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Enlarged perivascular spaces (EPVS) are MRI markers of impaired glymphatic clearance and have been associated with neurodegenerative diseases. However, their clinical significance in amyotrophic lateral sclerosis (ALS) and underlying mechanisms remain poorly understood. This study investigated the prevalence, clinical relevance, and pathophysiological basis of EPVS in ALS. MRI data from 114 ALS patients and 119 matched controls were analyzed, with high-degree EPVS defined as more than 20 visible spaces. High-degree EPVS in the centrum semiovale (CSO) was more prevalent in ALS patients (49.1%) than in controls (15.1%, p < 0.001). Age, male sex, and ALS diagnosis were independent predictors, while disease severity and aggressiveness were not associated. ALS patients with high-degree CSO-EPVS were older at disease onset and MRI but showed similar clinical progression. In SOD1/G93A ALS mice, cerebral perivascular spaces were significantly enlarged at 5 months compared to wild-type and younger ALS mice. Cervical lymphatic ligation promoted misfolded SOD1 accumulation in motor neurons and cerebral vessels, further increasing perivascular space width without altering motor function. These findings suggest that about half of ALS patients exhibit high-degree CSO-EPVS, reflecting impaired protein clearance rather than disease aggressiveness.

Using Million Dollar Round Table member qualification as the performance indicator of life insurance agents, this research investigated the relationship of familial and marital status variables with the performance of female life insurance agents in Taiwan by using male insurance agents as the comparison sample. In all samples, the performance of agents who were married, single parent, re-married, or whose spouse or sibling was also a life insurance agent was better than other agents. In the comparison samples, married, or re-married of male life insurance agents had better performance than other male agents. In the female samples, the performance of insurance agents who were single parents and whose spouse or sibling was also a life insurance agent was better than other female agents. Comparing familial and marital status factors with performance between male and female agents, familial responsibilities and economic stress were common significant factors that drove insurance agents to pursue higher levels of performance.

Background The applicability and therapeutic efficacy of specific personalized immunotherapy for cancer patients is limited by the genetic diversity of the host or the tumor. Side-effects such as immune-related adverse events (IRAEs) derived from the administration of immunotherapy have also been observed. Therefore, regulatory immunotherapy is required for cancer patients and should be developed. Methods The cationic lipo-PEG-PEI complex (LPPC) can stably and irreplaceably adsorb various proteins on its surface without covalent linkage, and the bound proteins maintain their original functions. In this study, LPPC was developed as an immunoregulatory platform for personalized immunotherapy for tumors to address the barriers related to the heterogenetic characteristics of MHC molecules or tumor associated antigens (TAAs) in the patient population. Here, the immune-suppressive and highly metastatic melanoma, B16F10 cells were used to examine the effects of this platform. Adsorption of anti-CD3 antibodies, HLA-A2/peptide, or dendritic cells’ membrane proteins (MP) could flexibly provide pan-T-cell responses, specific Th1 responses, or specific Th1 and Th2 responses, depending on the host needs. Furthermore, with regulatory antibodies, the immuno-LPPC complex properly mediated immune responses by adsorbing positive or negative antibodies, such as anti-CD28 or anti-CTLA4 antibodies. Results The results clearly showed that treatment with LPPC/MP/CD28 complexes activated specific Th1 and Th2 responses, including cytokine release, CTL and prevented T-cell apoptosis. Moreover, LPPC/MP/CD28 complexes could eliminate metastatic B16F10 melanoma cells in the lung more efficiently than LPPC/MP. Interestingly, the melanoma resistance of mice treated with LPPC/MP/CD28 complexes would be reversed to susceptible after administration with LPPC/MP/CTLA4 complexes. NGS data revealed that LPPC/MP/CD28 complexes could enhance the gene expression of cytokine and chemokine pathways to strengthen immune activation than LPPC/MP, and that LPPC/MP/CTLA4 could abolish the LPPC/MP complex-mediated gene expression back to un-treatment. Conclusions Overall, we proved a convenient and flexible immunotherapy platform for developing personalized cancer therapy. Graphical Abstract

Deformed wing virus (DWV) prevalence is high in honey bee ( Apis mellifera ) populations. The virus infects honey bees through vertical and horizontal transmission, leading to behavioural changes, wing deformity, and early mortality. To better understand the impacts of viral infection in the larval stage of honey bees, artificially reared honey bee larvae were infected with DWV (1.55 × 10 10 copies/per larva). No significant mortality occurred in infected honey bee larvae, while the survival rates decreased significantly at the pupal stage. Examination of DWV replication revealed that viral replication began at 2 days post inoculation (d.p.i.), increased dramatically to 4 d.p.i., and then continuously increased in the pupal stage. To better understand the impact of DWV on the larval stage, DWV-infected and control groups were subjected to transcriptomic analysis at 4 d.p.i. Two hundred fifty-five differentially expressed genes (DEGs) (fold change ≥ 2 or ≤ -2) were identified. Of these DEGs, 168 genes were downregulated, and 87 genes were upregulated. Gene Ontology (GO) analysis showed that 141 DEGs (55.3%) were categorized into molecular functions, cellular components and biological processes. One hundred eleven genes (38 upregulated and 73 downregulated) were annotated by KO (KEGG Orthology) pathway mapping and involved metabolic pathways, biosynthesis of secondary metabolites and glycine, serine and threonine metabolism pathways. Validation of DEGs was performed, and the related gene expression levels showed a similar tendency to the DEG predictions at 4 d.p.i.; cell wall integrity and stress response component 1 ( wsc1 ), cuticular protein and myo-inositol 2-dehydrogenase ( iolG ) were significantly upregulated, and small conductance calcium-activated potassium channel protein ( SK ) was significantly downregulated at 4 d.p.i. Related gene expression levels at different d.p.i. revealed that these DEGs were significantly regulated from the larval stage to the pupal stage, indicating the potential impacts of gene expression levels from the larval to the pupal stages. Taken together, DWV infection in the honey bee larval stage potentially influences the gene expression levels from larvae to pupae and reduces the survival rate of the pupal stage. This information emphasizes the consequences of DWV prevalence in honey bee larvae for apiculture.

Background Children with unilateral cerebral palsy (UCP) are encouraged to participate in the regular school curriculum. However, even when using the less-affected hand for handwriting, children with UCP still experience handwriting difficulties. Visual-motor integration (VMI) is a predictor of handwriting quality. Investigating VMI in children with UCP is important but still lacking. Conventional paper-based VMI assessments is subjective and use all-or-nothing scoring procedures, which may compromise the fidelity of VMI assessments. Moreover, identifying important shapes that are predictive of VMI performance might benefit clinical decision-making because different geometric shapes represent different developmental stepping stones of VMI. Therefore, a new computer-aided measure of VMI (the CAM-VMI) was developed to investigate VMI performance in children with UCP and to identify shapes important for predicting their VMI performance. Methods Twenty-eight children with UCP and 28 typically-developing (TD) children were recruited. All participants were instructed to complete the CAM-VMI and Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery-VMI). The test items of the CAM-VMI consisted of nine simple geometric shapes related to writing readiness. Two scores of the CAM-VMI, namely, Error and Effort, were obtained by image registration technique. The performances on the Beery-VMI and the CAM-VMI of children with UCP and TD children were compared by independent t -test. A series of stepwise regression analyses were used to identify shapes important for predicting VMI performance in children with UCP. Results Significant group differences were found in both the CAM-VMI and the Beery-VMI results. Furthermore, Error was identified as a significant aspect for predicting VMI performance in children with UCP. Specifically, the square item was the only significant predictor of VMI performance in children with UCP. Conclusions This study was a large-scale study that provided direct evidence of impaired VMI in school-aged children with UCP. Even when using the less-affected hand, children with UCP could not copy the geometric shapes as well as TD children did. The copied products of children with UCP demonstrated poor constructional accuracy and inappropriate alignment. Furthermore, the predictive model suggested that the constructional accuracy of a copied square is an important predictor of VMI performance in children with UCP.

Background One of the most common and recurrent vaginal infections is bacterial vaginosis (BV). The diagnosis is based on changes to the “normal” vaginal microbiome; however, the normal microbiome appears to differ according to reproductive status and ethnicity, and even among individuals within these groups. The Amsel criteria and Nugent score test are widely used for diagnosing BV; however, these tests are based on different criteria, and so may indicate distinct changes in the vaginal microbial community. Nevertheless, few studies have compared the results of these test against metagenomics analysis. Methods Vaginal flora samples from 77 participants were classified according to the Amsel criteria and Nugent score test. The microbiota composition was analyzed using 16S ribosome RNA gene amplicon sequencing. Bioinformatics analysis and multivariate statistical analysis were used to evaluate the microbial diversity and function. Results Only 3 % of the participants diagnosed BV negative using the Amsel criteria (A−) were BV-positive according to the Nugent score test (N+), while over half of the BV-positive patients using the Amsel criteria (A+) were BV-negative according to the Nugent score test (N−). Thirteen genera showed significant differences in distribution among BV status defined by BV tests (e.g., A − N−, A + N− and A + N+). Variations in the four most abundant taxa, Lactobacillus , Gardnerella , Prevotella , and Escherichia , were responsible for most of this dissimilarity. Furthermore, vaginal microbial diversity differed significantly among the three groups classified by the Nugent score test (N−, N+, and intermediate flora), but not between the Amsel criteria groups. Numerous predictive microbial functions, such as bacterial chemotaxis and bacterial invasion of epithelial cells, differed significantly among multiple BV test, but not between the A− and A+ groups. Conclusions Metagenomics analysis can greatly expand our current understanding of vaginal microbial diversity in health and disease. Metagenomics profiling may also provide more reliable diagnostic criteria for BV testing.

Physical activity has long been associated with chronic diseases. However, the association between physical activity and renal progression in hypertensive patients remains unclear. This study investigated the relationship between the level of physical activity and renal function in hypertensive patients. We analyzed 3543 patients with hypertension. Data on patients’ demographic characteristics, comorbidities, physical activity, and lifestyle characteristics were collected via questionnaires. An estimated glomerular filtration rate (eGFR) that was reduced by more than 25% from the baseline eGFR was defined as renal progression. This study divided physical activity into three levels (low, moderate, and high) based on their metabolic equivalent of tasks (METs) levels. The mean age was 63.32 ± 12.29 years. After we adjusted for covariates, renal progression was significantly higher among patients with low levels of physical activity (odds ratio (OR), 1.39; 95% confidence interval (CI), 1.01–1.90)) and moderate levels of physical activity (OR, 1.39; 95% CI, 1.04–1.86) than among patients with high levels of physical activity. We found a significant association between physical activity and renal progression in hypertensive patients, especially in elderly patients and men. Therefore, to reduce the risk of renal progression, we recommend that clinicians should encourage patients to improve their physical activity.

Background Nurses are faced with varying job stressors depending on their positions and duties. Few previous studies have compared job stress and related chronic conditions among different nursing positions. The objectives were to compare job stressors among clinical registered nurses, nurse practitioners, and head nurses and explore the impact of job stressors and stress level on hyperlipidemia, hyperglycemia, and hypertension. Methods Secondary data extracted from a survey of health-care workers conducted from May to July 2014 across 113 hospitals in Taiwan was used. This analysis included 17,152 clinical registered nurses, 1438 nurse practitioners, and 2406 head nurses. Socio-demographic characteristics, job stressors, stress levels, and hyperlipidemia, hyperglycemia, and hypertension variables were extracted. Results Perceived stressors differed among clinical registered nurses, nurse practitioners, and head nurses, but overall stress level did not. Nurse practitioners and head nurses showed significantly higher prevalence of hyperlipidemia, hyperglycemia, and hypertension than clinical registered nurses. Higher stress levels, age, body mass index, work hours, and caring for family members were positively associated with hyperlipidemia, hyperglycemia, and hypertension. After adjustment for these variables, risk of hyperlipidemia, hyperglycemia, and hypertension did not differ across the nursing positions. Conclusions Although stressors vary by different nursing positions, overall stress level does not. Hyperlipidemia, hyperglycemia, and hypertension are related to stress level, age, body mass index, weekly working hours, and caring for family members. Hence, alleviating job stress and avoiding long working hours are likely to reduce the risk of hyperlipidemia, hyperglycemia, and hypertension in nurses.

Background Elderly patients with aged physical status and increased underlying disease suffered from more postoperative complication and mortality. We design this retrospective cohort study to investigate the relationship between existing comorbidity of elder patients and 30 day post-anesthetic mortality by using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) from Health Insurance Database. Methods Patients aged above 65 years old who received anesthesia between 2000 and 2010 were included from 1 million Longitudinal Health Insurance Database in (LHID) 2005 in Taiwan. We use age, sex, type of surgery to calculate propensity score and match death group and survival one with 1:4 ratio (death: survival = 1401: 5823). Multivariate logistic model with stepwise variable selection was employed to investigate the factors affecting death 30 days after anesthesia. Results Thirty seven comorbidities can independently predict the post-anesthetic mortality. In our study, the leading comorbidities predict post-anesthetic mortality is chronic renal disease (OR = 2.806), acute myocardial infarction (OR = 4.58), and intracranial hemorrhage (OR = 3.758). Conclusions In this study, we present the leading comorbidity contributing to the postoperative mortality in elderly patients in Taiwan from National Health Insurance Database. Chronic renal failure is the leading contributing comorbidity of 30 days mortality after anesthesia in Taiwan which can be explained by the great number of hemodialysis and prolong life span under National Taiwan Health Insurance. Large scale database can offer enormous information which can help to improve quality of medical care.

Blast-related mild traumatic brain injury (bmTBI) often leads to long-term sequalae, but diagnostic approaches are lacking due to insufficient knowledge about the predominant pathophysiology. This study aimed to build a diagnostic model for future verification by applying machine-learning based support vector machine (SVM) modeling to diffusion tensor imaging (DTI) datasets to elucidate white-matter features that distinguish bmTBI from healthy controls (HC). Twenty subacute/chronic bmTBI and 19 HC combat-deployed personnel underwent DTI. Clinically relevant features for modeling were selected using tract-based analyses that identified group differences throughout white-matter tracts in five DTI metrics to elucidate the pathogenesis of injury. These features were then analyzed using SVM modeling with cross validation. Tract-based analyses revealed abnormally decreased radial diffusivity (RD), increased fractional anisotropy (FA) and axial/radial diffusivity ratio (AD/RD) in the bmTBI group, mostly in anterior tracts (29 features). SVM models showed that FA of the anterior/superior corona radiata and AD/RD of the corpus callosum and anterior limbs of the internal capsule (5 features) best distinguished bmTBI from HCs with 89% accuracy. This is the first application of SVM to identify prominent features of bmTBI solely based on DTI metrics in well-defined tracts, which if successfully validated could promote targeted treatment interventions.