A prospective cohort study of renal function and bone turnover in adults with hepatitis B virus (HBV)-HIV co-infection with high prevalence of tenofovir-based antiretroviral therapy use.

OBJECTIVE: Tenofovir disoproxil fumarate (TDF) is a common component of antiretroviral therapy in hepatitis B virus (HBV)-HIV co-infected adults but few studies have evaluated worsening renal function and bone turnover, known effects of TDF. METHODS: Adults from eight North American sites were enrolled in this cohort study. Research assessments were conducted at entry and every 24 weeks for ≤192 weeks. Bone markers were tested at baseline, week 96 and week 192 from stored serum. We evaluated changes in markers of renal function and bone turnover over time and potential contributing factors. RESULTS: A total of 115 patients were prospectively followed; median age 49 years, 91% male and 52% non-Hispanic Black. Duration of HIV was 20.5 years. TDF use ranged from 80% to 92% throughout follow-up. Estimated glomerular filtration rate (eGFR) (ml/min/1.73m2 ) decreased from 87.1 to 79.9 over 192 weeks (p < 0.001); however, the prevalence of eGFR <60 ml/min/1.73m2 did not appear to differ over time (always <16%; p = 0.43). From baseline to week 192, procollagen type I N-terminal propeptide (P1NP) (146.7 to 130.5 ng/ml; p = 0.001), osteocalcin (14.4 to 10.2 ng/ml; p < 0.001) and C-terminal telopeptides of type I collagen (CTX-1) (373 to 273 pg/ml; p < 0.001) decreased. Younger age, male sex and overweight/obesity versus normal weight predicted a decrease in eGRF. Black race, healthy weight versus underweight, advanced fibrosis, undetectable HBV DNA, and lower parathyroid hormone level predicted worsening bone turnover. CONCLUSION: In this HBV-HIV cohort with high prevalence of TDF use, several biomarkers of renal function and bone turnover indicated worsening status over approximately 4 years, highlighting the importance of clinical awareness in co-infected adults.

Challenges and opportunities faced by nurse scientists in integrating data and technology in research to promote health equity.

Advances in technologies including omics, apps, imaging, sensors, and big data are increasingly being integrated into research by nurse scientists, but the impact on improving health equity is still unclear. In this article, nursing research faculty from one institution discuss challenges and opportunities experienced when integrating various technologies into their research aimed at promoting health equity. Using exemplars from faculty experiences, a three-pronged approach to keeping patients and communities and the goal of health equity central in research while incorporating advancing technologies is described. This approach includes establishing long-term engagement with populations underrepresented in research, adopting strategies to increase diversity in study participant recruitment, and training and collaboration among a diverse workforce of educators, clinicians, and researchers. Training nurse scientists in integrating data and technology for advancing the science on health equity will shift the culture of how we understand, collaborate, and grow with the communities in which we train and practice as nurse scientists.

Breast tumor DNA methylation patterns associated with smoking in the Carolina Breast Cancer Study.

PURPOSE: Tobacco smoking is a risk factor in several cancers, yet its roles as a putative etiologic exposure or poor prognostic factor in breast cancer are less clear. Altered DNA methylation contributes to breast cancer development and may provide a mechanistic link between smoking and gene expression changes leading to cancer development or progression. METHODS: Using a cancer-focused array, we examined methylation at 933 CpGs in 517 invasive breast tumors in the Carolina Breast Cancer Study to determine whether methylation patterns differ by exposure to tobacco smoke. Multivariable generalized linear regression models were used to compare tumor methylation profiles between smokers and never smokers, overall, or stratified on hormone receptor (HR) status. RESULTS: Modest differences in CpG methylation were detected at p < 0.05 in breast tumors from current or ever smokers compared with never smokers. In stratified analyses, HR- tumors from smokers exhibited primarily hypomethylation compared with tumors from never smokers; hypomethylation was similarly detected within the more homogeneous basal-like subtype. Most current smoking-associated CpG loci exhibited methylation levels in former smokers that were intermediate between those in current and never smokers and exhibited progressive changes in methylation with increasing duration of smoking. Among former smokers, restoration of methylation toward baseline (never smoking) levels was observed with increasing time since quitting. Moreover, smoking-related hypermethylation was stronger in HR+ breast tumors from blacks than in whites. CONCLUSIONS: Our results suggest that breast tumor methylation patterns differ with tobacco smoke exposure; however, additional studies are needed to confirm these findings.

Genetic polymorphisms regulating dopamine signaling in the frontal cortex interact to affect target detection under high working memory load.

Frontal-dependent task performance is typically modulated by dopamine (DA) according to an inverted-U pattern, whereby intermediate levels of DA signaling optimizes performance. Numerous studies implicate trait differences in DA signaling based on differences in the catechol-O-methyltransferase (COMT) gene in executive function task performance. However, little work has investigated genetic variations in DA signaling downstream from COMT. One candidate is the DA- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), which mediates signaling through the D1-type DA receptor, the dominant DA receptor in the frontal cortex. Using an n-back task, we used signal detection theory to measure performance in a healthy adult population (n = 97) genotyped for single nucleotide polymorphisms in the COMT (rs4680) and DARPP-32 (rs907094) genes. Correct target detection (hits) and false alarms were used to calculate d' measures for each working memory load (0-, 2-, and 3-back). At the highest load (3-back) only, we observed a significant COMT × DARPP-32 interaction, such that the DARPP-32 T/T genotype enhanced target detection in COMT(ValVal) individuals, but impaired target detection in COMT(Met) carriers. These findings suggest that enhanced dopaminergic signaling via the DARPP-32 T allele aids target detection in individuals with presumed low frontal DA (COMT(ValVal)) but impairs target detection in those with putatively higher frontal DA levels (COMT(Met) carriers). Moreover, these data support an inverted-U model with intermediate levels of DA signaling optimizing performance on tasks requiring maintenance of mental representations in working memory.

DNA methylation profiling in the Carolina Breast Cancer Study defines cancer subclasses differing in clinicopathologic characteristics and survival.

INTRODUCTION: Breast cancer is a heterogeneous disease, with several intrinsic subtypes differing by hormone receptor (HR) status, molecular profiles, and prognosis. However, the role of DNA methylation in breast cancer development and progression and its relationship with the intrinsic tumor subtypes are not fully understood. METHODS: A microarray targeting promoters of cancer-related genes was used to evaluate DNA methylation at 935 CpG sites in 517 breast tumors from the Carolina Breast Cancer Study, a population-based study of invasive breast cancer. RESULTS: Consensus clustering using methylation (ß) values for the 167 most variant CpG loci defined four clusters differing most distinctly in HR status, intrinsic subtype (luminal versus basal-like), and p53 mutation status. Supervised analyses for HR status, subtype, and p53 status identified 266 differentially methylated CpG loci with considerable overlap. Genes relatively hypermethylated in HR+, luminal A, or p53 wild-type breast cancers included FABP3, FGF2, FZD9, GAS7, HDAC9, HOXA11, MME, PAX6, POMC, PTGS2, RASSF1, RBP1, and SCGB3A1, whereas those more highly methylated in HR-, basal-like, or p53 mutant tumors included BCR, C4B, DAB2IP, MEST, RARA, SEPT5, TFF1, THY1, and SERPINA5. Clustering also defined a hypermethylated luminal-enriched tumor cluster 3 that gene ontology analysis revealed to be enriched for homeobox and other developmental genes (ASCL2, DLK1, EYA4, GAS7, HOXA5, HOXA9, HOXB13, IHH, IPF1, ISL1, PAX6, TBX1, SOX1, and SOX17). Although basal-enriched cluster 2 showed worse short-term survival, the luminal-enriched cluster 3 showed worse long-term survival but was not independently prognostic in multivariate Cox proportional hazard analysis, likely due to the mostly early stage cases in this dataset. CONCLUSIONS: This study demonstrates that epigenetic patterns are strongly associated with HR status, subtype, and p53 mutation status and may show heterogeneity within tumor subclass. Among HR+ breast tumors, a subset exhibiting a gene signature characterized by hypermethylation of developmental genes and poorer clinicopathologic features may have prognostic value and requires further study. Genes differentially methylated between clinically important tumor subsets have roles in differentiation, development, and tumor growth and may be critical to establishing and maintaining tumor phenotypes and clinical outcomes.

MicroRNA Profiles in Hematopoietic Stem Cell Transplant Recipients.

Background: Hematopoietic Stem Cell Transplant (HCT) is a potentially curative treatment for hematologic malignancies, including multiple myeloma. Biomarker investigation can guide identification of HCT recipients at-risk for poor outcomes. MicroRNAs (miRNAs) are a class of non-coding RNAs involved in the modulation and regulation of pathological processes and are emerging as prognostic and predictive biomarkers for multiple health conditions. This pilot study aimed to examine miRNA profiles associated with HCT-related risk factors and outcomes in patients undergoing autologous HCT. Methods: Patients eligible for autologous HCT were recruited and blood samples and HCT-related variables were collected. Differential expression analysis of miRNA was conducted on 24 patient samples to compare changes in miRNA profile in HCT eligible patients before and after transplant. Results: Unsupervised clustering of differentially expressed (p < .05) miRNAs pre- and post- HCT identified clusters of up- and down-regulated miRNAs. Four miRNAs (miR-125a-5p, miR-99b-5p, miR-382-5p, miR-145-5p) involved in hematopoiesis (differentiation of progenitor cells, granulocyte function, thrombopoiesis, and tumor suppression) were significantly downregulated post-HCT. Correlation analyses identified select miRNAs associated with risk factors (such as frailty, fatigue, cognitive decline) and quality of life pre- and post-HCT. Select miRNAs were correlated with platelet engraftment. Conclusion: Future studies should examine miRNA signatures in larger cohorts in association with HCT outcomes; and expand investigations in patients receiving allogeneic transplants. This will lead to identification of biomarkers for risk stratification of HCT recipients.

Differential methylation relative to breast cancer subtype and matched normal tissue reveals distinct patterns.

Due to the heterogeneous nature of breast cancer and the widespread use of single-gene studies, there is limited knowledge of multi-gene, locus-specific DNA methylation patterns in relation to molecular subtype and clinical features. We, therefore, quantified DNA methylation of 70 candidate gene loci in 140 breast tumors and matched normal tissues and determined associations with gene expression and tumor subtype. Using Sequenom's EpiTYPER platform, approximately 1,200 CpGs were interrogated and revealed six DNA methylation patterns in breast tumors relative to matched normal tissue. Differential methylation of several gene loci was observed within all molecular subtypes, while other patterns were subtype-dependent. Methylation of numerous gene loci was inversely correlated with gene expression, and in some cases, this correlation was only observed within specific breast tumor subtypes. Our findings were validated on a larger set of tumors and matched adjacent normal tissue from The Cancer Genome Atlas dataset, which utilized methylation data derived from both Illumina Infinium 27 and 450 k arrays. These findings highlight the need to control for subtype when interpreting DNA methylation results, and the importance of interrogating multiple CpGs across varied gene regions.

Vimentin DNA methylation predicts survival in breast cancer.

The Vimentin gene plays a pivotal role in epithelial-to-mesenchymal transition and is known to be overexpressed in the prognostically poor basal-like breast cancer subtype. Recent studies have reported Vimentin DNA methylation in association with poor clinical outcomes in other solid tumors, but not in breast cancer. We therefore quantified Vimentin DNA methylation using MALDI-TOF mass spectrometry in breast tumors and matched normal pairs in association with gene expression and survival in a hospital-based study of breast cancer patients. Gene expression data via qRT-PCR in cell lines and oligomicroarray data from breast tissues were correlated with percent methylation in the Vimentin promoter. A threshold of 20 percent average methylation compared with matched normal pairs was set for bivariate and multivariate tests of association between methylation and tumor subtype, tumor histopathology, and survival. Vimentin was differentially methylated in luminal breast cancer cell lines, and in luminal A, luminal B, and HER2-enriched breast tumor subtypes, but was rare in basal-like cell lines and tumors. Increased methylation was strongly correlated with decreased mRNA expression in cell lines, and had a moderate inverse correlation in breast tumors. Vimentin methylation predicted poor overall survival independent of race, subtype, stage, nodal status, or metastatic disease and holds promise as a new prognostic biomarker for breast cancer patients.

DNA Methylation Research in Autologous Hematopoietic Stem Cell Transplant Population.

Despite increased sophistication in DNA methylation (DNAm) measurement and methods, conducting studies in specific populations such as the hematopoietic stem cell transplant (HCT) population, presents unique challenges and study design considerations. In this article, we explain the motivation for investigating DNAm in the HCT population, highlighting important study design features and key findings in a longitudinal prospective pilot study of DNAm in 32 patients undergoing autologous HCT in Central Virginia, USA. We also discuss limitations and challenges to generating robust results. We observed that HCT does not prevent high-quality DNA from being extracted from whole blood for DNAm research and that longitudinal prospective studies that span pre- and 2-months post-HCT are feasible. Critically, we did not observe significant impacts of cancer diagnosis, time since transplant, age, or chromosomal sex on overall DNAm data dimensionality. These observations demonstrate that while extreme care is required to ensure generalizable, accurate, and interpretable results, researchers should not avoid HCT-DNAm research simply for fear that the transplant procedure or presence of a cancer diagnosis will prevent meaningful conclusions from being drawn. DNAm is an attractive biomarker that is understudied in patients undergoing HCT and needs to expand to improve precise prediction of HCT outcomes.

DNA Methylation Changes in Autologous Hematopoietic Stem Cell Transplant Patients.

BACKGROUND: Blood cancers may be potentially cured with hematopoietic stem cell transplantation (HCT); however, standard pre-assessments for transplant eligibility do not capture all contributing factors for transplant outcomes. Epigenetic biomarkers predict outcomes in various diseases. This pilot study aims to explore epigenetic changes (epigenetic age and differentially methylated genes) in patients before and after autologous HCT, that can serve as potential biomarkers to better predict HCT outcomes. METHODS: This study used a prospective longitudinal study design to compare genome wide DNA methylation changes in 36 autologous HCT eligible patients recruited from the Cellular Immunotherapies and Transplant clinic at a designated National Cancer Center. RESULTS: Genome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 850K BeadChip, showed a significant difference in DNA methylation patterns post-HCT compared to pre-HCT. Compared to baseline levels of DNA methylation pre-HCT, 3358 CpG sites were hypo-methylated and 3687 were hyper-methylated. Identified differentially methylated positions overlapped with genes involved in hematopoiesis, blood cancers, inflammation and immune responses. Enrichment analyses showed significant alterations in biological processes such as immune response and cell structure organization, however no significant pathways were noted. Though participants had an advanced epigenetic age compared to chronologic age before and after HCT, both epigenetic age and accelerated age decreased post-HCT. CONCLUSION: Epigenetic changes, both in epigenetic age and differentially methylated genes were observed in autologous HCT recipients, and should be explored as biomarkers to predict transplant outcomes after autologous HCT in larger, longitudinal studies.

Factors Affecting Quality of Life in Patients Receiving Autologous Hematopoietic Stem Cell Transplantation.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) is a potentially curative treatment for hematologic malignancies, with 22 000 HSCTs performed annually in the United States. However, decreased quality of life (QoL) is a frequent and concerning state reported by HSCT recipients. OBJECTIVES: We sought to determine if measurements of frailty and cognitive impairment were associated with fatigue and QoL in adult HSCT recipients after autologous HSCT. METHODS: Using a longitudinal study design, 32 participants 18 years or older receiving autologous HSCT were recruited from a bone marrow transplant clinic. Each participant completed 2 visits: pre-HSCT and post-HSCT. At each visit, participants completed assessment tools to measure frailty, cognitive impairment, fatigue, and QoL (assesses physical, social/family, emotional, functional, and transplant-related well-being). RESULTS: Participants with increased fatigue scores reported decreased QoL pre- and post-HSCT. Participants with increased frailty showed decreased functional well-being before HSCT and showed correlations with decreased physical, social, and transplant-related well-being post-HSCT. As expected, fatigued participants also showed increased frailty post-HSCT. Participants showed significant changes in physical well-being and fatigue between pre-HSCT and post-HSCT visits. CONCLUSION: Data analyses from this pilot study show significant correlations between subsets of QoL with fatigue and frailty in autologous HSCT participants pre- and post-HSCT. IMPLICATIONS FOR PRACTICE: Understanding the impact of frailty on fatigue and QoL in HSCT recipients is critical to assist nurses in initiating educational and behavioral interventions to help mitigate the effects of HSCT.

Extracellular Vesicle MicroRNA in Malignant Pleural Effusion.

Lung and breast cancer are the two most common causes of malignant pleural effusion (MPE). MPE diagnosis plays a crucial role in determining staging and therapeutic interventions in these cancers. However, our understanding of the pathogenesis and progression of MPE at the molecular level is limited. Extracellular Vesicles (EVs) and their contents, including microRNAs (miRNAs), can be isolated from all bodily fluids, including pleural fluid. This study aims to compare EV-miRNA patterns of expression in MPE caused by breast (BA-MPE) and lung (LA-MPE) adenocarcinomas compared to the control group of heart-failure-induced effusions (HF-PE). We conducted an analysis of 24 pleural fluid samples (8 LA-MPE, 8 BA-MPE, and 8 HF-PE). Using NanoString technology, we profiled miRNAs within EVs isolated from 12 cases. Bioinformatic analysis demonstrated differential expression of miR-1246 in the MPE group vs. HF-PE group and miR-150-5p and miR-1246 in the BA-MPE vs. LA-MPE group, respectively. This difference was demonstrated and validated in an independent cohort using real-time PCR (RT-PCR). miRNA-1246 demonstrated 4-fold increased expression (OR: 3.87, 95% CI: 0.43, 35) in the MPE vs. HF-PE group, resulting in an area under the curve of 0.80 (95% CI: 0.60, 0.99). The highest accuracy for differentiating MPE vs. HF-PE was seen with a combination of miRNAs compared to each miRNA alone. Consistent with prior studies, this study demonstrates dysregulation of specific EV-based miRNAs in breast and lung cancer; pleural fluid provides direct access for the analysis of these EV-miRNAs as biomarkers and potential targets and may provide insight into the underlying pathogenesis of tumor progression. These findings should be explored in large prospective studies.

Frailty in Patients With Hematologic Malignancies and Those Undergoing Transplantation: A Scoping Review.

PROBLEM IDENTIFICATION: Although frailty is an important parameter in treatment planning and in predicting prognosis and overall survival among patients with hematologic malignancies and recipients of hematopoietic stem cell transplantation, frailty assessment tools are not standardized in clinical care settings. The purpose of this article is to provide an overview of the literature on frailty assessment tools in these patient populations. LITERATURE SEARCH: A systematic search of CINAHL®, Embase®, MEDLINE®, PubMed®, and Web of Science was performed using keywords and controlled vocabulary for the concepts "bone marrow transplants," "hematologic neoplasms," and "frailty." DATA EVALUATION: Extracted data included study type, diagnosis, transplantation status, frailty tools used, and outcome measures. SYNTHESIS: A systematic search resulted in 24 studies that met the inclusion criteria. There were significant differences in how various groups define and assess frailty. IMPLICATIONS FOR PRACTICE: Addressing the lack of standardized frailty assessments will assist healthcare providers to routinely integrate frailty measures in clinical assessments to identify those at risk for poor outcomes, improving personalized care.

Exploring Associations Between Metabolites and Symptoms of Fatigue, Depression and Pain in Women With Fibromyalgia.

Fibromyalgia (FM) is a chronic noncommunicable disorder characterized by a constellation of symptoms that include fatigue, depression and chronic pain. FM affects 2%-8% of the U.S. population, 2% of the global population, with 61%-90% of FM diagnoses attributed to women. Key causal factors leading to the development and severity of FM-related symptoms have not yet been identified. The purpose of this article is to report relationships among identified metabolites and levels of fatigue, depression, pain severity, and pain interference in a sample of 20 women with FM. In this secondary analysis, we conducted global metabolomic analysis and examined the data for relationships of metabolite levels with self-reported symptoms of fatigue, depression, pain severity, and pain interference. Results revealed six metabolites (6-deoxy-hexose; pantothenic acid; ergothioneine; l-carnitine; n-acetylserotonin; butyrobetaine) and their associated metabolic pathways such as carnitine synthesis, lipid oxidation, tryptophan metabolism, beta-alanine metabolism and pantothenic and Coenzyme-A biosynthesis that were either positively or inversely related to pain severity, pain interference, or both. The preliminary data presented suggest that metabolites representing energy, amino acid, or lipid classification may be associated with pain symptom severity and interference in women with FM. Future work will confirm these findings in a large, comparative cohort, targeting metabolites and metabolite pathways to better understand the relationships of metabolites and symptomology.

Obesity and 1-Year Mortality in Adults After Sepsis: A Systematic Review.

PURPOSE: In recent years, researchers have noted an "obesity paradox," where individuals with obesity survive sepsis at higher rates than their nonobese counterparts. This systematic review summarizes the literature on studies examining the association between obesity and 1-year mortality among patients admitted with sepsis, severe sepsis, or septic shock. MATERIALS AND METHODS: Using a comprehensive search strategy, a systematic review was conducted to identify studies examining the association of obesity and sepsis mortality. PubMed, Cumulative Index of Nursing and Allied Health Literature, and Elton B. Stephens Company host databases were searched for the terms sepsis, obesity, mortality, and adult. RESULTS: The initial search identified 189 studies, 9 of which met inclusion criteria. Of these, four provided evidence that obese or very obese patients with sepsis have lower mortality than nonobese patients. Methodologic differences in the remaining five studies, which reported conflicting results, limit generalizability. CONCLUSION: This systematic review on the association of obesity and sepsis mortality found three studies that demonstrated lower sepsis mortality among obese patients in the first 30 days and one showing that this protective effect extends up to 1 year. Given the increased number of patients surviving sepsis, it is important to consider long-term mortality and further describe the variables associated with increased survival.

The Obesity Paradox in Sepsis: A Theoretical Framework.

Sepsis is a life-threatening syndrome that occurs in response to a severe infection. In recent years, the understanding of the pathobiology of sepsis has been refined, with research describing an altered host response as the underlying cause. Survivors of sepsis often have long hospital stays and suffer from subsequent frailty and long-term health consequences. Predicting attributes of sepsis survivors remains challenging; however, an obesity paradox exists, wherein obese individuals survive sepsis at higher rates than their normal-weight counterparts. We present a model that describes the relationships between sepsis and obesity, focusing on inflammation as a shared pathway for dysregulation in obese and healthy-weight adults. Understanding the interaction of these complex variables is an important first step toward developing interventions and treatments to augment sepsis survival.

A mindful yoga intervention for children with severe asthma: A pilot study.

INTRODUCTION: Children with severe asthma may benefit from non-pharmacological approaches to symptom management, yet little is known regarding the impact of mind-body approaches such as mindful yoga in this population. This pilot study examined the tolerability, feasibility, acceptability and immediate effects of a mindful yoga intervention in children with severe asthma. METHOD: Fifteen children ages 7-11 with severe asthma participated in a single mindful yoga session, followed by semi-structured interviews with the child and caregiver. Vital signs and pulmonary function tests were collected pre- and post-intervention. RESULTS: All children reported positive experiences and caregivers were generally supportive of their participation. One child experienced self-limited bronchoconstriction with asthma symptoms. There was no significant change in lung function or vital signs after the mindful yoga session. DISCUSSION: Our results warrant additional larger studies to evaluate the safety and benefits of mindful yoga in children with severe asthma.

Metabolomic Differentials in Women With and Without Fibromyalgia.

A nontargeted plasma metabolomic analysis was conducted to compare differentially expressed metabolites in women with and without fibromyalgia (FM) using data and samples collected from two parent studies in women with FM (n = 20) and comparative data collected from newly recruited age-matched women (n = 20). Blood plasma samples were analyzed for metabolite content using liquid chromatography mass spectrometry. Consolidation of positive and negative ion mode metabolomics data with fold change (>2 or <0.5) and variable importance of projection scores ≥1 revealed statistically significant metabolites comparing samples from women with and without FM. Metabolite profiles in patients with FM differed from the comparison group in energy, lipid and amino acid metabolites reflecting heightened oxidative stress, inflammation, and tryptophan degradation in patients with FM. Study results may contribute to further identification of unique metabolomic profiles enhancing understanding of the pathophysiology of FM and for the development of effective therapeutic options.

Shared mechanisms for cognitive impairment and physical frailty: A model for complex systems.

INTRODUCTION: We describe findings from a large study that provide empirical support for the emerging construct of cognitive frailty and put forth a theoretical framework that may advance the future study of complex aging conditions. While cognitive impairment and physical frailty have long been studied as separate constructs, recent studies suggest they share common etiologies. We aimed to create a population predictive model to gain an understanding of the underlying biological mechanisms for the relationship between physical frailty and cognitive impairment. METHODS: Data were obtained from the longitudinal "Invecchaiare in Chianti" (Aging in Chianti, InCHIANTI Study) with a representative sample (n = 1453) of older adults from two small towns in Tuscany, Italy. Our previous work informed the candidate 132 single nucleotide polymorphisms (SNPs) and 155 protein biomarkers we tested in association with clinical outcomes using a tree boosting, machine learning (ML) technique for supervised learning analysis. RESULTS: We developed two highly accurate predictive models, with a Model I area under the curve (AUC) of 0.88 (95% confidence interval [CI] 0.83-0.90) and a Model II AUC of 0.86 (95% CI 0.80-0.90). These models indicate cognitive frailty is driven by dysregulation across multiple cellular processes including genetic alterations, nutrient and lipid metabolism, and elevated levels of circulating pro-inflammatory proteins. DISCUSSION: While our results establish a foundation for understanding the underlying biological mechanisms for the relationship between cognitive decline and physical frailty, further examination of the molecular pathways associated with our predictive biomarkers is warranted. Our framework is in alignment with other proposed biological underpinnings of Alzheimer's disease such as genetic alterations, immune system dysfunction, and neuroinflammation.

Vitamin C Intravenous Treatment In the Setting of Atrial Fibrillation Ablation: Results From the Randomized, Double-Blinded, Placebo-Controlled CITRIS-AF Pilot Study.

Background Catheter ablation is an effective treatment for atrial fibrillation (AF), but high levels of post-procedure inflammation predict adverse clinical events. Ascorbic acid (AA) has shown promise in reducing inflammation but is untested in this population. We sought to test the feasibility, safety, and preliminary effects on inflammatory biomarkers in the CITRIS-AF (Vitamin C Intravenous Treatment In the Setting of Atrial Fibrillation Ablation) pilot study. Methods and Results Patients scheduled to undergo AF ablation (N=20) were randomized 1:1 to double-blinded treatment with AA (200 mg/kg divided over 24 hours) or placebo. C-reactive protein and interleukin-6 levels were obtained before the first infusion and repeated at 24 hours and 30 days. Pain levels within 24 hours and early recurrence of AF within 90 days were recorded. Median and interquartile range were aged 63 (56-70) years, 13 (65%) men, and 18 (90%) white. Baseline data were similar between the 2 groups except ejection fraction. Baseline C-reactive protein levels were 2.56 (1.47-5.87) mg/L and similar between groups (P=0.48). Change in C-reactive protein from baseline to 24 hours was +10.79 (+6.56-23.19) mg/L in the placebo group and +3.01 (+0.40-5.43) mg/L in the AA group (P=0.02). Conversely, change in interleukin-6 was numerically higher in the AA group, though not statistically significant (P=0.32). One patient in each arm developed pericarditis; no adverse events related to the infusions were seen. There were no significant differences between aggregated post-procedure pain levels within 24 hours or early recurrence of AF (both P>0.05). Conclusions High-dose AA is safe and well tolerated at the time of AF ablation and may be associated with a blunted rise in C-reactive protein, although consistent findings were not seen in interleukin-6 levels. Further studies are needed to validate these findings and explore the potential benefit in improving clinically relevant outcomes. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03148236.