Investigation of plasmid-mediated quinolone resistance among extended-spectrum ß-lactamase isolates of E. coli and K. pneumoniae.

Escherichia coli and Klebsiella pneumoniae are important members of the Enterobacteriaceae family, involved in many infections. The increased resistance rate towards ß-lactams and fluoroquinolones -which are the main therapeutic options- limits their treatment options. This study aimed to assess the local resistance patterns against different antimicrobials and to determine the extended-spectrum ß-lactamase (ESBLs) producers. The study revealed that 36% of clinical isolates were ESBL producers, showing high resistance rates towards ß-lactams and non-ß-lactams, especially sulphamethoxazole-trimethoprim and fluoroquinolones. However, they were susceptible to chloramphenicol and doxycycline (33% and 20%; respectively). Also, the investigation aimed to screen the plasmid profile of quinolone-resistant ESBLs-producers and to detect the plasmid-mediated quinolone resistance genes including qnrA, qnrS, qnrB, qnrC, qnrD, and qnrVC. Moreover, the conjugative plasmid among the quinolone-resistant isolates was elucidated. The results showed that extracted plasmids of sizes ranging from ≈0.9 to 21.23 Kb, divided into 7 plasmid patterns were detected. A plasmid of approximately 21.23 Kb was found in all isolates and the QnrS gene was the most predominant gene. Moreover, the frequency of transconjugation within the same genus was higher than that recorded between different genera; where 68% of E. coli isolates transferred the resistance genes compared to Klebsiella isolates (36.6%). Plasmid profiles of transconjugants demonstrated great similarity, where 21.23 Kb plasmid was detected in all transconjugants. Since these transconjugants were quinolone-resistant ESBL producers, it has been suggested that quinolone resistance determinants might be carried on that plasmid.

Cocktail Approach with Polyserotonin Nanoparticles and Peptides for Treatment of Streptococcus mutans.

Dental plaque, formed by a Streptococcus mutans biofilm, is a major contributor to cavity formation. While antimicrobial strategies exist, the growing risk of antibiotic resistance necessitates alternative therapeutic solutions. Polyserotonin nanoparticles (PSeNPs), recently recognized for their photothermal property and promising biomedical applications, open up a new avenue for antimicrobial use. Here, we introduced a UV-initiated synthetic route for PSeNPs with improved yield. Using these PSeNPs, a cocktail treatment to reduce the viability of this cavity-causing bacteria was developed. This cocktail comprises an S. mutans-targeting antimicrobial peptide (GH12), an intraspecies competence-stimulating peptide that triggers altruistic cell death in S. mutans, and laser-activated heating of PSeNPs. The "peptide + PSeNP + laser" combination effectively inhibits S. mutans growth in both planktonic and biofilm states. Moreover, the cocktail approach remains effective in reducing the viability of S. mutans in a more virulent dual-species biofilm with Candida albicans. Overall, our results reinforce the utility of a multipronged therapeutic strategy to reduce cariogenic bacteria in the complex model oral biofilm.

Role of homelessness and psychiatric disorders in suicide deaths among veterans: A four-way decomposition analysis.

Homelessness and suicide are top priorities in the U.S. Department of Veterans Affairs (VA). This study examined the various pathways involving homelessness, substance use, and mental health disorders in relation to suicide deaths among veterans in the VA healthcare system. A retrospective cohort study was conducted among 6,128,921 veterans-399,125 homeless and 5,729,796 non-homeless-followed-up between 2017 and 2021 using VA/Department of Defense linked databases. Multivariable Cox regression was applied for homelessness and psychiatric disorders as predictor of suicide deaths, sequentially controlling for demographic, clinical, substance use, and mental health characteristics. Four-way decomposition analysis was used to calculate proportions of suicide deaths mediated and/or moderated by homelessness, substance use, and mental health disorders. The relationship between homelessness and suicide-specific mortality risk was reduced from 40 % greater risk in unadjusted to 9 % greater risk in fully-adjusted models. Nearly 26 % of the total effect of homelessness on suicide-specific mortality risk was mediated by substance use disorders, whereas 49 % was mediated and 36 % was moderated by mental health disorders. In conclusion, excess suicide-specific mortality risk in homeless veterans is partly explained by substance use and mental health disorders, highlighting the importance of wrap-around health and social services for homeless veterans in mitigating suicide risk.

Infection burden, periodontal pathogens, and their interactive association with incident all-cause and Alzheimer's disease dementia in a large national survey.

INTRODUCTION: Relationships and interplay of an infection burden (IB) and periodontal pathogens or periodontal disease (Pd) markers with Alzheimer's disease (AD) and all-cause dementia among US adults were examined. METHODS: Less than or equal to 2997 participants from the National Health and Nutrition Survey III were linked to CMS-Medicare [≥45 years (1988-1994); ≤30 years follow-up]. RESULTS: Hepatitis C (hazard ratio = 3.33, p = 0.004) and herpes simplex virus 2 were strongly associated with greater all-cause dementia risk. Porphyromonas gingivalis and Streptococcus oralis were associated with greater AD risk at higher IB. The red-green periodontal pathogen cluster coupled with higher IB count increased the risk of all-cause dementia among minority racial groups. Pocket probing depth associated with dementia risk at lower IB in the overall sample. DISCUSSION: Select viruses and bacteria were associated with all-cause and AD dementia, while the IB interacted with Pd markers in relation to these outcomes. HIGHLIGHTS: Interplay of infection burden (IB) and periodontal disease with dementia was tested. ≤2997 participants from NHANES III were linked to Medicare. Hepatitis C and herpes simplex virus 2 strongly associated with dementia risk. Tetanus sero-positivity increased Alzheimer's disease (AD) risk. Porphyromonas gingivalis and Streptococcus oralis associated with AD at higher IB. Red-green periodontal cluster at high IB, increased dementia in racial minorities. Pocket probing depth associated with dementia risk at lower IB.

Stress-induced eosinophil activation contributes to postoperative morbidity and mortality after lung resection.

Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor-dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration-approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology.

Plasma homocysteine and longitudinal change in cognitive function among urban adults.

BACKGROUND: Cross-sectional and longitudinal studies have inconsistently linked cognitive performance and change over time to an elevated level of homocysteine (Hcy), with few conducted among urban adults. METHODS: Longitudinal data [Visit 1 (2004-2009) and Visit 2 (2009-2013)] were analyzed from up to 1430 selected Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) participants. Baseline and follow-up blood Hcy was measured, while 11 cognitive function test scores were assessed at either of these two visits. Overall, sex- and race-stratified associations were evaluated using mixed-effects linear regression models, adjusting for key potential confounders. Interaction effects between Hcy and serum levels of folate and vitamin B-12 were also tested. RESULTS: We found that greater LnHcyv1 was significantly associated with poorer baseline attention based on higher Loge (TRAILS A, in seconds) [ß (SE): 0.101 (0.031), P = 0.001]. Heterogeneity was also found by sex and by race. Most notably, among men only, LnHcyv1 was associated with faster decline on the BVRT (# of errors), a measure of visuo-spatial memory (ß (SE): 0.297(0.115), P = 0.010, reduced model); while among African American adults only, an elevated and increasing LnHcy over time was associated with faster rate of decline on Loge (TRAILS B, in seconds) [ß (SE): +0.012 (0.005), p = 0.008], a measure of executive function. Interactions between Hcy, folate and vitamin B-12 blood exposures were also detected. CONCLUSIONS: In summary, sex- and race-specific adverse association between elevated Hcy and cognitive performance over time were detected among middle-aged urban adults, in domains of attention, visuo-spatial memory and executive functioning.

Mediating and moderating effects of plasma proteomic biomarkers on the association between poor oral health problems and brain white matter microstructural integrity: the UK Biobank study.

The plasma proteome can mediate associations between periodontal disease (Pd) and brain white matter integrity (WMI). We screened 5089 UK Biobank participants aged 40-70 years for poor oral health problems (POHP). We examined the association between POHP and WMI (fractional anisotropy (FA), mean diffusivity (MD), Intracellular Volume Fraction (ICVF), Isotropic Volume Fraction (ISOVF) and Orientation Diffusion (OD)), decomposing the total effect through the plasma proteome of 1463 proteins into pure mediation, pure interaction, neither, while adjusting for socio-demographic and cardiovascular health factors. Similarly, structural equations modeling (SEM) was conducted. POHP was more prevalent among men (12.3% vs. 9.6%), and was associated with lower WMI on most metrics, in a sex-specific manner. Of 15 proteins strongly associated with POHP, growth differentiation factor 15 (GDF15) and WAP four-disulfide core domain 2 (WFDC2; also known as human epididymis protein 4; HE4) were consistent mediators. Both proteins mediated 7-8% of total POHP effect on FAmean. SEM yielded significant total effects for FAmean, MDmean and ISOVFmean in full models, with %mediated by common latent factor (GDF15 and WFDC2) ranging between 13% (FAmean) and 19% (ISOVFmean). For FA, mediation by this common factor was found for 16 of 49 tract-specific and global mean metrics. Protein metabolism, immune system, and signal transduction were the most common pathways for mediational effects. POHP was associated with poorer WMI, which was partially mediated by GDF15 and WFDC2.

Functional analysis of a panel of molecular markers for diagnosis of systemic lupus erythematosus in rats.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a diverse autoimmune disease that arises from a combination of complex genetic factors and environmental influences. While circRNAs and miRNAs have recently been identified as promising biomarkers for disease diagnosis, their specific expression patterns, and clinical implications in SLE are not yet fully understood. AIM OF THE WORK: The aim of the present study was to determine the role of a panel of noncoding-RNAs specifically circRNAs (circ-TubD1, circ-CDC27, and circ-Med14), along with miRNA (rno-miR-146a-5p) and mRNA (TRAF6), as novel minimally invasive diagnostic biomarkers for experimentally induced SLE. Additionally, the study involved an insilico bioinformatics analysis to explore potential pathways involved in the pathogenesis of SLE, aiming to enhance our understanding of the disease, enable early diagnosis, and facilitate improved treatment strategies. MATERIALS AND METHODS: SLE was induced in rats using single IP injection of incomplete Freund's adjuvant (IFA). The Induction was confirmed by assessing the ANA and anti-ds DNA levels using ELSA technique. qPCR analysis was conducted to assess the expression of selected RNAs in sera collected from a group of 10 rats with induced SLE and a control group of 10 rats. In addition, bioinformatics and functional analysis were used to construct a circRNA-miRNA-mRNA network and to determine the potential function of these differentially expressed circRNAs. RESULTS: SLE rats demonstrated significantly higher expression levels of circ-CDC27, circ-Med14, and rno-miR-146a-5p as well as TRAF6, with lower expression level of circ-TubD1 in sera of SLE rats relative to controls. ROC curve analysis indicated that all the selected non-coding RNAs could serve as potential early diagnostic markers for SLE. In addition, the expression level of circ-TubD1 was negatively correlated with rno-miR-146a-5p, however, rno-miR-146a-5p was positively correlated with TRAF6. Bioinformatic analysis revealed the incorporation of the circRNAs targeted genes in various immune system and neurodegeneration pathways. CONCLUSIONS: Therefore, circRNAs; circ-TubD1, circ-CDC27, and circ-Med14, in addition to the miRNA (rno-miR-146a-5p) and mRNA (TRAF6) may be involved in the development of SLE and may have promising roles for future diagnosis and targeted therapy.

Depression Is Associated with a Higher Risk of Mortality among Breast Cancer Survivors: Results from the National Health and Nutrition Examination Survey-National Death Index Linked Study.

Breast cancer (BC) and depression are globally prevalent problems. Numerous reviews have indicated the high prevalence of depression among BC survivors. However, the long-term impact of depression on survival among BC survivors has not been well explored. For this investigation, we aimed to explore the relationship between BC, depression, and mortality from a national random sample of adult American women. Data from the U.S. National Health and Nutrition Examination Survey (years 2005-2010) were linked with mortality data from the National Death Index up to December 31st, 2019. A total of 4719 adult women (ages 45 years and older) were included in the study sample with 5.1% having breast cancer and more than a tenth (12.7%) having depression. The adjusted hazard ratio (HR) for all-cause mortality risk among those with BC was 1.50 (95% CI = 1.05-2.13) compared to those without BC. In the adjusted analysis, the risk of all-cause mortality was highest among women with both depression and BC (HR = 3.04; 95% CI = 1.15-8.05) compared to those without BC or depression. The relationship between BC and mortality was moderated by cardiovascular diseases, anemia, smoking, age, PIR, and marital status. Our analysis provides vital information on factors that could be helpful for interventions to reduce mortality risk among those with BC and depression. In addition, given the higher risk of mortality with co-occurring BC and depression, collaborative healthcare practices should help with widespread screening for and treatment of depression among BC survivors.

Posttraumatic stress disorder and insomnia in US military veterans: Prevalence, correlates, and psychiatric and functional burden.

Military veterans have high rates of psychiatric conditions such as posttraumatic stress disorder, which can complicate the clinical management of insomnia. Population-based data are lacking on the prevalence, characteristics and mental health burden of veterans with co-occurring posttraumatic stress disorder and insomnia. The current cross-sectional study analysed data from a nationally representative sample of 4069 US veterans examining the prevalence and comorbidity between posttraumatic stress disorder and insomnia, and their associations with psychiatric and medical comorbidities, suicidality, and psychosocial functioning. Results revealed that 4.0% of US veterans screened positive for posttraumatic stress disorder + insomnia, 7.4% for insomnia only, and 3.2% for posttraumatic stress disorder only. Compared with controls, higher odds of major depressive disorder and generalized anxiety disorder were observed in the posttraumatic stress disorder + insomnia and posttraumatic stress disorder only groups. Moreover, compared with the control group, posttraumatic stress disorder + insomnia and posttraumatic stress disorder only groups had higher odds of current suicidal ideation, while the posttraumatic stress disorder + insomnia group had also higher odds of attempting suicide. Relative to the posttraumatic stress disorder only group, the posttraumatic stress disorder + insomnia group scored substantially lower on measures of cognitive, emotional and social functioning (d = 1.05, 1.04 and 0.87, respectively). This study provides contemporary data regarding current prevalence, correlates, and psychiatric and functional burden of posttraumatic stress disorder + insomnia among US veterans. The results underscore the importance of assessing, monitoring and treating posttraumatic stress disorder and insomnia as part of the efforts to mitigate suicide risk and promote multi-domain functioning in this population.

Is the Risk of Alzheimer's Disease and Related Dementias Among U.S. Veterans Influenced by the Intersectionality of Housing Status, HIV/AIDS, Hepatitis C, and Psychiatric Disorders?

BACKGROUND: Homelessness and housing instability disproportionately affect U.S. veterans with psychiatric disorders, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), hepatitis C, and Alzheimer's disease and related disorders (ADRD). We examined housing status and/or HIV/AIDS in relation to ADRD risk and evaluated hepatitis C, substance use, and mental health disorders as mediators and/or moderators of hypothesized relationships, among U.S. veterans ≥50 years of age seeking Department of Veterans Affairs (VA) healthcare services. METHODS: A retrospective cohort study was conducted using linked VA Homeless Operations Management and Evaluation System and Corporate Data Warehouse databases (2017-2023) on 3 275 098 eligible veterans yielding 133 388 ADRD cases over 5 years of follow-up. Multivariable regression and causal mediation analyses were performed, controlling for demographic and clinical characteristics. RESULTS: Taking stably housed veterans without HIV/AIDS as referent, ADRD risk was higher among veterans with homelessness/housing instability alone (adjusted hazard ratio [aHR] = 1.67, 95% confidence interval [CI]: 1.63,1.72), lower among veterans with HIV/AIDS alone (aHR = 0.65, 95% CI: 0.58,0.73), but similar to veterans with homelessness/housing instability and HIV/AIDS (aHR = 1.01, 95% CI: 0.79,1.29). In adjusted models, hepatitis C and psychiatric disorders were positively related to homelessness/housing instability and ADRD risk, but negatively related to HIV/AIDS. Statistically significant mediation and/or moderation of hepatitis C and psychiatric disorders were observed, although <10% of total effects were explained by these characteristics, controlling for confounders. CONCLUSIONS: Among older veterans, ADRD diagnoses over 5 years were less among those with HIV/AIDS, but more among those with homelessness/housing instability, and these relationships were partly explained by hepatitis C and psychiatric disorders.

New sulfonamide-based glycosides incorporated 1,2,3-triazole as cytotoxic agents through VEGFR-2 and carbonic anhydrase inhibitory activity.

New sulfonamide-triazole-glycoside hybrids derivatives were designed, synthesised, and investigated for anticancer efficacy. The target glycosides' cytotoxic activity was studied with a panel of human cancer cell lines. Sulfonamide-based derivatives, 4, 7 and 9 exhibited promising activity against HepG-2 and MCF-7 (IC50 = 8.39-16.90 µM against HepG-2 and 19.57-21.15 µM against MCF-7) comparing with doxorubicin (IC50 = 13.76 ± 0.45, 17.44 ± 0.46 µM against HepG-2 and MCF-7, rescpectively). To detect the probable action mechanism, the inhibitory activity of these targets was studied against VEGFR-2, carbonic anhydrase isoforms hCA IX and hCA XII. Compoumds 7 and 9 gave favorable potency (IC50 = 1.33, 0.38 µM against VEGFR-2, 66, 40 nM against hCA IX and 7.6, 3.2 nM against hCA XII, respectively), comparing with sorafenib and SLC-0111 (IC50 = 0.43 µM, 53 and 4.8 nM, respectively). Moreover, the docking simulation was assessed to supply better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes that was used for further modification in the anticancer field.

Association between Flavonoid Intake and Cognitive Executive Function among African American and White Adults in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) Study.

Healthy dietary patterns rich in flavonoids may benefit cognitive performance over time. Among socioeconomically disadvantaged groups, the association between flavonoid intake and measures of cognition is unclear. This study sought to identify associations between flavonoid intake and cognitive performance among Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study participants (n = 1947) across three study visits. Flavonoid intakes were assessed via two 24-h dietary recalls. Cognitive performance was assessed via the Trail Making Test (TMT)-A and TMT-B, which provide measures of attention and executive function, respectively. Mixed effects linear regression was used to model TMT scores over three study visits against visit 1 (v1) flavonoid intake, time (years from v1), and the interaction between v1 flavonoid intake and time, capturing both the cross-sectional association between flavonoid intake and time at v1 as well as the longitudinal association between v1 flavonoid intake and the change in TMT scores over time. Prior to adjustment, inverse cross-sectional associations at v1 were observed between (1) anthocyanidin intake and TMT-A scores for the overall sample and (2) total flavonoid, anthocyanidin, flavan-3-ol, flavone, and flavonol intake and TMT-B scores for the overall sample and among White adults. Only the association between anthocyanidin intake and TMT-B at v1 among White adults persisted after adjustment (for demographic characteristics such as age). One possible explanation for the few significant associations is universally low flavonoid intakes resulting from the consumption of an unhealthy dietary pattern.

Loneliness, Dementia Status, and Their Association with All-Cause Mortality Among Older US Adults.

Background: Loneliness, dementia, and mortality are interconnected. Objective: We aimed at understanding mediating pathways and interactions between loneliness and dementia in relation to mortality risk. Methods: The study tested bi-directional relationships between dementia, loneliness, and mortality, by examining both interactions and mediating effects in a large sample of older US adults participating in the nationally representative Health and Retirement Study. Out of≤6,468 older participants selected in 2010, with mean baseline age of 78.3 years and a follow-up time up to the end of 2020, 3,298 died at a rate of 64 per 1,000 person-years (P-Y). Cox proportional hazards and four-way decomposition models were used. Results: Algorithmically defined dementia status (yes versus no) was consistently linked with a more than two-fold increase in mortality risk. Dementia status and Ln(odds of dementia) were strongly related with mortality risk across tertiles of loneliness score. Loneliness z-score was also linked to an elevated risk of all-cause mortality regardless of age, sex, or race or ethnicity, and its total effect (TE) on mortality was partially mediated by Ln(odds of dementia), z-scored, (≤40% of the TE was a pure indirect effect). Conversely, a small proportion (<5%) of the TE of Ln(odds of dementia), z-scored, on mortality risk was explained by the loneliness z-score. Conclusions: In sum, dementia was positively associated with all-cause mortality risk, in similar fashion across loneliness score tertiles, while loneliness was associated with mortality risk. TE of loneliness on mortality risk was partially mediated by dementia odds in reduced models.

Plasma proteomic biomarkers and the association between poor cardiovascular health and incident dementia: The UK Biobank study.

BACKGROUND: The study examined how plasma proteome indicators may explain the link between poor cardiovascular health (CVH) and dementia risk. METHODS: The present study involved 28,974 UK Biobank participants aged 50-74y at baseline (2006-2010) who were followed-up for ≤ 15 y for incidence of dementia. CVH was calculated using Life's Essential 8 (LE8) total scores. The scores were standardized and reverse coded to reflect poor CVH (LE8z_rev). OLINK proteomics was available on this sample (k = 1,463 plasma proteins). The study primarily tested the mediating effects of the plasma proteome in LE8z_rev-dementia effect. The total effect was decomposed into "mediation only" or pure indirect effect (PIE), "interaction only" or interaction referent (INTREF), "neither mediation nor interaction" or controlled direct effect (CDE), and "both mediation and interaction" or mediated interaction (INTMED). RESULTS: The study found poorer CVH assessed by LE8z_rev increased the risk of all-cause dementia by 11 % [per 1 SD, hazard ratio, (HR) = 1.11, 95 % CI: 1.03-1.20, p = 0.005). The study identified 11 plasma proteins with strong mediating effects, with GDF15 having the strongest association with dementia risk (per 1 SD, HR = 1.24, 95 % CI: 1.16, 1.33, P < 0.001 when LE8z_rev is set at its mean value) and the largest proportion mediated combining PIE and INTMED (62.6 %; 48 % of TE is PIE), followed by adrenomedullin or ADM. A first principal component with 10 top mediators (TNFRSF1A, GDF15, FSTL3, COL6A3, PLAUR, ADM, GFRAL, ACVRL1, TNFRSF6B, TGFA) mediated 53.6 % of the LE8z_rev-dementia effect. Using all the significant PIE (k = 526) proteins, we used OLINK Insight pathway analysis to identify key pathways, which revealed the involvement of the immune system, signal transduction, metabolism, disease, protein metabolism, hemostasis, membrane trafficking, extracellular matrix organization, developmental biology, and gene expression among others. STRING analysis revealed that five top consistent proteomic mediators were represented in two larger clusters reflecting numerous interconnected biological gene ontology pathways, most notably cytokine-mediated signaling pathway for GDF15 cluster (GO:0019221) and regulation of peptidyl-tyrosine phosphorylation for the ADM cluster (GO:0050730). CONCLUSION: Dementia is linked to poor CVH mediated by GDF15 and ADM among several key proteomic markers which collectively explained âˆ¼ 54 % of the total effect.

Relationships of depression and antidepressant use with epigenetic age acceleration and all-cause mortality among postmenopausal women.

We investigated relations of depressive symptoms, antidepressant use, and epigenetic age acceleration with all-cause mortality risk among postmenopausal women. Data were analyzed from ≤1,900 participants in the Women's Health Initiative study testing four-way decomposition models. After a median 20.4y follow-up, 1,161 deaths occurred. Approximately 11% had elevated depressive symptoms (EDS+), 7% were taking antidepressant medication at baseline (ANTIDEP+), while 16.5% fell into either category (EDS_ANTIDEP+). Baseline ANTIDEP+, longitudinal transition into ANTIDEP+ and accelerated epigenetic aging directly predicted increased mortality risk. GrimAge DNA methylation age acceleration (AgeAccelGrim) partially mediated total effects of baseline ANTIDEP+ and EDS_ANTIDEP+ on all-cause mortality risk in socio-demographic factors-adjusted models (Pure Indirect Effect >0, P < 0.05; Total Effect >0, P < 0.05). Thus, higher AgeAccelGrim partially explained the relationship between antidepressant use and increased all-cause mortality risk, though only prior to controlling for lifestyle and health-related factors. Antidepressant use and epigenetic age acceleration independently predicted increased all-cause mortality risk. Further studies are needed in varying populations.

Cell based and In vivo systematic evaluation of some Egyptian plant extracts targeting breast cancer.

The prevalence of breast cancer as a significant public health concern necessitates continued exploration of natural resources for novel anti-cancer agents is crucial. MATERIAL AND METHODS: Anticancer activity of plant extracts on monolayer breast cancer cell line (MCF7) with lower levels of toxicity towards normal (RPE1) underwent further assessment using a three-dimensional model (3D). The extract's effects were investigated through multiple assays including apoptosis induction using quantifying cleaved cytokeratin-18 (CK18) and DNA fragmentation. Additionally, the expression of Bcl-2 and Bax was quantitative using real-time PCR. The median lethal dose (LD50) was determined by the acute oral toxicity, while biomarkers associated with tumorigenesis, metastasis, and cell death were quantified by ELISA. RESULTS: Limoniastrum monopetalum and Bauhinia variegata exhibited the most potent antitumor efficacy among the investigated extracts. They demonstrated potent cytotoxicity against MCF7 with no significant effect on hTERT RPE-1, with an IC50 of 100 µM. The extract demonstrated effectiveness in killing cancer cells within 3D tumor-like structures, induced apoptosis through caspase-3 activation and cleavage of cytokeratin-18, up-regulated the tumor suppressor p53, down-regulated the anti-apoptotic Bcl-2 gene, and caused DNA fragmentation. Acute oral toxicity studies in mice indicated low toxicity, and in a syngeneic mouse tumor model, the extract significantly inhibited tumor growth, suggesting its potential for further development. CONCLUSION: Limoniastrum monopetalum and Bauhinia variegata exhibited the most potent antitumor efficacy among the investigated extracts.

Effect of hospitalization on equine local intestinal immunoglobulin A (IgA) concentration measured in feces.

During hospitalization horses may develop gastrointestinal conditions triggered by a stress-associated weak local immune system. The prospective, clinical trial was conducted to find out whether fecal immunoglobulin A (IgA) concentrations could be determined in hospitalized horses and how they changed during hospitalization and in response to various stressors. Samples were obtained from 110 horses and a control group (n = 14). At arrival in the hospital, horses were categorized into pain grades (1-5), and elective versus strenuous surgery (> 2 hours, traumatic and emergency procedures). Feces were collected on day 1, day 2, day 3, and day 7 in all horses. Blood samples were obtained at the same intervals, but additionally after general anaesthesia in horses undergoing surgery (day 2). IgA concentration in feces was determined by ELISA and measured in optical density at 450nm. The control group showed constant IgA concentrations on all days (mean value 0.30 OD450 ±SD 0.11, 1.26 mg/g; n = 11). After general anaesthesia fecal IgA concentrations decreased considerably independent of duration and type of surgery (P < 0.001 for elective and P = 0.043 for traumatic surgeries). High plasma cortisol concentrations were weakly correlated with low fecal IgA on the day after surgery (P = 0.012, day 3, correlation coefficient r = 0.113). Equine fecal IgA concentrations showed a decline associated with transport, surgery, and hospitalization in general, indicating that stress has an impact on the local intestinal immune function and may predispose horses for developing gastrointestinal diseases such as enterocolitis.

Serum neurofilament light chain as a prognostic marker of all-cause mortality in a national sample of US adults.

Neurofilament light chain (NfL) is a neuron-specific structural protein released into the extracellular space, including body fluids, upon neuroaxonal damage. Despite evidence of a link in neurological disorders, few studies have examined the association of serum NfL with mortality in population-based studies. Data from the National Health and Nutrition Survey were utilized including 2,071 Non-Hispanic White, Non-Hispanic Black and Hispanic adult participants and adult participants of other ethnic groups (20-85 years) with serum NfL measurements who were followed for ≤ 6 years till 2019. We tested the association of serum NfL with mortality in the overall population and stratified by sex with the addition of potential interactive and mediating effects of cardio-metabolic risk factors and nutritional biomarkers. Elevated serum NfL levels (above median group) were associated with mortality risk compared to the below median NfL group in the overall sample (P = 0.010), with trends observed within each sex group (P < 0.10). When examining Loge NfL as a continuum, one standard deviation of Loge NfL was associated with an increased mortality risk (HR = 1.88, 95% CI 1.60-2.20, P < 0.001) in the reduced model adjusted for age, sex, race, and poverty income ratio; a finding only slightly attenuated with the adjustment of lifestyle and health-related factors. Four-way decomposition indicated that there was, among others, mediated interaction between NfL and HbA1c and a pure inconsistent mediation with 25(OH)D3 in predicting all-cause mortality, in models adjusted for all other covariates. Furthermore, urinary albumin-to-creatinine ratio interacted synergistically with NfL in relation to mortality risk both on the additive and multiplicative scales. These data indicate that elevated serum NfL levels were associated with all-cause mortality in a nationally representative sample of US adults.

Mediating and moderating effects of plasma proteomic biomarkers on the association between poor oral health problems and incident dementia: The UK Biobank study.

The plasma proteome can mediate poor oral health problems (POHP)'s link to incident dementia. We screened 37,269 UK Biobank participants 50-74 years old (2006-2010) for prevalent POHP, further tested against 1463 plasma proteins and incident dementia over up to 15 years of follow-up. Total effect (TE) of POHP-dementia through plasma proteomic markers was decomposed into pure indirect effect (PIE), interaction referent (INTREF), controlled direct effect (CDE), or mediated interaction (INTMED). POHP increased the risk of all-cause dementia by 17% (P < 0.05). Growth differentiation factor 15 (GDF15) exhibited the strongest mediating effects (PIE > 0, P < 0.001), explaining 28% the total effect of POHP on dementia, as a pure indirect effect. A first principal component encompassing top 4 mediators (GDF15, IL19, MMP12, and ACVRL1), explained 11% of the POHP-dementia effect as a pure indirect effect. Pathway analysis including all mediators (k = 173 plasma proteins) revealed the involvement of the immune system, signal transduction, metabolism, disease, and gene expression, while STRING analysis indicated that top mediators within the first principal component were also represented in the two largest proteomic clusters. The dominant biological GO pathway for the GDF15 cluster was GO:0007169 labeled as "transmembrane receptor protein tyrosine kinase signaling pathway." Dementia is linked to POHP mediated by GDF15 among several proteomic markers.