The heterogeneity of lung adenocarcinoma (LUAD) indicated that target therapies and immunotherapies may not be effective in all patients. The exploration of the feature of the immune landscape of different gene mutations may provide novel perspectives. In this study, we obtained LUAD samples from The Cancer Genome Atlas. By applying ESTIMATE and ssGSEA, KRAS-mutated group was discovered to be associated with lower immune infiltration, lower expression of immune checkpoints, especially, a lower abundance of B cell, CD8+ T cell, dendritic cell, natural killer cell, and macrophage, higher abundance of neutrophil and endothelial cell. Through ssGSEA, we found that the process of antigen-presenting cell co-inhibition and co-stimulation were inhibited, cytolytic activity and human leukocyte antigen molecules were downregulated in the KRAS-mutated group. And KRAS mutation is negatively related to antigen presentation and procession, cytotoxic lymphocyte activity, cytolytic activities, and cytokine interaction signaling pathway via gene function enrichment analysis. Finally, 24 immune-related genes were identified to establish an immune-related gene signature with excellent prognostic prediction capacity, whose 1-, 3- and 5-year AUCs were 0.893, 0.986, and 0.999. Our findings elucidate the features of the immune landscape of KRAS-mutated groups and successfully established a prognostic signature on the basis of immune-related genes in LUAD. Lung cancer remains a severe challenge to human health with the second highest morbidity and the first highest mortality worldwide . HistoloKirsten Rat sarcoma virus (KRAS) is a member of RAS gene family, encoding small GTPases . KRAS muAlthough KRAS oncogene was used to be considered an “undruggable” target, in recent years, some targeted drugs targeting KRAS p.G12C mutation in LUAD had gradually entered the phase of clinical trials, for instance, AMG510 and Adagrasib . This meWhether KRAS could be used as a biomarker for immunotherapy remains uncertain. Some studies suggested that KRAS mutation cannot be used as a biomarker of immunotherapy. Passiglia et al.  confirmeThe current studies on the immune microenvironment of KRAS mutant patients are scattered and do not fully reflect the characteristics of the immune landscape of KRAS-mutated LUAD. Hence, based on transcriptome data of LUAD from the public database, this study utilized bioinformatic technology to comprehensively analyze the immune landscape characteristics of KRAS-mutated LUAD from various aspects, explored the underlying immune mechanism, established corresponding immune-related prognostic signatures, and identified hub genes.https://www.immport.org/resources”). The work flowchart of our study is displayed in We downloaded high-throughput RNA sequencing (TPM), corresponding clinicopathological data, and somatic mutation information of LUAD from The Cancer Genome Atlas (TCGA) on July 28, 2022. TCGA database has been updated with TPM data. And GSE72094 dataset was acquired from Gene Expression Omnibus (GEO), serving as an independent validation cohort. Mutation Annotation Format (MAF) files of LUAD were merged to obtain somatic mutation data. Only cases with primary lung adenocarcinoma, complete follow-up data, and clear KRAS status were included for subsequent analysis. Genes with no expression in more than half samples were excluded. And TPM data were normalized by log2(TPM+1). We used “removeBatchEffect” method from “limma” package to remove batch effects. The 1793 immune-related genes (IRGs) were collected from the immPort database (“http://timer.cistrome.org/) and single sample Gene Set Enrichment Analysis (ssGSEA) algorithm were employed to calculate the abundances of immune cells in LUAD. Meanwhile, we also compared the expressions of human leukocyte antigen (HLA)-related genes and immune checkpoints under different KRAS statuses. The “GSVA” and “GSEABase” packages were utilized in this process.We first utilized the ESTIMATE algorithm to evaluate the stromal score, immune score, and tumor purity of different KRAS status subgroups via the “estimate” package. Secondly, to analyze the immune infiltration of the KRAS-mutated and KRAS-wild groups in more detail, TIMER  and Gene Ontology (GO) sets. And the outcomes would be visualized via the “ggplot 2” and “goplot” packages. In addition, we also utilized Gene set enrichment analysis (GSEA) to probe activating and suppressing signaling pathways. The gene sets were acquired from the MsigDB (http://www.gsea-msigdb.org/gsea/msigdb/).We conducted differential expression analysis between the KRAS-mutated and KRAS-wild subgroups by “limma” package. The filtering conditions for differentially expressed genes (DEGs) were log2|Fold Change| > 0.58 and adjust Since we found that different KRAS states have different immune microenvironments, we decided to establish immune-related prognostic signatures on KRAS mutated group. TCGA cohort served as the training set, and GSE72094 was the testing set. We firstly applied the univariate COX analysis to screen out the IRGs which were strongly correlated with the survival of patients in the KRAS-mutated subgroup of the TCGA cohort. These prognosis-related IRGs were then put into the least absolute shrinkage and selection operator (LASSO) analysis to eliminate the over-fitting genes via “glmnet” package. The risk score is determined using the following formula:Exp (RNA) represented the expression value of the selected IRGs, and coef (RNA) is the corresponding risk coefficient of the selected IRGs. And samples were assigned to different risk subgroups based on the median value.For evaluating the prognostic prediction capacity of this signature, we conducted Kaplan-Meier analysis, time-dependent receiver operating characteristic (timeROC), and calculated the area under the curve (AUC). The “survival”, “survminer” and “timeROC” packages were utilized in this progress.Univariate and multivariate Cox regression analyses were conducted to screen the independent prognostic factors by “survival” package. Then, a nomogram was constructed. Meanwhile, the Concordance index (C-index) was calculated and calibration curves were drawn to investigate the 1-, 3- and 5-year OS probabilities. The “rms” package was used in this process.https://cn.string-db.org/). The top 5 hub genes were determined by the Cytoscape software plugin cytoHubba (3.10.0 version).After identifying signature genes in KRAS-mutated subgroups, Protein-Protein Interaction (PPI) network (minimum required interaction score was 0.40) was generated using the STRING database (p < 0.05). And the top 5 activated and suppressed pathways of KEGG in the high-risk subgroup selected by the GSEA algorithm were visualized using the GSEA plot. The “clusterProfiler” and “enrichplot” packages were employed in this process. The pathways of KEGG and hallmarks were acquired from the MsigDB.Spearman correlation analysis was performed to detect the pathways correlated with the risk score, using the risk score of samples and the ssGSEA activity score of pathways of hallmark and KEGG . The comparison between two groups of the normal distributed quantitative data was implemented through Student’s By using the criteria, 454 samples from TCGA and 359 samples from GEO were used for the analysis. The characteristic feature of the TCGA cohort and GSE72094 cohort were displayed in The TCGA cohort contained 121 KRAS-mutated samples and 333 KRAS-wild samples. The comparison of vital clinical information showed, there were no significant difference in gender, age, stage, T, N, and M between KRAS-mutated and KRAS-wild type groups . And basThe result of ESTIMATE revealed the stromal score, immune score, and ESTIMATE score were inferior, while the purity was higher in the KRAS-mutated group, suggesting a lower overall immune level and immunogenicity of the tumor microenvironment in the KRAS-mutated group –3D. The Immune-related DEGs including 26 upregulated and 4 downregulated genes were identified between the KRAS-mutated and KRAS-wild groups. To explore underlined molecular mechanisms, GO and KEGG analyses were performed , 4B. GO In the GSEA plots of KEGG pathways in the KRAS mutant groups, peptide antigen assembly with MHC class I or II protein complex, T cell activation via T cell receptor, and NK cell chemotaxis were inhibited, while netrin activated signaling pathway, oxalated transport, and cellular response to acidic PH were upregulated –4F. Simip = 0.032)  . And in = 0.032) . These iThrough chi-analysis, we found that high-risk samples were associated with later stage and more lymph node metastases . Merged Protein interaction diagrams were made using the STRING website. Cytoscape was used to screen out the most closely related genes . The hubThe Hallmark pathways most correlated with risk scores were displayed in The advent of immunotherapy has greatly extended the survival of many solid tumors, including lung adenocarcinoma. However, the effect of immunotherapy in NSCLC with oncogenic driver alteration was unsatisfactory and immunotherapy should only be recommended after exhaustion of standard chemotherapies and targeted therapies . As a reIn our study, we discovered that KRAS mutation was not significantly correlated with patient’s gender, age, T, N, M, and stage. And the frequency of other gene mutations varies between different KRAS status groups. Among them, Skoulidis et al. found the loss of STK11 in the KRAS-mutated LUAD patients promoted immune checkpoint inhibitor resistance .The result of ESTIMATE suggested that the KRAS-mutated group had an inferior stromal score, immune score, and ESTIMATE score, while the purity was superior, which means the KRAS-mutated group may have stronger immune suppression and lower immune infiltration. By our subsequent immune infiltration analysis, the KRAS-mutated group was marked by a low abundance of B cells, CD8+ T cells, dendritic cells (DC), NK cells and macrophages. B cells and CD8+ T cells, the central effector cells in the tumor microenvironment, the low infiltration of them are negatively associated with the prognosis of LUAD . Tumor-aNotably, the activities of APC co-inhibition, APC co-stimulation, cytolytic activity, and HLA were downregulated in the KRAS-mutated group. As is known to all, the APCs were composed of dendritic cells (DCs), macrophages, and monocytes, which were essential for tissue initiation and facilitation of antitumor response . And accOn the other hand, in the KRAS-mutated group, there was fewer abundance of cytotoxic lymphocyte, and the cytolytic activity, as well as the expression of (HLA), were downregulated. Cytotoxic lymphocytes, containing NK cell, NK T cell, and cytotoxic T lymphocyte, take essential roles in killing tumor cells . And theTo sum up, the features of the immune landscape in the KRAS-mutated group were low immune cell infiltration, low antigen presentation capacity, and low cytolytic activity. These characteristics can be the breakthrough points to improve the efficacy of immune-related therapy in KRAS-mutated LUAD.The underlying mechanisms and biological features were further explored by the functional enrichment of the GO and KEGG pathways and GSEA analysis. Based on these results, we can know that the function of DEGs between KRAS-mutated and KRAS-wild groups mainly enriched on MHC molecular, antigen processing and presentation, immune response-activating cells surface receptor signaling pathway, ERK1, and ERK2 cascade, and cytokine-related pathway. Moreover, the outcomes of GSEA further suggested that both the assembly of MHC class I molecules with endogenous antigens and the assembly of MHC class II molecules with exogenous antigens were downregulated in the KRAS-mutated groups. On the other hand, T cell activation by contacting T cell receptor (TCR) with antigen bound to MHC molecules on APC was also suppressed. These were all the underlying mechanisms of the dysfunction of cytolytic activity and the decline of immune response in KRAS-mutated LUAD samples. This suggested that KRAS-mutated patients may benefit from adoptive cellular immunotherapy, including tumor-infiltrating lymphocytes (TIL) therapy and chimeric antigen receptor-modified T cells (CAR-T cells) therapy. To date, several experimental studies have made some related attempts. Srivastava et al.  reportedAs for the ERK1 and ERK2 cascade, it is essential for cells to regulate fundamental cell functions, including cell cycle progression, survival, cell migration, and differentiation . And it The prediction ability of our immune-related signature is outstanding. Both AUC of the signature and C-index of the corresponding nomogram were extremely high. Therefore, it may have the value of application and promotion in the clinic. The hub gene in the KRAS-mutated type was FYN, SYK, PIK3CB, PTPN6, and NRG2. FYN, whose protein belongs to tyrosine-protein kinase, takes part in the development and activation of T lymphocytes. The overexpressed FYN had been demonstrated to be associated with a good prognosis of LUAD, suppressing the EMT via down-regulating the PI3K/AKT pathway . Spleen Undeniably, our article still needs some improvement. Firstly, our research was based on a public database and bioinformatic technology, further laboratory and clinical studies are needed to verify our findings. Secondly, our research only analyzed LUAD sequencing data, in the future, we could comprehensively analyze the immune landscape characteristics of KRAS-mutated LUAD from multiple perspectives, such as proteomics and metabolomics.Taken together, the immune landscape of KRAS-mutated LUAD was featured with the exhaustion of APC, the low abundance of cytotoxic lymphocytes, the dysfunction of and cytolytic activity, and the loss of antigen processing and presentation. Moreover, the assembly of MHC class I and MHC class II molecules with antigens was downregulated, and T cell activation by contacting T cell receptor (TCR) with antigen bound to MHC molecules on APC was also suppressed. These were important underlying mechanisms in the formation of KRAS-mutated immune microenvironment. Our study elucidated the special immune landscape characteristics of LUAD with KRAS mutation, and offered a novel insight to improving the immunotherapy response in KRAS-mutated LUAD patients and established a prognostic gene signature with high accuracy.


To determine the immediate (compensatory) and longer term (rehabilitative) effect of the effortful swallow (ES) maneuver on physiological swallowing parameters in Parkinson disease.Virtual intervention protocol via Microsoft Teams with pre- and post-videofluoroscopic swallowing studies.Outpatient hospital setting, with intervention performed virtually.Eight participants (median age 74 years [63-82])with Parkinson disease (years post onset 3-20) with a Hoehn and Yahr scale score between 2 and 4 (N=8).ES maneuver, initiated using a maximum effort isometric tongue-to-palate press, with biofeedback provided using the Iowa Oral Performance Instrument. The protocol included 30 minute sessions twice daily, 5 days/week for 4 weeks.Penetration-Aspiration Scale scores, time-to-laryngeal-vestibule-closure, total pharyngeal residue, and pharyngeal area at maximum constriction as seen on lateral view videofluoroscopy.No consistent, systematic trends were identified in the direction of improvement or deterioration across Penetration-Aspiration Scale scores, time-to-laryngeal-vestibule-closure, pharyngeal area at maximum constriction, or total pharyngeal residue.Heterogeneous response to the ES as both a compensatory and rehabilitative technique. Positive response on the compensatory probe was predictive of positive response after rehabilitation. We hypothesized that use and repeated practice of the ES would lead to shorter time-to-LVC and better pharyngeal constriction, with corresponding functional outcomes of reduced penetration-aspiration and reduced pharyngeal residue.This study received human subjects approval (CAPCR ID 21-5814). We adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelineshttps://steeleswallowinglab.ca/srrl/).Participants were recruited from an outpatient clinic based on the criteria in https://steeleswallowinglab.ca/srrl/).We adopted a descriptive approach to analyzing the data, by plotting the worst value for each participant per parameter per consistency on graphs comparing conditions . Error bars were used to illustrate parameter score ranges and an estimated effect size for each comparison was calculated, by dividing the individual change in scores by the pooled group standard deviation of worst-scores across the conditions of interest. These effect size estimates were interpreted according to the guidance for interpreting Cohen's d, where d=0.2 is considered a “small” effect size, 0.5 represents a “medium” effect size, and 0.8 a “large” effect size.Demographics are presented in The relation between changes in Penetration-Aspiration Scale scores and time-to-LVC can be appreciated in The relation between changes in total pharyngeal residue and PhAMPC can be appreciated in The purpose of this study was to explore the preliminary efficacy of a targeted, effort-based swallowing intervention, both as a short-term compensatory technique, and after 4 weeks of intensive practice as a rehabilitation technique in people with PD. Our findings show variability in the direction of change (improvement and deterioration) for specific parameters across participants and bolus consistencies. No systematic trends were observed when comparing the effect of the ES on thin liquid vs mildly thick liquid trials; patients with earlier vs later onset of PD; mild vs severe PD severity; or related to the subjective burden of dysphagia as reported on the Munich Dysphagia Test.The parameters of interest in this study were selected based on hypothesized physiological and functional relations. Longer time-to-LVC is thought to contribute to penetration-aspiration, while reduced pharyngeal constriction is thought to contribute to post-swallow residue,However, the story is not so clear with respect to changes in swallowing efficiency. The heterogeneous findings in our study may be attributable to variations in individual participant responsiveness to intensive therapy. This may have been influenced by a variety of factors, including baseline oral intake status, time since PD onset, and PD severity. Although we attempted to recruit a homogeneous sample, with inclusion criteria mandating the presence of specific physiological impairments, the resulting sample was quite heterogeneous in nature. Despite these differences, the protocol intensity, duration, and frequency were held constant across all participants; individualizing the treatment protocol might have shown different outcomes. Future studies should explore the hypothesized mechanistic-functional relations between swallowing parameters, across a wider range of bolus textures, considering additional physiological mechanisms, which may also affect swallowing efficiency.This study was not without limitations. First, this study is a case series with a small sample size; therefore, caution is warranted when interpreting the results. A case series design was chosen given expected heterogeneity among participants, and given the goal of detecting improvements in swallowing safety/efficiency in a pilot study. However, in this case, where mixed results were scattered across all parameters in all 8 participants, it is challenging to derive conclusions regarding cause and effect relations and there is a risk of over-interpretation.,,Second, we only studied participants who were exposed to the intervention. We acknowledge that comparison to a no-treatment control group would be needed to make clear inferences regarding intervention effects, The potential for spurious findings in a small case series justifies a larger, well-powered evaluation. Third, in order to summarize results across multiple repetitions for each task and consistency, the “worst” values per task and consistency condition were captured for each participant. This approach is common in dysphagia clinical practice, particularly for the Penetration-Aspiration Scale, which has categorical rather than interval properties.Our findings highlight the heterogeneous response to using the ES as both a compensatory and rehabilitative technique in people with PD. No consistent, systematic trends were identified in the direction of improvement or deterioration across penetration-aspiration scale scores, time-to-LVC, pharyngeal residue, or PhAMPC. This study points to the need for much larger sample sizes in order to confidently ascertain group-level benefits of the ES maneuver reinforced with the use of biofeedback, as a therapeutic resource in the rehabilitation of oropharyngeal dysphagia in people with PD.


Vero cell culture-derived Japanese encephalitis (JE) vaccine  was approved in the United States in 2009. The previous JE vaccine, an inactivated mouse brain-derived vaccine, had been associated with rare, but serious, allergic and neurologic adverse events (AE). Studies and AE surveillance have supported JE-VC’s safety, but one evaluation among military personnel found elevated hypersensitivity and neurologic AE rates. However, co-administration of multiple vaccines to some personnel might have affected results. We retrospectively compared rates of hypersensitivity and neurologic AEs within 28 days following vaccination of military personnel with JE-VC or parenteral Vi capsular polysaccharide typhoid vaccine administered without other vaccines from July 1, 2011, through August 31, 2019. Rates of most events were similar between the vaccines. Only delayed hypersensitivity reactions occurred more frequently following JE-VC , but rates were low for both vaccines. These results support JE-VC’s safety. While most JE virus infections are asymptomatic, encephalitis can develop in < 1 % of persons and is often severe. Initial symptoms can include sudden onset of head-ache, vomiting, and fever, followed by mental status changes, weakness, convulsions, focal neurologic deficits, and movement disorders. Of those who develop encephalitis, 20 %–30 % die, and 30 %–50 % of survivors experience serious neurologic, cognitive, or psychiatric sequelae. There is no specific treatment for JE. U.S. persons who travel abroad to endemic areas are at risk of JE virus infection, but preventive measures such as mosquito avoidance and vaccination can reduce the risk [Japanese encephalitis (JE) virus, a single-stranded RNA flavivirus, is a leading cause of encephalitis in Asia and the western Pacific . JE viruIn March 2009, the U.S. Food and Drug Administration (FDA) licensed Vero cell culture-derived JE vaccine  for use in persons aged ≥ 17 years. In 2013, licensure was extended to include children aged ≥ 2 months. As JE-VC became available in the United States, the production of mouse brain-derived JE vaccine  was discontinued, and all doses expired by May 2011. Although JE-MB had been administered safely and offered protection for hundreds of thousands of persons who received the vaccine, it was noted to be associated with rare, but serious, allergic and neurologic adverse events [In pre-licensure clinical trials among approximately 5,000 adults, rates of local and systemic adverse events following JE-VC were comparable to rates among recipients of placebo adjuvant . HoweverThe manufacturer’s analysis showed that among 21,347 U.S. military personnel vaccinated with JE-VC from July 2010 through May 2011, there were no statistically significant increased incidence rates for multiple neurologic and hypersensitivity events compared with the rates among personnel vaccinated with JE-MB . HoweverGiven the findings of the military study and the value of additional data given concerns about similar events with the previous mouse-brain derived vaccine, we conducted a study to assess selected neurologic and hypersensitivity adverse events in military personnel following JE-VC and a comparator vaccine after removing potential confounding caused by coadministration or recent receipt of other vaccinations.2.Data from military personnel vaccinated with JE-VC were compared to those from vaccinees who received parenteral Vi capsular polysaccharide typhoid vaccine . This typhoid vaccine has been used for approximately 30 years in the United States and has been demonstrated in studies and post-marketing surveillance to be well-tolerated and have a favorable safety profile –10. DeidWe compared the occurrence of AESI, hospitalizations, and deaths in the 28-day period following vaccination among personnel receiving JE-VC to events among those receiving TY-VC. The rate ratio (RR) was estimated using modified Poisson regression with robust error variances. Analyses accounted for possible repeated measures on a person and were conducted using SAS version 9.4. Factors including gender, age, and branch of military service were initially included in the Poisson models but were removed due to model lack of convergence or non-significance. Only the first report of a specific AESI in the 28 days following vaccination in an individual was counted. For anaphylactic reactions, we ran a secondary analysis shortening the risk window to a 2-day period following vaccination.The Walter Reed National Military Medical Center Institutional Review Board (IRB) deemed the protocol to be exempt from IRB review. The Centers for Disease Control and Prevention received a non-engagement determination. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.3.Data from a total of 718,239 military personnel were included. The median age of personnel was 25 years (interquartile range (IQR): 9) and the majority (87 %) were male . Race anp = 0.03). Hospitalizations were rare and rates were not significantly different between the vaccines . Very few deaths occurred, and the rates were again similar in both groups .The combined rates of all selected hypersensitivity or neurologic AESI occurring in the 28 days following vaccination with JE-VC or TY-VC were similar . The occ4.Our analysis of U.S. military personnel found an acceptable safety profile for JE-VC when compared to TY-VC. Overall, the rates of hypersensitivity or neurologic AESI, hospitalizations, and deaths following administration of JE-VC were comparable to those following TY-VC –10. WhilHypersensitivity and neurologic adverse events were of interest when JE-VC was licensed because the previously available JE vaccine, JE-MB, had been associated with rare, serious allergic and neurologic adverse events . SpecifiAlthough we identified an elevated rate of delayed hypersensitivity events with JE-VC compared with TY-VC, the rate for JE-VC was substantially lower than in the previous military study that did not control for coadministration or recent receipt of other vaccinations . In addiOur analysis had several limitations. The accuracy of classification of adverse events based on the ICD codes could not be assessed and might have impacted our estimates of adverse event rates. The specific aim of this study was to further investigate the occurrence of neurologic and hypersensitivity reactions in the same population from which the original AESI concerns were generated  while removing potential confounding factors caused by coadministration of other vaccines. Given this, our findings are not generalizable beyond this population and the occurrence of these specific AESI could differ from the general population. DMSS data were deidentified so we could not conduct medical record review to enable an assessment of potential relatedness. Lastly, the DMSS may contain coding errors that misclassify the vaccines administered.JE virus infection can cause severe clinical disease which often results in long-term sequelae or death. While the risk for JE is very low for most travelers to JE-endemic countries, some travelers will be at increased risk based on factors such as longer periods of travel, travel during the JE virus transmission season, spending time in rural areas, participating in extensive outdoor activities, and staying in accommodations without air conditioning, screens, or bed nets. All travelers to JE-endemic countries should take steps to avoid mosquito bites. Both travelers and their healthcare providers should consider the need for JE-VC vaccination. The findings from this analysis, in combination with results from prelicensure clinical trials and post-marketing surveillance, continue to demonstrate the good safety profile of JE-VC and provide reassuring data to support its use among at-risk travelers.


Objectives: With the development of new technologies capable of detecting low concentrations of Alzheimer’s disease (AD) relevant biomarkers, the idea of a blood-based diagnosis of AD is nearing reality. This study aims to consider the evidence of total and phosphorylated tau as blood-based biomarkers for mild cognitive impairment (MCI) and AD when compared to healthy controls. Methods: Studies published between 1 January 2012 and 1 May 2021 (Embase and MEDLINE databases) measuring plasma/serum levels of tau in AD, MCI, and control cohorts were screened for eligibility, including quality and bias assessment via a modified QUADAS. The meta-analyses comprised 48 studies assessing total tau (t-tau), tau phosphorylated at threonine 181 (p-tau181), and tau phosphorylated at threonine 217 (p-tau217), comparing the ratio of biomarker concentrations in MCI, AD, and cognitively unimpaired (CU) controls. Results: Plasma/serum p-tau181 ) and t-tau ) were elevated in AD study participants compared to controls. Plasma/serum p-tau181 ) and t-tau ) were also elevated with moderate effect size in MCI study participants compared to controls. p-tau217 was also assessed, albeit in a small number of eligible studies, for AD vs. CU ) and for MCI vs. CU groups ). Conclusions: This paper highlights the growing evidence that blood-based tau biomarkers have early diagnostic utility for Alzheimer’s disease. Registration: PROSPERO No. CRD42020209482. Alzheimer’s disease (AD) is a debilitating neurodegenerative disease associated with progressive cognitive decline. AD is the most common type of dementia and a major global burden. Approximately 50 million people were reported to be suffering from dementia in 2018, and this number is expected to triple by 2050 ..40]. WitDiagnosing Alzheimer’s disease at an early stage, and in particular, from a convenient blood sample, has been the focus of many studies over the past decade. Such a valuable test would provide significant benefits for patients and healthcare systems. These benefits would include: meeting the demands of the increasing numbers of people seeking a diagnosis; allowing precious time for patients to make lifestyle changes and manage their affairs; improving patient stratification into clinical trials; and permitting potential therapeutic intervention upon early diagnosis. Furthermore, identifying dynamic AD-specific blood biomarkers can serve as an important screening tool for clinical observation of patient response to treatment. The results, summarised in this systematic review, provide evidence for the utility of plasma/serum t-tau, p-tau181, and p-tau217 as diagnostic biomarkers for AD. It also suggests that these biomarkers may be able to predict the future development of AD because sensitive assays allow them to distinguish between CU individuals and MCI patients on the AD continuum. Such evidence signifies a promising future for AD blood-based diagnostics, and with the increasing number of studies currently being performed, as well as the encouraging rate at which the field is advancing, we are hopeful that reliable prognostic tau biomarkers that are associated with disease status and progression will be identified and brought into routine clinical practice.


This case report presents a late middle-aged man with a right infra-hilar lung mass and pericardial effusion (PE). The patient was diagnosed with metastatic small-cell lung carcinoma, with metastases to the liver, pancreas, and cerebellum. The pericardial fluid cytology confirmed the presence of malignant cells most compatible with non-small-cell carcinoma. The patient received carbo/etoposide chemotherapy, and his treatment plan included adding atezolizumab and radiation therapy. Despite the excellent efficacy of immunotherapy, immune-related adverse events (IRAEs), including cardiac toxicity, were noted in some patients. PE related to immune checkpoint inhibitor (ICI) use is rare but potentially severe. This case highlights the importance of vigilant monitoring for cardiovascular symptoms during immunotherapy and the significance of pericardial fluid analysis in diagnosing malignant pericardial disease. Prompt diagnosis and appropriate treatment can lead to improved patient outcomes in cases of lung cancer-associated cardiac complications. The most common cause of cancer-related death globally is lung cancer. Eighty-five percent of lung cancer cases are caused by non-small-cell lung cancer, and as most afflicted patients' cancers are well advanced when they are diagnosed, their prognosis is not good . The parMalignancy has been linked to serious cardiac complications such as cardiac tamponade and PE. Exertional dyspnea and a progressive inability to exercise may be symptoms of chronic PE. If a chronic PE becomes severe, it may result in cardiac tamponade and an immediate hemodynamic compromise that calls for immediate treatment . A potenAmong various treatment modalities, immune checkpoint inhibitor (ICI)-based immunotherapies have been proven effective in treating various cancers, with anti-PD-1/PD-L1 complementing conventional chemotherapies. However, immune-related adverse events (IRAEs), including cardiac toxicity, are becoming more common. Fewer than 1% of patients experience significant hemodynamic impairment due to PE. It's interesting to note that none of these individuals had a myocardial illness, which prompted some writers to use the more precise term pericardial-only ICI-associated disease ,7.We present a case of a 62-year-old male with extensive-stage non-small-cell lung carcinoma who presented with symptoms of chest pain and shortness of breath and was diagnosed with PE and metastases. The treatment plan involves carbo/etoposide chemotherapy, atezolizumab immunotherapy, and radiation therapy, with close monitoring for response and side effects.We present the case of a 62-year-old male who was referred from a previous facility for further treatment of extensive-stage non-small-cell lung carcinoma. The patient's symptoms had been present for six months and was admitted to our hospital with right-sided chest pain, shortness of breath, and orthopnea. Upon examination, the patient displayed a healthy appearance and showed no immediate signs of distress. He was on continuous oxygen therapy at a rate of 2 liters per minute and had diminished lung sounds on the right. The remainder of the physical examinations were unremarkable, with no significant findings in the eyes, neck, cardiovascular system, gastrointestinal system, or skin. Chest X-ray revealed a bilateral enlarged cardiac silhouette which raised suspicion for PE as shown in Figure A CT chest revealed a right infra-hilar mass, mediastinal and hilar adenopathy, as well as a right-sided pleural effusion and PE as shown in Figure Subsequent imaging studies, including an MRI of the abdomen and head, showed evidence of metastatic disease in the liver, pancreas, and cerebellum. The patient received one cycle of carbo/etoposide chemotherapy during his hospital stay. At the follow-up visit, he reported mild improvement in shortness of breath and cough, although he continued to experience pain in the right lower chest, which remained uncontrolled with over-the-counter medications.After a comprehensive discussion, the patient was educated about the aggressive nature of metastatic non-small-cell carcinoma affecting the liver, pancreas, and cerebellum, along with the potential advantages and drawbacks of chemotherapy and radiation therapy. Subsequently, the treatment strategy was devised to encompass the continuation of carbo/etoposide chemotherapy, the introduction of atezolizumab immunotherapy, and a referral for radiation oncology assessment.The patient agreed to the proposed treatment plan and demonstrated an understanding of the risks and benefits involved. Their follow-up appointment was scheduled in four weeks to assess the response to treatment and evaluate the need for further interventions. On follow-up, the patient responded well to the treatment given.A combination of autopsy series reveals that 15.4% of cancer autopsies find cardiac metastatic disease, suggesting that the heart might be involved in neoplastic illness . A cardiClinically speaking, immunotherapy's cardiovascular toxicities, albeit uncommon, may be severe and have a surprisingly high risk of fatal consequences -13. The Malignant pericardial disease is identified by irregular pericardial thickness and mediastinal lymphadenopathy . PericarCompared to pericardial biopsy, pericardial fluid cytology has a higher diagnostic value for identifying cancer . With vaThis case report addresses the management challenges of advanced non-small-cell lung carcinoma with pericardial involvement. The patient's severe symptoms, diagnostic findings, and treatment plan underscore the importance of recognizing cardiac complications in advanced lung cancer. The effectiveness of ICI requires vigilance in managing potential cardiac toxicities. A multidisciplinary approach, including chemotherapy, immunotherapy, and close monitoring, is crucial for comprehensive care and improved patient outcomes.


Accumulating evidence suggests that patients with nonalcoholic fatty liver disease (NAFLD) have a significantly high risk of incident atrial fibrillation (AF). Systemic inflammation, metabolic disorders and oxidative stress could be the potential mechanisms by which NAFLD drives AF. Monocyte-to- high-density lipoprotein ratio (MHR) has emerged as a novel biomarker of inflammation and oxidative stress that has not been studied in AF with NAFLD patients. We aimed to investigate the relationship between MHR and the risk of AF among NAFLD patients.A retrospective analysis was performed for the clinical data of the patients with NAFLD in the Second Hospital of Shanxi Medical University from January 2019 to October 2022, among whom 204 patients with AF were enrolled as NAFLD+AF group and 613 patients without AF were enrolled as NAFLD control, and 152 patients were selected from each group based on propensity score matching (PSM) at a ratio of 1:1 to balance the covariates between groups. The t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups; the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. Logistic regression analysis was performed to identify the independent predictor for occurrence of AF among NAFLD patients. Trend chi-square test to analyze the prevalence of AF among MHR tertiles, and then the correlation between MHR and the risk of AF confirmed by restricted cubic splines (RCS). The receiver operating characteristic (ROC) curve analysis was used to determine the optimum MHR cutoff value to predict AF.Univariate analysis showed that AF patients had higher MHR than non-AF patients (P < 0.001). Meanwhile, compared with pure NAFLD patients, multivariate logistic regression analysis showed that MHR remained to be an independent risk factor for AF after adjusting for confounding risk factors . TC、HDL-C were also independent risk factors for AF. Among them, TC and HDL-C are protective factors for AF. The trend chi-square test showed that the risk of AF increased with an increase in MHR (P < 0.05). However, the RCS showed a nonlinear and J-shaped relationship between MHR and the risk of AF (P for non-linearity = 0.023). The occurrence of AF increased with increasing MHR only when MHR > 0.44. The ROC curve showed that MHR combined with traditional risk factors can improve the ability to predict AF.MHR is an independently associated with incident AF in patients with NAFLD and show a certain predictive value. Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the general population, carrying a considerable risk of morbidity and mortality . AccordiNon-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease, and its incidence continues to increase globally . And it The monocyte to high density-lipoprotein (HDL) cholesterol ratio (MHR), a novel indicator of inflammation, oxidative stress and metabolic syndrome, has been proved as a predictor and prognostic marker of cardiovascular diseases (CVD) . PreviouWe retrospectively analyzed the clinical data of patients who were diagnosed with NAFLD and recorded the surface electrocardiogram (ECG) at the Second Affiliated Hospital of Shanxi Medical University from January 2019 to October 2022. All participants were divided into NAFLD + AF and NAFLD groups based on the current or past ECG. Among them, 94 patients have paroxysmal AF and 58 patients have non-paroxysmal AF.NAFLD was diagnosed  based onAccording to 2020 European Society of Cardiology guidelines, a standard 12-lead ECG recording or a single-lead ECG tracing of ≥30 s showing heart rhythm with no discernible repeating P waves and irregular RR intervals (when atrioventricular conduction is not impaired) is diagnostic of clinical AF . CHD is Our exclusion criteria included rheumatic heart disease, structural cardiomyopathy, congenital heart disease, valvular disease, severe heart failure, infectious disease, autoimmune disease, hematologic disease, malignancy, hyperthyroidism, severe hepatorenal insufficiency and a history of chronic alcohol consumption.This study was approved by the local ethics committee of the Second Affiliated Hospital of Shanxi Medical University. We obtained informed consent from all participants.2 (m2). MHR was calculated as the monocytes count (109/L)/HDL-C (mmol/L), NLR was calculated as the neutrophils count (109/L)/lymphocytes count (109/L), and NHR was calculated as the neutrophils count (109/L)/HDL-C (mmol/L).The following information was collected through the electronic medical record system (1): Demographic characteristics: age and gender (2); Previous history: smoking history, hypertension, diabetes and coronary heart disease (CHD) (3); Laboratory indicators: blood count levels , total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Scr) and fasting plasma glucose (FPG). Blood samples were obtained from the patients in the morning after 12 h of fasting. BMI was calculated as the patient’s weight (kg)/heightThe continuous variables were expressed as mean ± standard deviation (SD) or median (IQR) and were compared between groups of patients with or without AF. Categorical variables are expressed as percentages. For univariate analysis between AF and non-AF, the independent samples t-test or Mann-Whitney test was used for comparison of continuous variables, and the chi-square test or Fisher’s exact test was used for comparison between categorical variables. Binary logistic regression analysis was performed to identify independent factors associated with AF among NAFLD, and variables with p-values less than 0.05 in the univariate logistic regression analysis were included in the multivariate logistic regression analysis. chi-square test for trend analysis between multiple groups of categorical variables, Kruskal–Wallis test analysis between multiple groups of continuous variables. We also used restricted cubic splines (RCS) to flexibly model the association of MHR with the prevalent AF. P<0.05 (two-sided) was considered statistically significant. Statistical analysis was carried out using SPSS version 26.0  and R version 4.0.1 software.vs. non-AF was assessed using absolute standard differences and a quartile, reporting a non-significant value of <10%. After PSM (1:1), the AF and non-AF groups were matched, with a good balance between groups.Propensity score matching (PSM) was utilized to eliminate bias and control for potential confounding variables. A logistic regression model was built with the presence or non-presence of atrial fibrillation as the dependent variable and confounding factors affecting the incidence of atrial fibrillation as the independent variable, including age, gender, BMI, hypertension, diabetes, CHD and smoking history. The propensity score value of each study object was calculated, the calliper value was 0.02. The ability of the matching to balance baseline characteristics in AF Meanwhile, the ALT, AST, Scr, TC, TG, LDL-C and HDL-C were significantly different among all groups  was still independently associated with the presence of AF. TC  and HDL-C  were protective factors for AF Figure 3To understand the relationship between different MHR levels and AF in NAFLD patients, we divided the patients into tertiles according to MHR. As shown in Our study further employed the restricted cubic splines (RCS) to validate the correlation between MHR and the risk of prevalent AF, which was displayed in ROC analysis was performed to assess the usefulness of MHR in detecting the prevalent AF among NAFLD patients Figure 5NAFLD is by far the most common metabolic disease in the world, placing a heavy burden on human health and health care systems, a burden that comes overwhelmingly from an increase in cardiovascular disease . AF is oIn NAFLD, excessive accumulation of hepatic fat can lead to significant metabolic stress inflammation, enhancing the local inflammatory response and promoting progression from simple steatosis degeneration to nonalcoholic steatohepatitis (NASH) and fibrosis . ActivatIn addition, the important role of chronic low-grade inflammation in the pathophysiology of arrhythmia has been increasingly recognized . A meta-Epicardial adipose tissue (EAT) may also be another important mediator in the association between NAFLD and AF. A cross-sectional study  found thTaken together, atrial electrophysiology and structure may be altered by NAFLD-triggered inflammatory responses, which may lead to increased susceptibility to AF. The activation of monocytes plays a crucial role in the whole process of chronic inflammation . MonocytOn the other hand, monocytogenic cells, including phagocytes and Kupffer cells, are also key regulators of the progression and regression of liver fibrosis in non-alcoholic steatohepatitis (NASH) . Large aInflammation and oxidative stress, as major contributors to CVD, have been identified as risk factors for AF. Mediators of the inflammatory response can lead to electrical and structural remodeling of the atria, thereby increasing susceptibility to AF. As an important source of pro-inflammatory and pro-oxidative factors, monocytes play a key role in the initiation, continuation and recurrence of AF by activating the inflammatory cascade. The relationship between HDL-C and CVD has been extensively studied. Low HDL-C adversely affects the pathogenesis of AF by decreasing its anti-inflammatory and antioxidant effects, which is consistent with our results. In conclusion, monocytes combined with HDL-C could better predicted the risk of AF in NAFLD patients.Based on the inflammatory profile of monocytes and the anti-inflammatory profile of HDL cholesterol, MHR has been proposed as a new indicator of inflammation –43. In tOur findings indicate that MHR is closely related to the risk of developing AF. Interestingly, the association between the MHR index as a continuous measure and the AF hazard ratio in patients with NAFLD was J-shaped. Although this is relatively common , this haOur study has some limitations. First, this study is a retrospective cross-sectional study with a small single-center sample, which may have some impact on the results. Second, clinical confounders not included in this study may affect the accuracy of the results. Third, The diagnosis of NAFLD is made by ultrasonography. Ultrasonography is not the most sensitive method for the diagnosis of fatty liver, and there are some false positives. However, ultrasonography is simple, convenient and repeatable, so it is still the most effective method for clinical diagnosis of NAFLD. Finally, this study is a cross-sectional study, and its results can only indicate that MHR is associated with the risk of AF among patients with NAFLD but not its predictive value. A large number of large-scale, multicenter prospective studies are still needed in the future to further illustrate the predictive value of MHR for the development of AF in patients with NAFLD.In conclusion, our study found that MHR was significantly higher in patients with NAFLD combined with AF than in non-AF patients. MHR, as a simple and practical new inflammatory index, could be used to assess the risk of AF in the clinical management of NAFLD patients.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Medical Ethics Committee of Shanxi Medical University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.LW and BL: study design. LW and YZ: data analysis. LW and JZ: manuscript drafting. LW, YZ and BY: data collection. WZ, HF, ZR and BL: review and final approval. All authors contributed to the article and approved the submitted version.


Periodontal disease was assessed using probing depth, gingival recession, and bleeding on probing. Dietary intake was measured using a food frequency questionnaire (FFQ). A self-developed anti-inflammatory dietary score served as the key explanatory variable. Higher scores reflected lower inflammatory processes (measured through the biomarkers hsCRP and IL-6). Several covariates were included in the regression analysis. Regressions revealed that a higher anti-inflammatory dietary score was significantly associated with lower odds to be affected by periodontal disease in an unadjusted model  and in an adjusted model  . Our study demonstrated a significant inverse association between an anti-inflammatory dietary score and periodontitis. Individuals with higher intake of proinflammatory nutrition should be specifically addressed to avoid periodontitis.While the effects of dietary patterns on cardiovascular risk and diabetes have been well studied, the evidence is scarce as to which diet has the greatest anti-inflammatory potential and how dietary patterns are associated with periodontitis. In the Hamburg City Health Study (HCHS), we developed an anti-inflammatory dietary score using a data-driven approach based on the relationship of relevant selected food groups with inflammatory biomarkers (hsCRP and IL-6). The aim of this cross-sectional study was to evaluate the association between the anti-inflammatory dietary score and the incidence of periodontitis in Hamburg, Germany. A total of  Periodontitis is an inflammatory disease of the tooth surrounding tissues, which affects up to 11.5 million people in Germany . AdditioYet, evidence as to which food groups have the greatest proinflammatory and anti-inflammatory potential and how these are associated with periodontitis has not been firmly established. Ideally, such a classification should be derived from the investigation of associations with eating patterns across different populations. In the HCHS, we developed an anti-inflammatory dietary score based on the relationship of relevant selected food groups with inflammatory biomarkers (hsCRP and IL-6). Potentially anti- and proinflammatory food groups were both considered. Our aim was to evaluate the association between the anti-inflammatory dietary score and the incidence of periodontitis in the older population in Hamburg, Germany. Based on this, recommendations can be derived regarding the consumption of these foods.n = 5642 participants fit the required inclusion criteria and were selected for analysis.We based our findings on data from the HCHS—an ongoing population-based, prospective cohort study conducted at the University Medical Center Hamburg-Eppendorf. The HCHS aims to collect health-related data from 45,000 citizens aged 45–75 years from the greater area of Hamburg, Germany to gather information regarding disease burden of the older northern population . BaselinWe used a validated food-frequency questionnaire (FFQ), developed for the European Prospective Investigation into Cancer and Nutrition (EPIC) study, to collect data on the dietary intake of the participants . It recoAs no established anti-inflammatory diet was available, we defined the adherence to an anti-inflammatory diet using a data-driven approach based on our own data on established dietary pattern scores. All items of the Mediterranean, DASH, and MIND diets were considered for the composition of the anti-inflammatory diet. Firstly, adherence to the Mediterranean diet was measured using a validated German version of the original Mediterranean Diet Adherence Screener (MEDAS) . This ve2 = 42.9, p < 0.001; IL-6: χ2 = 59.3, p < 0.001), fruits , total dairy , and nuts/seeds/legumes ; 8 items of the MIND diet , other vegetables , berries , nuts , cheese , red and processed meat , fast fried food , and wine ; and 6 items of the Mediterranean diet , fruits , red meat , sugar sweetened carbonated drinks , nuts , and tomato sauce . Among these, several items were duplicates representing the same food group, of which the one with the largest difference between tertiles was selected. The removal of duplicates resulted in the final version of the anti-inflammatory dietary score containing a total of 9 items ; 3 items from the MIND diet ; and 2 items from the Mediterranean diet . For the final anti-inflammatory dietary score (0–9 points), both anti- and proinflammatory food items were considered. A higher score reflects a nutritional pattern with lower inflammatory potential.The following items were significantly correlated with inflammatory markers: 4 items of the DASH diet , performed by trained and calibrated examiners under supervision of a dentist according to a pre-specified SOP ,33,34. T2), smoking (current smoker), diabetes , and/or fasting glucose >126 mg/dL, not fasting glucose >200 mg/dL), hypertension , intake of hypertension medication (yes), and lipid lowering medication (yes). HbA1c plasma levels (in %), high-density lipoprotein (HDL) cholesterol (mg/dL), and triglycerides (mg/dL) were determined by standard techniques. Low-density lipoprotein (LDL) cholesterol (mg/dL) was calculated using the Friedewald formula. Participants were also asked about their physical activity  and their total sport hours per week. Nutrition was reported as gram/day and included fiber, protein, fat, carbohydrates, and alcohol. IL-6 (mg/L) and hsCRP (mg/dL) were assessed via established ELISA. Further information on the assessment of biomarkers can be found in the HCHS-based study by Struppek et al. [For all participants, the following information on confounding variables was retrieved from the HCHS database: sex, age (in years), education (according to ISCED-97 ), body mk et al. .n (%)). Within-group differences were calculated using the chi-squared test for categorical variables and the Kruskal–Wallis rank sum test for continuous variables. The anti-inflammatory dietary score was dichotomized into “low” and “high” (low (0–4.5 points) vs. high (>4.5 points)). Ordinal logistic regression models were applied to determine the association between periodontitis (dependent variable) and the anti-inflammatory dietary score (independent variable)  . All stap < 0.001) and in the following three stepwise adjusted models: adjusted Model 1  , adjusted Model 2  , and adjusted Model 3  . The results of the ordinal regressions are given in The ordinal logistic regression models revealed a significant association between a higher anti-inflammatory dietary score and lower odds to present periodontitis in an unadjusted model  and lower odds to present periodontitis. Our study adds to previous knowledge, and is the first study to examine the association between potentially anti- and proinflammatory food groups and periodontitis in an older German population.In our study and various other studies, periodontitis was associated with increased levels of inflammatory biomarkers ,39,40,41Currently, there is no established definition of an anti-inflammatory diet available and proinflammatory nutrition is still poorly understood, especially when it comes to oral health. Nevertheless, other dietary patterns that comprise inflammatory components have been studied. The Mediterranean and DASH diets have both been shown to be associated with a reduction in inflammatory markers ,45,46,47The literature-derived, population-based dietary inflammatory index (DII) , which cIt is important to note that the DASH, Mediterranean, and MIND diets were not specifically developed for the HCHS study population. Thus, the dietary patterns might not fully reflect the dietary behaviors of the target population. Findings of certain dietary patterns differ across populations . For exaConsidering that we use our teeth to chew our foods and that the mouth, or oral cavity, is where the digestive system begins, it seems logical that our dietary habits play an important role in our periodontal health. We could, however, also consider how our periodontal health might affect our dietary habits. Periodontitis, if untreated, can lead to the loss of teeth . As a coOur study has some limitations. The population of the HCHS is middle-aged white Caucasian from Northern Germany. Hence, our findings may not be generalized to other ethnicities, regions, or to a much younger population. Furthermore, the cross-sectional nature of our study does not allow for any inference of causality between periodontitis and our anti-inflammatory dietary score. Additionally, a further limitation is that with self-reported dietary intake, some measurement error is to be expected. Yet, the FFQ appears to be a reasonably valid tool for the assessment of dietary intake among German adults ,106. ForNevertheless, there are a number of strengths that are worth mentioning. The large sample size is based on data from the HCHS and representative of the older German adult population. We conducted a full periodontal examination and examiners were calibrated, which increases the validity and accuracy of the results. Moreover, a variety of covariates that could potentially affect the association were included in our analyses, therefore ensuring the comprehensiveness and consistency of study results.Based on a data-driven approach, we used sub-items (both anti- and proinflammatory foods) from other dietary patterns to define an anti-inflammatory dietary score, with a focus on the inflammatory potential of certain food groups. Our study shows a significant association between a proinflammatory diet and periodontitis. Therefore, we hypothesize that the consumption of a proinflammatory diet may aggravate the clinical symptoms of periodontitis patients. Nevertheless, whether or not an anti-inflammatory diet might help in the regression of disease, warrants the implementation of randomized controlled trials. In addition to periodontal therapy and emphasizing appropriate oral hygiene routines, dental professionals could provide dietary recommendations to their patients. However, most dentists focus on making recommendations about limiting sugar consumption or ask about exposure to cavity-producing foods, especially for children/adolescents . Recomme


The pandemic necessitated a change to the historical diagnostics model. It accelerated a shift to a hybrid approach that includes an analysis of patient samples collected in distributed settings, such as at the point of care and in workplaces, schools, and community centers. Perhaps the most radical change in response to the pandemic was the large-scale production and distribution of over-the-counter SARS-CoV-2 testing technologies that could be purchased. It produced a foundational shift in the approaches of nations and their health systems for detecting and diagnosing diseases and conditions, especially infectious diseases. The demand for diagnostic, monitoring, and measuring sensors with clinical applications is growing . The devNew biosensors are needed for diagnostic tools for evaluating patient samples, such as blood, saliva, and urine in non-laboratory settings, and real-time patient data ,3. In adThese devices can expand the capabilities of primary care physicians, nurses, pharmacists, and other health care practitioners, as well as patients, to rapidly determine and deliver the appropriate treatments and prevention strategies. These smart devices will save patients’ lives, assist in controlling bacterial and viral outbreaks, and reduce healthcare costs.Point-of-care (POC) technologies involve the use of portable devices to medically examine a patient during a consultation. POC devices can provide instantaneous results, enabling patients to receive better-informed healthcare information. POCs also provide an opportunity to deliver healthcare in low-resource settings, such as in low- and middle-income countries or disaster environments, where there is often a lack of diagnostic and monitoring tools. The combination of highly sensitive biosensor designs with microfluidics has increased in various lab-on-a-chip devices. These devices can reduce sample volume and detection time and improve sensitivity with high throughput operation .With this in mind, the goal of this Special Issue of the Journal Sensors, belonging to the section “Biosensor Development and Innovation in Healthcare and Medical Applications”, was to collect original research manuscripts which describe cutting-edge developments in biosensor technology for medicine and clinical translational applications, as well as reviews that provide an update on the latest progress in this field.A total of seven manuscripts have been accepted for publication. The final collection includes five original research manuscripts and two reviews by authors from several different countries. A quick overview and general classification of the manuscripts are provided below.(1). “DE-PNN: Differential Evolution-Based Feature Optimization with Probabilistic Neural Network for Imbalanced Arrhythmia Classification” was authored by Amanah Nasim and Yoon Sang Kim. A heartbeat classification method was developed based on evolutionary feature optimization using differential evolution (DE) and classification using a probabilistic neural network (PNN) to discriminate between normal and arrhythmic heartbeats. The proposed method follows four steps: (1) preprocessing; (2) heartbeat segmentation; (3) DE feature optimization; and (4) PNN classification and employed direct signal amplitude points constituting the heartbeat acquired from the ECG holter device with no secondary feature extraction steps. The proposed DE-PNN scheme can provide better classification accuracy considering 8 classes with only 36 features optimized from a 253-element feature set, thus implying an 85.77% reduction in direct amplitude features. Our proposed method achieved overall 99.33% accuracy, 94.56% F1, 93.84% sensitivity, and 99.21% specificity.(2). The article, “Wearable E-Textile and CNT Sensor Wireless Measurement System for Real-Time Penile Erection Monitoring”, was authored by Yongki Heo, Jinhyung Kim, Cheolung Cha, Kyusik Shin, Jihyoung Roh, and Jungki Jo. Erectile measurements are an important indicator of male urological disease diagnosis, treatment, and results. Rigiscan has been widely used in studies and diagnoses for evaluating nocturnal erectile dysfunction during sleep. There are some limitations to this technique. In this study, we used a real-time wearable monitoring system that can quantitatively measure the length and circumference of the penis using electronic textiles (E-textile) and carbon nanotube (CNT) sensors. The E-textile sensor was used to measure the length, circumference, and gradient with portability, convenience, and comfort. The results of this study call for supplementary sensor development coupled with new technologies or existing methods for measuring erection function.(3). “Open Software/Hardware Platform for Human-Computer Interface Based on Electrooculography (EOG) Signal Classification” was authored by Jayro Martínez-Cerveró, Majid Khalili Ardali, Andres Jaramillo-Gonzalez, Shizhe Wu et al. They discuss electrooculography (EOG) signals and Human–Computer Interfaces (HCI) for classifying four directions of eye movements employing EOG signals. The system is based on open-source ecosystems, the Raspberry Pi single-board computer, the OpenBCI biosignal acquisition device, and an open-source python library. The design is inexpensive, compact, and transportable. Their classification system can be used for input into an HCI and new assistive technology for assisted communication in paralyzed people.(4). “Hydration Assessment Using the Bio-Impedance Analysis Method”, authored by Reem AlDisi, Qamar Bader, and Amine Bermak, discusses the bio-impedance analysis technique for the measurement of skin hydration. The study simulated a human skin model and considered the change in dielectric properties for hydration and dehydration and the frequency of the applied signal. Impedance measurements were performed using silver ink jet-printed electrodes. Simulations were performed to investigate the relationship between skin mode, the electrode design, and the measured parameters. The skin model considered the change in the dielectric properties of the skin based on the hydration status and the frequency of the applied signal. The experimental study measured and analyzed the resistance, capacitance, and phase change. The measurements for hydrated and dehydrated skin display the distinguishable difference that can be used for a non-invasive assessment of hydration levels. (5). “Parametric Study of Bolt Clamping Effect on Resonance Characteristics of Langevin Transducers with Lumped Circuit Models” was authored by Jinhyuk Kim and Jungwoo Lee. They developed a numerical model to analyze the resonance characteristics of Langevin transducers and experimentally compare them with corresponding experimental data, regarding the input electrical impedance and effective electromechanical coupling coefficient for the transducer at resonance modes. The experimental and theoretical values of the resonance and anti-resonance frequencies and impedance differences were closely matched. The work presented in this study provides guidelines for the pre-loading conditions of intended resonance characteristics of Langevin transducers. (6). “Situation Awareness-Oriented Patient Monitoring with Visual Patient Technology: A Qualitative Review of the Primary Research”, authored by David Werner Tscholl, Julian Rössler, Sadiq Said, Alexander Kaserer, Donat Rudolf Spahn, and Christoph Beat Nöthiger, discusses the current state of research on the Visual Patient technology, of which is a situation-awareness-oriented patient monitoring approach. This review provides a historical context of the patient monitoring approach and discusses its limitations. Clinical studies were discussed to assess the effects of Visual Patient technology on outcomes closely related to the concept of situation awareness. In multiple computer-based laboratory studies, Visual Patients transferred more information per unit of time with a reduced subjectively perceived workload and increased diagnostic certainty. (7). “Advances in Biosensors Technology for Detection and Characterization of Extracellular Vesicles”, authored by Saif Mohammad Ishraq Bari, Faria Binte Hossain, and Gergana G. Nestorova, discusses the most recent advancement in lab-on-a-chip biosensing for the isolation, detection, and characterization of extracellular vesicles. The review summarizes the principle of operation, sensitivity, and specificity of fluorescence-based, colorimetric, magnetic, surface plasmon resonance, electrochemical, and immunoaffinity sensors for the detection and molecular characterization of extracellular vesicles. In conclusion, we are pleased to serve as editors on this Special Issue of which is focused on biosensors for analytical, diagnostic, and predictive functions. We hope our efforts and the authors’ insightful manuscripts may assist the readers in conceiving new directions in biosensor development. Biosensors have been widely employed as they are cost-effective, provide data quickly, enable in situ placement, and provide real-time analytical data. There is an urgent need for their use in the detection of monitoring for air, water, soil pollutants, toxins, endocrine-disrupting chemicals, precision agriculture, and for monitoring climate change and its impacts.


As the COVID-19 pandemic continues to spread, e-learning has increased. This is a challenge for nursing and midwifery students, as clinical training is an essential part of their education. The aim of this review was to identify the advantages and limitations of e-learning for nursing and midwifery students during the COVID-19 pandemic. A systematic review of the literature was conducted following the PRISMA guidelines. The international databases PubMed, CINAHL/MEDLINE, Web of Science, and ScienceDirect were searched. Articles were critically appraised. Thematic analysis was used to synthesise the data. The search resulted in 91 hits. Thirteen studies were included in the final analysis. Three main themes were identified: (1) the benefits of e-learning; (2) the challenges/limitations of e-learning; and (3) recommendations for e-learning. E-learning in nursing and midwifery is an effective alternative learning process during the COVID-19 pandemic. Students perceive several benefits and challenges related to internet access, technical equipment, financial aspects, and work and family commitments. Before the COVID-19 pandemic, e-learning was becoming an increasingly common form of education, albeit less common in health sciences such as medicine, dentistry, midwifery, and nursing. E-learning refers to a course when the learning has been partially or fully taken online, using information and communication technology, eBooks, text messages, and videos, links, and discussions [During the COVID-19 pandemic, countries worldwide began to use e-learning for students. Faculties were trying to make the most of the technological transformation and provide a better learning environment for students. E-learning has witnessed a massive boom, as it allows flexibility in studying and options to determine a convenient time frame and study space . It alsoE-learning students face different challenges during the COVID-19 pandemic . The sudThis systematic review aimed to identify the advantages and limitations of e-learning for nursing and midwifery students during the COVID-19 pandemic. The research question was: How does existing evidence explain the benefits and limitations of e-learning for nursing and midwifery students during the COVID-19 pandemic?A systematic review was conducted using a literature review method, analysis and synthesis, and the method of compilation . The revThe literature search was conducted in four international databases  in the spring of 2022 using predefined search terms according to the PI(C)OT  inclusive and exclusion criteria . The seaThe Joanna Briggs Institute (JBI) tools were used to evaluate the studies. The JBI Qualitative Assessment Research Instrument was used for the qualitative studies, and the Critical Appraisal Checklist for Analytical Cross-Sectional Studies or the Critical Appraisal Checklist Cohort Studies were used for studies based on quantitative methods. To assess the article quality in qualitative studies, we considered a scoring system. The three categories were: “low quality” (0–4), “medium quality” (5–7), and “high quality” (8–10). For cross-sectional studies, the scores determined “low quality” (0–2), “medium quality” (3–5), and “high quality” (6–8). Cohort studies yielded “low quality” (0–4), “medium quality” (5–8), and “high quality” (9–11) categories .The Mixed Methods Appraisal Tool (MMAT) was used for the quality assessment of the mixed-methods studies . The MMAData were extracted from all the included studies: author, year of publication, country, purpose, participants, research design, and main findings. The thematic analysis was performed according to Thomas and Harden’s  guidelinn = 4) were found and eliminated using Mendeley Reference Management Software. Then, the records (n = 87) were screened and excluded as not appropriate according to the predefined inclusion criteria. Articles (n = 30) were selected for eligibility by reading the full text. In total, 13 studies were included in the final analysis  advantages of e-learning; (2) challenges/limitations of e-learning; and (3) recommendations for e-learning, as presented in The findings of this study emphasise the crucial role of e-learning as a consequential and efficacious alternative in the field of nursing and midwifery education during the COVID-19 pandemic. E-learning emerges as a facilitator, allowing students to seamlessly integrate academic pursuits ,32, famiMoreover, the financial economy of e-learning is evident, manifesting in the conservation of resources otherwise expended on commuting. Simultaneously, the time savings from eliminating travel are redirected towards familial responsibilities ,31. The Furthermore, e-learning presents an ancillary benefit in mitigating health risks, specifically the reduction of exposure to COVID-19, by enabling students to engage in learning within the safety of their homes . This duLong-time exposure to e-learning burdened nursing and midwifery students and caused high anxiety levels , stress Implementing e-learning engendered heightened daily academic demands for students, notably those enrolled part-time, for whom the virtual learning environment induced significant stress. The confluence of employment-related commitments constrained their ability to engage fully in e-study. Furthermore, the strain was exacerbated by familial obligations, as changes in family dynamics introduced additional burdens, particularly for part-time students in contexts where caregiving responsibilities traditionally fall within the purview of women .An in-depth review of the data collected reveals several challenges related to students’ infrastructure. Predominantly, disruptions and/or suboptimal internet connectivity emerged as pervasive impediments, a recurring theme highlighted across multiple data sources ,31,32,34E-learning is also influenced by the space available to students at home. The lack of privacy and adequate space for studying presented challenges, especially for students in environments where families are large  or the cGood relationships and communication are essential for a successful learning process between lecturer and student. Body language and eye contact  contribuThe findings show that faculty anxiety about using online tools and student anxiety about technology during exams can be significantly decreased by targeted training interventions, thereby improving the efficacy of e-learning . NursingThe findings emphasise that recorded lectures emerge as the most effective modality, facilitating iterative review ,31. VideStudents must take care of their psychophysical, social, and spiritual well-being during e-learning. Spending time in the garden  and physThis systematic review presents the advantages and limitations of e-learning for nursing and midwifery students during the COVID-19 pandemic. Our findings show that e-learning offers some benefits. Nursing and midwifery students could adjust to listening to lectures, listen to lectures repeatedly, save time because of no travelling needs, and take more responsibility for their studies. In addition to the many advantages, midwifery and nursing students faced challenges like social isolation brought about by e-learning during the pandemic. Unique challenges associated with clinical training in the context of e-learning underscored the need for innovative solutions in terms of practical skill acquisition. The evolving landscape of teaching methodologies in the digital realm necessitated reevaluating and adapting traditional instructional approaches to align with the nuances of e-learning. Both academically and personally, strategies for coping with the increased burdens imposed by e-learning emerged as a crucial area for exploration, suggesting avenues for support and intervention. E-learning during the COVID-19 pandemic increased loneliness and social isolation among nursing and midwifery students. Both pose a significant threat to mental health and well-being.In 2020, the world faced the COVID-19 pandemic, which affected healthcare, social institutions, and society . Also, tE-learning saves students and teachers time they would have spent travelling  and enabDespite its many advantages, e-learning presents some challenges and limitations ,24,35. AIn the following, we offer some recommendations for effective and successful e-learning in nursing and midwifery. Adequate technical and infrastructural equipment with access to the online network is imperative for e-learning. Clinical training represents the core of the nursing and midwifery profession; therefore, it must be provided in the clinical environment, not only in simulated environments. Clinical training imbues students with confidence and professional competence for nursing and midwifery practice. Nevertheless, e-learning could be considered an alternative nursing and midwifery education approach. It could be used for teaching learning modules or complementing face-to-face training in training programmes . We alsoIt would be also interesting for future research to evaluate e-learning’s effectiveness compared to traditional learning in-person.This literature review has some limitations. In the search strategy, we limited the research articles to English and excluded the remaining articles in other languages, which could affect the analysis. Studies, mostly conducted outside Europe, were included in the review, representing a limitation of the implementation and use of the findings in the education of nurses and midwifery in Europe.The COVID-19 pandemic has caused a sudden shift from traditional classroom teaching to e-learning. E-learning brings new challenges for both students and teachers.It has many advantages, such as safety against SARS-CoV-2 infection, greater accessibility to educational content independent of time, independence and greater student innovation in studies, saving time and financial resources, adjustment of study time and more time for family.However, some limitations and challenges were also revealed. The limitations present increased burdens in terms of coordinating private life and studies, inadequate or deficient information and infrastructure support. Furthermore, poorer social contact with fellow students, health problems related to e-learning, the financial burden that comes with the purchase of new telecommunications equipment, inadequate space and lack of privacy and communication problems present challenges to e-learning.Experience with e-learning brought new knowledge, insights and feelings that can encourage further research and improvements in this area.


The predictability of GNRI for long-term survival was more pronounced when evaluated at hospital discharge than at hospital admission . Our study suggested that GNRI should be evaluated at hospital discharge, regardless of the assessment at hospital admission, to predict the long-term prognosis for patients hospitalized with ADHF.Geriatric Nutritional Risk Index (GNRI) is known both as a reliable indicator of nutritional status and a predictor of long-term survival among patients with acute decompensated heart failure (ADHF). However, the optimal timing to evaluate GNRI during hospitalization remains unclear. In the present study, we retrospectively analyzed patients hospitalized with ADHF in the West Tokyo Heart Failure (WET-HF) registry. GNRI was assessed at hospital admission (a-GNRI) and discharge (d-GNRI). Out of 1474 patients included in the present study, 568 (40.1%) and 796 (57.2%) patients had lower GNRI (<92) at hospital admission and discharge, respectively. After the follow-up (median 616 days), 290 patients died. The multivariable analysis showed that all-cause mortality was independently associated with d-GNRI (per 1 unit decrease, adjusted hazard ratio [aHR]: 1.06, 95% confidence interval [CI]: 1.04–1.09,  Acute decompensated heart failure (ADHF) has a strong relationship with malnutrition ; ADHF caNotwithstanding the importance of nutritional assessment for ADHF patients, there is a lack of consensus regarding the methodology for the assessment. Some objective scores have been advocated for the purpose of nutritional evaluation among patients with HF. Geriatric Nutritional Risk Index (GNRI) is one of the objective scores to assess a patient’s nutritional condition. GNRI consists of body mass index (BMI) and albumin, both of which are commonly measured in dairy clinical practice, and therefore, GNRI could be easily calculated and applied even in a busy clinical setting . PreviouThe present study aimed to investigate the effects of GNRI assessed at the time of hospital admission and discharge on the long-term survival among hospitalized patients presenting with ADHF.The present study is a sub-study of the West Tokyo Heart Failure Registry (WET-HF Registry). Details of the WET-HF Registry have been described previously and well-validated by prognostic models for patients hospitalized with heart failure ,15,16,17We collected conventional clinical variables, including age, sex, etiology of HF, medical history, vital status at admission and discharge, laboratory data , and medications (at admission and discharge). Patients who did not have available data of serum albumin and BMI at hospital admission and/or discharge and at the follow-up vital status were excluded from the current study.The primary endpoint of the present study was all-cause mortality at the maximum follow-up period from the discharge of the index hospitalization (defined as day 0), which is the most robust clinical endpoint without the necessity of adjudication.We calculated patients’ GNRI at both admission  and discharge  by the following formula : GNRI = When a patient’s body weight exceeded the ideal body weight, “body weight/ideal body weight” was set to 1, according to the original criteria . PatientContinuous variables were reported as median with interquartile range (IQR) and were compared using the Kruskal–Wallis H test. Categorical variables were presented as counts and percentage and were compared using the chi-square test or Fisher’s exact test as appropriate. A scatter plot between a-GNRI and d-GNRI was drawn, depicting the linear regression line with the 95% confidence interval (CI), and the Pearson correlation was used to quantify the relation between a-GNRI and d-GNRI. To visualize the impacts of BMI and albumin on d-GNRI, as well as changes in GNRI from hospital admission to discharge (∆GNRI), we made heatmaps in which d-GNRI and ∆GNRI were color-coded for each observed pair of BMI-albumin at hospital admission and pair of ∆BMI-∆albumin during hospitalization, respectively.The Kaplan–Meier method was used to estimate the cumulative rates of events, and the log-rank test was performed to examine the differences between groups. The cumulative incidence of all-cause death during the follow-up period was compared between the lower GNRI (<92) and higher GNRI (≥92) groups at both timepoints  using unadjusted and adjusted Cox proportional hazard models to calculate unadjusted and adjusted HRs with 95% CIs, respectively. Adjusted baseline variables included age (years), sex, hypertension, dyslipidemia, diabetes mellitus, renal failure requiring hemodialysis, current smoking, chronic pulmonary occlusive disease (COPD), history of HF admission, New York Heart Association Functional Classification (NYHA class) 3 or 4, laboratory data  at discharge, left ventricular ejection fraction (LVEF), use of beta-blockers, use of mineralocorticoid receptor antagonists (MRA), use of statins, use of either angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) at discharge, length of index hospitalization (days), and a-GNRI (for d-GNRI) or d-GNRI (for a-GNRI) that had been selected based on prior knowledge of the association of these covariables with the outcomes .The association between a-GNRI or d-GNRI and the primary endpoint was also assessed as a continuous variable, depicting restricted cubic spline curves derived from the unadjusted proportional hazards models. In order to determine the best variable for predicting the clinical outcome, the area under the receiver-operating characteristic (ROC) curves and areas under the curves (AUC) were estimated for several variables, including a-GNRI, d-GNRI, ∆GNRI, BMI at discharge, ∆BMI, albumin at discharge, and ∆albumin for the primary endpoint, and were compared by using the DeLong method .p value of less than 0.05 was considered to indicate statistical significance. All analyses were performed in SPSS Statistics, version 29  and R software version 4.0.1 .A two-sided From 2006 to 2017, 4000 patients were enrolled in the WET-HF Registry. Out of those patients, 2410 patients who did not have available GNRI data and 116 patients without any follow-up data were excluded in this study. Finally, a total number of 1474 patients  were included in the present study . p < 0.001), the majority of the patients showed decreased GNRI from hospital admission to discharge .During a median follow-up period of 616 days (IQR: 271 to 925 days), 290 of the study patients died. The Kaplan–Meier curves for all-cause death up to 4 years are shown in p < 0.001) and a continuous variable . Similarly, patients who had higher d-GNRI showed a lower risk of all-cause death . After adjusting for confounding variables, patients with higher d-GNRI showed a significantly lower risk of all-cause death, both as a categorical  and a continuous variable . On the other hand, a-GNRI was not independently associated with all-cause death (p > 0.05).The unadjusted and adjusted hazard ratios with those 95% Cis, according to a-GNRI or d-GNRI, are shown in p = 0.140, p < 0.001).The major findings of the present study are as follows: (1) Although there was a strong correlation between a-GNRI and d-GNRI, GNRI had decreased significantly during the ADHF hospitalization. The changes in GNRI depended more on serum albumin than on BMI. (2) Lower d-GNRI, but not a-GNRI, was independently associated with long-term all-cause mortality in patients with ADHF. (3) Compared to a-GNRI, d-GNRI had more prognostic value for long-term mortality. Together, these findings suggest that the GNRI should be evaluated at the time of hospital discharge rather than at admission among patients hospitalized with ADHF so as to evaluate the patients’ prognosis appropriately.Nutritional evaluation is of paramount importance for the management of HF patients . MalnutrOur study demonstrated that d-GNRI had better predictability for all-cause death than a-GNRI . In the Nakayama et al.  reportedAs shown in Of noted, the higher prevalence of hemodialysis in the lower GNRI group was observed at discharge, but not at admission . AlthougOur study has several limitations. First, this was a retrospective observational study. Hence, we could not consider unmeasured or unknown variables affecting the results. Second, we could not analyze a lot of patients enrolled in the WET-HF registry due to the lack of data, which might introduce selection bias. Third, we suggest that higher GNRI indicates a better nutritional condition, though we have no additional confirmatory indices of nutritional status from this cohort, such as controlling nutritional status (CONUT) score or prognostic nutritional index (PNI), due to lack of those data. Finally, we do not have data regarding nutritional intervention or the administration of albumin during hospitalization. Past studies have demonstrated the utility of nutritional intervention in HF patients ; howeverAmong patients hospitalized with ADHF, GNRI at the time of hospital discharge was independently associated with long-term all-cause mortality and had more predictability than GNRI at the time of hospital admission. Our study suggested that GNRI should be evaluated at the time of hospital discharge, regardless of the assessment at hospital admission in ADHF patients.