Adverse outcomes of intrinsic capacity in older adults: A scoping review.

Background and Purpose Intrinsic capacity (IC) has been shown to have the greatest impact on an individual's health status and health trajectory and can independently predict adverse outcomes such as mortality and care dependency in older adults. However, the current understanding of adverse outcomes associated with IC is incomplete. Methods A scoping review of the literature from PubMed, Web of Science (WOS), The Cochrane Library, CINAHL, and Embase databases was conducted from January 2015 to March 2023 to identify articles related to the adverse outcomes associated with IC in older adults. Results 711 studies met screening criteria, and 25 studies met inclusion criteria. These studies reported a total of 17 adverse outcomes related to IC across four domains. (1) Adverse outcomes in the physiological function domains included frailty, pneumonia onset, memory impairment, polypharmacy, incontinence, and poor/fair self-rated health. (2) Clinical outcomes domains included IADL disability, ADL disability, mortality, falls, autonomy decline, and incident dependence. (3) The resource utilization domains included hospitalization, nursing home stays, polypharmacy healthcare costs, and emergency department visits. (4) The other domains mainly included poor quality of life. Conclusion It is evident that IC decline in older adults is associated with a broad spectrum of adverse outcomes spanning cognitive function, activity ability, sensory perception, physical and mental health and living standards. Future studies should further deepen the exploration of IC.

Factors associated with the intrinsic capacity in older adults: A scoping review.

INTRODUCTION: In 2015, the term 'intrinsic capacity' (IC) was proposed by the World Health Organisation to promote healthy aging. However, the factors associated with IC are still discrepant and uncertain. AIM: We aim to synthesise the factors connected with IC. METHODS: This scoping review followed the five-stage framework of Arksey and O'Malley and was reported using PRISMA-ScR guidelines. RESULTS: In all, 29 articles were included. IC of older adults is associated with demographic characteristics, socioeconomic factors, disease conditions, behavioural factors, and biomarkers. Age, sex, marital status, occupation status, education, income/wealth, chronic diseases, hypertension, diabetes, disability, smoking status, alcohol consumption, and physical activity were emerged as important factors related to the IC of older adults. CONCLUSIONS: This review shows that IC is related to multiple factors. Understanding these factors can provide the healthcare personnel with the theoretical basis for intervening and managing IC in older adults. RELEVANCE TO CLINICAL PRACTICE: The influencing factors identified in the review help to guide older adults to maintain their own intrinsic capacity, thereby promoting their health and well-being. The modifiable factors also provide evidence for healthcare personnel to develop targeted intervention strategies to delay IC decline. NO PATIENT OR PUBLIC CONTRIBUTION: As this is a scoping review, no patient or public contributions are required.

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19.

The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1ß, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1ß after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19.

The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1ß, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1ß after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.

Repeatability of radiomics studies in colorectal cancer: a systematic review.

BACKGROUND: Recently, radiomics has been widely used in colorectal cancer, but many variable factors affect the repeatability of radiomics research. This review aims to analyze the repeatability of radiomics studies in colorectal cancer and to evaluate the current status of radiomics in the field of colorectal cancer. METHODS: The included studies in this review by searching from the PubMed and Embase databases. Then each study in our review was evaluated using the Radiomics Quality Score (RQS). We analyzed the factors that may affect the repeatability in the radiomics workflow and discussed the repeatability of the included studies. RESULTS: A total of 188 studies was included in this review, of which only two (2/188, 1.06%) studies controlled the influence of individual factors. In addition, the median score of RQS was 11 (out of 36), range-1 to 27. CONCLUSIONS: The RQS score was moderately low, and most studies did not consider the repeatability of radiomics features, especially in terms of Intra-individual, scanners, and scanning parameters. To improve the generalization of the radiomics model, it is necessary to further control the variable factors of repeatability.

A correlative study between IVIM-DWI parameters and VEGF and MMPs expression in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Angiogenic factors may be valuable indices of tumor recurrence and treatment and potentially useful markers for predicting the response to antiangiogenesis therapy. Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are major drivers of tumor angiogenesis. Preoperatively predicting the expression of VEGF and MMPs is crucial for treating HCC. Intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) has been successfully used in the differential diagnosis of HCC, pathological grading, and treatment response evaluation. However, the correlations between IVIM-DWI parameters and VEGF and MMP expression have not been reported. This study provides a preliminary analysis of the correlation between IVIM-DWI parameters and the expression of VEGF, MMP-2, and MMP-9 to investigate the value of IVIM-DWI in the noninvasive evaluation of angiogenesis in HCC. Methods: IVIM-DWI was performed in 61 patients with HCC 1 week before they underwent surgical resection. VEGF, MMP-2, and MMP-9 expression was detected using immunohistochemistry staining. Spearman correlation analysis was used to analyze the correlations between the IVIM-DWI parameters and VEGF, MMP-2, and MMP-9 expression in HCC. Results: The fast apparent diffusion coefficient fraction (f) value was positively correlated with the expression of VEGF (P<0.001), MMP-2 (P=0.002), and MMP-9 (P<0.001). The fast apparent diffusion coefficient (D*) was positively correlated with VEGF (P<0.001) and MMP-9 (P<0.001) expression but was not correlated with MMP-2 (P=0.659) expression. The apparent diffusion coefficient (ADC) and slow apparent diffusion coefficient (D) values were not significantly correlated with the expression of VEGF (P=0.103 and P=0.543, respectively), MMP-2 (P=0.596 and P=0.338, respectively), or MMP-9 (P=0.102 and P=0.660, respectively). Conclusions: IVIM-DWI can be used to noninvasively evaluate angiogenesis in HCC.

CT radiomics combined with clinical variables for predicting the overall survival of hepatocellular carcinoma patients after hepatectomy.

PURPOSE: To establish a model for assessing the overall survival (OS) of the hepatocellular carcinoma (HCC) patients after hepatectomy based on the clinical and radiomics features. METHODS: This study recruited a total of 267 patients with HCC, which were randomly divided into the training (N = 188) and validation (N = 79) cohorts. In the training cohort, radiomic features were selected with the intra-reader and inter-reader correlation coefficient (ICC), Spearman's correlation coefficient, and the least absolute shrinkage and selection operator (LASSO). The radiomics signatures were built by COX regression analysis and compared the predictive potential in the different phases (arterial, portal, and double-phase) and regions of interest (tumor, peritumor 3 mm, peritumor 5 mm). A clinical-radiomics model (CR model) was established by combining the radiomics signatures and clinical risk factors. The validation cohort was used to validate the proposed models. RESULTS: A total of 267 patients 86 (45.74%) and 37 (46.84%) patients died in the training and validation cohorts, respectively. Among all the radiomics signatures, those based on the tumor and peritumor (5 mm) (AP-TP5-Signature) showed the best prognostic potential (training cohort 1-3 years AUC:0.774-0.837; validation cohort 1-3 years AUC:0.754-0.810). The CR model showed better discrimination, calibration, and clinical applicability as compared to the clinical model and radiomics features. In addition, the CR model could perform risk-stratification and also allowed for significant discrimination between the Kaplan-Meier curves in most of the subgroups. CONCLUSIONS: The CR model could predict the OS of the HCC patients after hepatectomy.

Progress of MRI Radiomics in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer-related death. Although the diagnostic scheme of HCC is currently undergoing refinement, the prognosis of HCC is still not satisfactory. In addition to certain factors, such as tumor size and number and vascular invasion displayed on traditional imaging, some histopathological features and gene expression parameters are also important for the prognosis of HCC patients. However, most parameters are based on postoperative pathological examinations, which cannot help with preoperative decision-making. As a new field, radiomics extracts high-throughput imaging data from different types of images to build models and predict clinical outcomes noninvasively before surgery, rendering it a powerful aid for making personalized treatment decisions preoperatively. OBJECTIVE: This study reviewed the workflow of radiomics and the research progress on magnetic resonance imaging (MRI) radiomics in the diagnosis and treatment of HCC. METHODS: A literature review was conducted by searching PubMed for search of relevant peer-reviewed articles published from May 2017 to June 2021.The search keywords included HCC, MRI, radiomics, deep learning, artificial intelligence, machine learning, neural network, texture analysis, diagnosis, histopathology, microvascular invasion, surgical resection, radiofrequency, recurrence, relapse, transarterial chemoembolization, targeted therapy, immunotherapy, therapeutic response, and prognosis. RESULTS: Radiomics features on MRI can be used as biomarkers to determine the differential diagnosis, histological grade, microvascular invasion status, gene expression status, local and systemic therapeutic responses, and prognosis of HCC patients. CONCLUSION: Radiomics is a promising new imaging method. MRI radiomics has high application value in the diagnosis and treatment of HCC.

Host RAB11FIP5 protein inhibits the release of Kaposi's sarcoma-associated herpesvirus particles by promoting lysosomal degradation of ORF45.

Open reading frame (ORF) 45 is an outer tegument protein of Kaposi's sarcoma-associated herpesvirus (KSHV). Genetic analysis of an ORF45-null mutant revealed that ORF45 plays a key role in the events leading to the release of KSHV particles. ORF45 associates with lipid rafts (LRs), which is responsible for the colocalization of viral particles with the trans-Golgi network and facilitates their release. In this study, we identified a host protein, RAB11 family interacting protein 5 (RAB11FIP5), that interacts with ORF45 in vitro and in vivo. RAB11FIP5 encodes a RAB11 effector protein that regulates endosomal trafficking. Overexpression of RAB11FIP5 in KSHV-infected cells decreased the expression level of ORF45 and inhibited the release of KSHV particles, as reflected by the significant reduction in the number of extracellular virions. In contrast, silencing endogenous RAB11FIP5 increased ORF45 expression and promoted the release of KSHV particles. We further showed that RAB11FIP5 mediates lysosomal degradation of ORF45, which impairs its ability to target LRs in the Golgi apparatus and inhibits ORF45-mediated colocalization of viral particles with the trans-Golgi network. Collectively, our results suggest that RAB11FIP5 enhances lysosome-dependent degradation of ORF45, which inhibits the release of KSHV particles, and have potential implications for virology and antiviral design.

NCOA2 promotes lytic reactivation of Kaposi's sarcoma-associated herpesvirus by enhancing the expression of the master switch protein RTA.

Reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) is important for persistent infection in the host as well as viral oncogenesis. The replication and transcription activator (RTA) encoded by KSHV ORF50 plays a central role in the switch from viral latency to lytic replication. Given that RTA is a transcriptional activator and RTA expression is sufficient to activate complete lytic replication, RTA must possess an elaborate mechanism for regulating its protein abundance. Previous studies have demonstrated that RTA could be degraded through the ubiquitin-proteasome pathway. A protein abundance regulatory signal (PARS), which consists of PARS I and PARS II, at the C-terminal region of RTA modulates its protein abundance. In the present study, we identified a host protein named Nuclear receptor coactivator 2 (NCOA2), which can interact with RTA in vitro and in vivo. We further showed that NCOA2 binds to the PARS II domain of RTA. We demonstrated that NCOA2 enhances RTA stability and prevents the proteasome-mediated degradation of RTA by competing with MDM2, an E3 ubiquitin ligase of RTA that interacts with the PARS II domain. Moreover, overexpression of NCOA2 in KSHV-infected cells significantly enhanced the expression level of RTA, which promotes the expression of RTA downstream viral lytic genes and lytic replication. In contrast, silencing of endogenous NCOA2 downregulated the expression of viral lytic genes and impaired viral lytic replication. Interestingly, we also found that RTA upregulates the expression of NCOA2 during lytic reactivation. Taken together, our data support the conclusion that NCOA2 is a novel RTA-binding protein that promotes RTA-driven lytic reactivation by increasing the stability of RTA, and the RTA-NCOA2 positive feedback regulatory loop plays an important role in KSHV reactivation.

Negative Regulation of Interferon-ß Production by Alternative Splicing of Tumor Necrosis Factor Receptor-Associated Factor 3 in Ducks.

Tumor necrosis factor receptor-associated factor 3 (TRAF3), an intracellular signal transducer, is identified as an important component of Toll-like receptors and RIG-I-like receptors induced type I interferon (IFN) signaling pathways. Previous studies have clarified TRAF3 function in mammals, but little is known about the role of TRAF3 in ducks. Here, we cloned and characterized the full-length duck TRAF3 (duTRAF3) gene and an alternatively spliced isoform of duTRAF3 (duTRAF3-S) lacking the fragment encoding amino acids 217-319, from duck embryo fibroblasts (DEFs). We found that duTRAF3 and duTRAF3-S played different roles in regulating IFN-ß production in DEFs. duTRAF3 through its TRAF domain interacted with duMAVS or duTRIF, leading to the production of IFN-ß. However, duTRAF3-S, containing the TRAF domain, was unable to bind duMAVS or duTRIF due to the intramolecular binding between the N- and C-terminal of duTRAF3-S that blocked the function of its TRAF domain. Further analysis identified that duTRAF3-S competed with duTRAF3 itself for binding to duTRAF3, perturbing duTRAF3 self-association, which impaired the assembly of duTRAF3-duMAVS/duTRIF complex, ultimately resulted in a reduced production of IFN-ß. These findings suggest that duTRAF3 is an important regulator of duck innate immune signaling and reveal a novel mechanism for the negative regulation of IFN-ß production via changing the formation of the homo-oligomerization of wild molecules, implying a novel regulatory role of truncated proteins.

Activation and counteraction of antiviral innate immunity by KSHV: an Update.

The innate immune responses triggering production of type I interferons and inflammatory cytokines constitute a nonspecific innate resistance that eliminates invading pathogens including viruses. The activation of innate immune signaling through pattern recognition receptors (PRRs) is by sensing pathogen-associated molecular patterns derived from viruses. According to their distribution within cells, PRRs are classified into three types of receptors: membrane, cytoplasmic, and nuclear. Kaposi's sarcoma-associated herpesvirus (KSHV), a large DNA virus, replicates in the nucleus. Its genome is protected by capsid proteins during transport in the cytosol. Multiple PRRs are involved in KSHV recognition. To successfully establish latent infection, KSHV has evolved to manipulate different aspects of the host antiviral innate immune responses. This review presents recent advances in our understanding about the activation of the innate immune signaling in response to infection of KSHV. It also reviews the evasion strategies used by KSHV to subvert host innate immune detection for establishing a persistent infection.

Hearing loss in children with e-waste lead and cadmium exposure.

Environmental chemical exposure can cause neurotoxicity and has been recently linked to hearing loss in general population, but data are limited in early life exposure to lead (Pb) and cadmium (Cd) especially for children. We aimed to evaluate the association of their exposure with pediatric hearing ability. Blood Pb and urinary Cd were collected form 234 preschool children in 3-7years of age from an electronic waste (e-waste) recycling area and a reference area matched in Shantou of southern China. Pure-tone air conduction (PTA) was used to test child hearing thresholds at frequencies of 0.25, 0.5, 1, 2, 4 and 8kHz. A PTA≥25dB was defined as hearing loss. A higher median blood Pb level was found in the exposed group (4.94±0.20 vs 3.85±1.81µg/dL, p<0.001), while no significance was found for creatinine-adjusted Cd. Compared with the reference group, the exposed group had a higher prevalence of hearing loss (28.8% vs 13.6%, p<0.001). The PTA in the left, right and both ears, and hearing thresholds at average low and high frequency, and single frequency of 0.5, 1 and 2kHz were all increased in the exposed group. Positive correlations of child age and nail biting habit with Pb, and negative correlations of parent education level and child washing hands before dinner with Pb and Cd exposure were observed. Logistic regression analyses showed the adjusted OR of hearing loss for Pb exposure was 1.24 (95% CI: 1.029, 1.486). Our data suggest that early childhood exposure to Pb may be an important risk factor for hearing loss, and the developmental auditory system might be affected in e-waste polluted areas.

Diffusion Tensor Imaging of the Auditory Neural Pathway for Clinical Outcome of Cochlear Implantation in Pediatric Congenital Sensorineural Hearing Loss Patients.

Although conventional structural MRI provides vital information in the evaluation of congenital sensorineural hearing loss (SNHL), it is relatively insensitive to white matter microstructure. Our objective was to evaluate possible changes in microstructure of the auditory pathway in children with congenital sensorineural hearing loss (SNHL), and the possible distinction between good and poor outcome of cochlear implantation (CI) patients by using diffusion tensor imaging (DTI). Twenty-four patients with congenital SNHL and 20 healthy controls underwent conventional MRI and DTI examination using a 1.5T MR scanner. The DTI metrics of fractional anisotropy (FA) and mean diffusivity (MD) of six regions of interest (ROIs) positioned along the auditory pathway-the trapezoid body, superior olivary nucleus, inferior colliculus, medial geniculate body, auditory radiation and white matter of Heschl's gyrus-was measured in all subjects. Among the 24 patients, 8 patients with a categorie of auditory performance (CAP) score over 6 were classified into the good outcome group, and 16 patients with a CAP score below 6 were classified into the poor outcome group. A significant decrease was observed in FA values while MD values remained unchanged at the six ROIs of SNHL patients compared with healthy controls. Compared to good outcome subjects, poor outcome subjects displayed decreased FA values at all of the ROIs. No changes were observed in MD values. Correlation analyses only revealed strong correlations between FA values and CAP scores, and strong correlations between CAP scores and age at implant were also found. No correlations of FA values with age at implant were observed. Our results show that preoperative DTI can be used to evaluate microstructural alterations in the auditory pathway that are not detectable by conventional MR imaging, and may play an important role in evaluating the outcome of CI. Early cochlear implantation might be more effectively to restore hearing in SNHL patients.