can regulate the state of development and lead to developmental disorders, aging, cardiovascular disease, Alzheimer's disease, cancers, and so on. However, epigenetic modifications are reversible. The use of specific epigenetic inhibitors targeting epigenetic changes in response to environmental exposure is useful in disease therapy. Here, we provide an overview of the role of epigenetics in various diseases. Furthermore, we summarize the mechanism of epigenetic alterations induced by different environmental exposures, the influence of different environmental exposures, and the crosstalk between environmental variation epigenetics, and genes that are implicated in the body's health. However, the interaction of multiple factors and epigenetics in regulating the initiation and progression of various diseases complicates clinical treatments. We discuss some commonly used epigenetic drugs targeting epigenetic modifications and methods to prevent or relieve various diseases regulated by environmental exposure and epigenetics through diet.

Emergence of the brain-border immune niches and their contribution to the development of neurodegenerative diseases

Historically, the central nervous system (CNS) was regarded as ‘immune-privileged’, possessing its own distinct immune cell population. This immune privilege was thought to be established by a tight blood-brain barrier (BBB) and blood-cerebrospinal-fluid barrier (BCSFB), which prevented the crossing of peripheral immune cells and their secreted factors into the CNS parenchyma. However, recent studies have revealed the presence of peripheral immune cells in proximity to various brain-border niches such as the choroid plexus, cranial bone marrow (CBM), meninges, and perivascular spaces. Furthermore, emerging evidence suggests that peripheral immune cells may be able to infiltrate the brain through these sites and play significant roles in driving neuronal cell death and pathology progression in neurodegenerative disease. Thus, in this review, we explore how the brain-border immune niches may contribute to the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). We then discuss several emerging options for harnessing the neuroimmune potential of these niches to improve the prognosis and treatment of these debilitative disorders using novel insights from recent studies.

Exploratory study to evaluate the acceptability of a wearable accelerometer to assess motor progression in motor neuron disease.

Motor neuron disease (MND) is a rapidly progressive condition traditionally assessed using a questionnaire to evaluate physical function, the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R). Its use can be associated with poor sensitivity in detecting subtle changes over time and there is an urgent need for more sensitive and specific outcome measures. The ActiGraph GT9X is a wearable device containing multiple sensors that can be used to provide metrics that represent physical activity. The primary aim of this study was to investigate the initial suitability and acceptability of limb-worn wearable devices to group of people with MND in Scotland. A secondary aim was to explore the preliminary associations between the accelerometer sensor data within the ActiGraph GT9X and established measures of physical function. 10 participants with MND completed a 12-week schedule of assessments including fortnightly study visits, both in-person and over videoconferencing software. Participants wore the device on their right wrist and right ankle for a series of movements, during a 6-min walking test and for a period of 24-h wear, including overnight. Participants also completed an ALSFRS-R and questionnaires on their experience with the devices. 80% of the participants found wearing these devices to be a positive experience and no one reported interference with daily living or added burden. However, 30% of the participants experienced technical issues with their devices. Data from the wearable devices correlated with established measures of physical function.