Whole Coffee Cherry Extract Improves Working Memory and Response Inhibition: Acute and Longitudinal Results from a Remote, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Earlier laboratory-based evidence has suggested that polyphenol-rich, decaffeinated whole coffee cherry extract (CCE) supports improvements in acute and long-term cognitive performance. To better understand CCE's potential to promote cognitive processing, we conducted a first-of-its-kind remote clinical trial. Participants were randomized into one of two intervention arms: placebo or 200 mg CCE. At the beginning of the study, participants were asked to complete a set of acute cognitive challenges as part of the baseline assessment. Tasks were nearly identical to those used in previous, laboratory-based research. Acute results support that CCE outperformed placebo, reducing omissions and improving accuracy, during working memory and inhibitory control tasks. Long-term results indicate that CCE outperformed placebo on a measure of accuracy. This contributes to the literature in three ways: (1) results improve upon previously reported robust and consistent findings in a real-world setting that a single-dose of CCE acutely improved cognitive performance; (2) results replicate previous laboratory findings but in a real-world setting that long-term CCE supplementation outperformed placebo on measures of accuracy in a working memory task; and (3) it serves as proof of concept of a novel remote clinical trial model that may provide real-world evidence of efficacy while increasing accessibility and cohort diversity.

Low-dose CT: A safe and effective imaging modality in post-operative pelvic & acetabular fixation.

INTRODUCTION: Post-operative pelvic & acetabular fixation patients are conventionally imaged using 3-view radiographs (AP, inlet and outlet). The efficacy of such radiographs is inconsistent due to technical difficulties capturing an adequate view, often necessitating repeat radiographs and therefore increasing radiation exposure. Radiographs can be difficult to interpret, limiting the assessment of fracture reduction and fixation, especially with respect to metalwork positioning around articular surfaces. Traditionally, post-operative pelvic & acetabular fixation patients undergo repeat 3-view radiographs post-operatively, at 6 weeks, followed by at 3, 6, 12, 18 and 24 months. We propose a new pathway, in which patients have one low-dose pelvic CT immediately post-operatively, followed by one radiograph (AP pelvis) at the same time points. METHODS: A new pelvic CT protocol was created to provide high quality 3D imaging whilst delivering a 5 times lower radiation dose (compared to normal pelvic CT). Data for all pelvic radiographs and CTs between January 2021 and March 2022 was exported. Using dose area product values, effective radiation dose and attributable lifetime cancer risk were calculated. RESULTS: There were 42 patients included in the analysis (age range 15 to 87).The average effective dose for the 3-view pelvic X-rays was 0.6mSv (range 0.2 to 2.8mSv), and 1.1mSv (range 0.5 to 2.2mSv) for the low-dose pelvic CT. Traditional 7 × 3-view post-operative radiographs: 7 × 0.6mSv = 4.2mSv (corresponding to 1 in 11,000 cancer risk) Low dose post-operative CT and 6 × 1-view radiographs: 1.1mSv + (6 × 0.6mSv / 3) = 2.3mSv (corresponding to 1 in 20,000 cancer risk) CONCLUSION: Low-dose CT scanning (in conjunction with 1-view radiographs) is an effective and safe imaging modality in the post-operative assessment of pelvic & acetabular fracture fixation, conferring a lower radiation burden, easier logistics, and higher quality images when compared to the traditional pathway of 3-view radiographs.

IL-6, but not TNF-α, response to alcohol cues and acute consumption associated with neural cue reactivity, craving, and future drinking in binge drinkers.

Objective and design: Preclinical studies suggest learned immune system responses to alcohol cues and consumption may contribute to alcohol's pharmacodynamic properties and/or Alcohol Use Disorder (AUD) pathogenesis. Mechanistically, these immune alterations may be associated with increased craving and alcohol consumption, both acutely and over time. We sought to characterize this relationship in a randomized, counter-balanced, crossover neuroimaging experiment which took place between June 2020-November 2021. Methods: Thirty-three binge drinkers (BD) and 31 non-binge, social drinkers (SD), matched for demographic and psychological variables, were exposed to alcohol cues and water cues in two separate 7 T functional magnetic resonance imaging (fMRI) scans. Each scan was followed by the Alcohol Taste Test (ATT) of implicit motivation for acute alcohol. Craving measures and blood cytokine levels were collected repeatedly during and after scanning to examine the effects of alcohol cues and alcohol consumption on craving levels, Tumor necrosis factor alpha (TNF-α), and Interleukin 6 (IL-6) levels. A post-experiment one-month prospective measurement of participants' "real world" drinking behavior was performed to approximate chronic effects. Results: BD demonstrated significantly higher peak craving and IL-6 levels than SD in response to alcohol cues and relative to water cues. Ventromedial Prefrontal Cortex (VmPFC) signal change in the alcohol-water contrast positively related to alcohol cue condition craving and IL-6 levels, relative to water cue condition craving and IL-6 levels, in BD only. Additionally, peak craving and IL-6 levels were each independently related to ATT alcohol consumption and the number of drinks consumed in the next month for BD, again after controlling for craving and IL-6 repones to water cues. However, TNF-α release in the alcohol cue condition was not related to craving, neural activation, IL-6 levels, immediate and future alcohol consumption in either group after controlling for water cue condition responses. Conclusions: In sum, BD show greater craving and IL-6 release in the alcohol cue condition than SD, both of which were associated with prefrontal cue reactivity, immediate alcohol consumption, and future alcohol consumption over the subsequent 30 days. Alcohol associated immune changes and craving effects on drinking behavior may be independent of one another or may be indicative of a common pathway by which immune changes in BD could influence motivation to consume alcohol. Trial registration: Clinical Trials NCT04412824.

Mesenchymal Stem Cell Extracellular Vesicles from Tissue-Mimetic System Enhance Epidermal Regeneration via Formation of Migratory Cell Sheets.

BACKGROUND: The secretome of adipose-derived mesenchymal stem cells (ASCs) offers a unique approach to understanding and treating wounds, including the critical process of epidermal regeneration orchestrated by keratinocytes. However, 2D culture techniques drastically alter the secretory dynamics of ASCs, which has led to ambiguity in understanding which secreted compounds (e.g., growth factors, exosomes, reactive oxygen species) may be driving epithelialization. METHODS: A novel tissue-mimetic 3D hydrogel system was utilized to enhance the retainment of a more regenerative ASC phenotype and highlight the functional secretome differences between 2D and 3D. Subsequently, the ASC-secretome was stratified by molecular weight and the presence/absence of extracellular vesicles (EVs). The ASC-secretome fractions were then evaluated to assess for the capacity to augment specific keratinocyte activities. RESULTS: Culture of ASCs within the tissue-mimetic system enhanced protein secretion ~ 50%, exclusively coming from the > 100 kDa fraction. The ASC-secretome ability to modulate epithelialization functions, including migration, proliferation, differentiation, and morphology, resided within the "> 100 kDa" fraction, with the 3D ASC-secretome providing the greatest improvement. 3D ASC EV secretion was enhanced two-fold and exhibited dose-dependent effects on epidermal regeneration. Notably, ASC-EVs induced morphological changes in keratinocytes reminiscent of native regeneration, including formation of stratified cell sheets. However, only 3D-EVs promoted collective cell sheet migration and an epithelial-to-mesenchymal-like transition in keratinocytes, whereas 2D-EVs contained an anti-migratory stimulus. CONCLUSION: This study demonstrates how critical the culture environment is on influencing ASC-secretome regenerative capabilities. Additionally, the critical role of EVs in modulating epidermal regeneration is revealed and their translatability for future clinical therapies is discussed.

Illuminating DEPDC1B in Multi-pronged Regulation of Tumor Progression.

DEPDC1B (aliases BRCC3, XTP8, XTP1) is a DEP (Dishevelled, Egl-1, Pleckstrin) and Rho-GAP-like domains containing predominately membrane-associated protein. Earlier, we and others have reported that DEPDC1B is a downstream effector of Raf-1 and long noncoding RNA lncNB1, and an upstream positive effector of pERK. Consistently, DEPDC1B knockdown is associated with downregulation of ligand-stimulated pERK expression. We demonstrate here that DEPDC1B N-terminus binds to the p85 subunit of PI3K, and DEPDC1B overexpression results in decreased ligand-stimulated tyrosine phosphorylation of p85 and downregulation of pAKT1. Collectively, we propose that DEPDC1B is a novel cross-regulator of AKT1 and ERK, two of the prominent pathways of tumor progression. Our data showing high levels of DEPDC1B mRNA and protein during the G2/M phase have significant implications in cell entry into mitosis. Indeed, DEPDC1B accumulation during the G2/M phase has been associated with disassembly of focal adhesions and cell de-adhesion, referred to as a DEPDC1B-mediated de-adhesion mitotic checkpoint. DEPDC1B is a direct target of transcription factor SOX10, and SOX10-DEPDC1B-SCUBE3 axis has been associated with angiogenesis and metastasis. The Scansite analysis of the DEPDC1B amino acid sequence shows binding motifs for three well-established cancer therapeutic targets CDK1, DNA-PK, and aurora kinase A/B. These interactions and functionalities, if validated, may further implicate DEPDC1B in regulation of DNA damage-repair and cell cycle progression processes. Finally, a survey of the publicly available datasets indicates that high DEPDC1B expression is a viable biomarker in breast, lung, pancreatic and renal cell carcinomas, and melanoma. Currently, the systems and integrative biology of DEPDC1B is far from comprehensive. Future investigations are necessary in order to understand how DEPDC1B might impact AKT, ERK, and other networks, albeit in a context-dependent manner, and influence the actionable molecular, spatial, and temporal vulnerabilities within these networks in cancer cells.

Tissue-mimetic culture enhances mesenchymal stem cell secretome capacity to improve regenerative activity of keratinocytes and fibroblasts in vitro.

Mesenchymal stem/stromal cells (MSCs) are a heterogenous population of multipotent and highly secretory cells currently being investigated in the field of wound healing for their ability to augment tissue responses. The adaptive response of MSC populations to the rigid substrate of current 2D culture systems has been considered to result in a deterioration of regenerative 'stem-like' properties. In this study, we characterise how the improved culture of adipose-derived mesenchymal stem cells (ASCs) within a tissue-mimetic 3D hydrogel system, that is mechanically similar to native adipose tissue, enhances their regenerative capabilities. Notably, the hydrogel system contains a porous microarchitecture that permits mass transport, enabling efficient collection of secreted cellular compounds. By utilising this 3D system, ASCs retained a significantly higher expression of ASC 'stem-like' markers while demonstrating a significant reduction in senescent populations, relative to 2D. Additionally, culture of ASCs within the 3D system resulted in enhanced secretory activity with significant increases in the secretion of proteinaceous factors, antioxidants and extracellular vesicles (EVs) within the conditioned media (CM) fraction. Lastly, treatment of wound healing cells, keratinocytes (KCs) and fibroblasts (FBs), with ASC-CM from the 2D and 3D systems resulted in augmented functional regenerative activity, with ASC-CM from the 3D system significantly increasing KC and FB metabolic, proliferative and migratory activity. This study demonstrates the potential beneficial role of MSC culture within a tissue-mimetic 3D hydrogel system that more closely mimics native tissue mechanics, and subsequently how the improved phenotype augments secretory activity and potential wound healing capabilities of the MSC secretome.

Novel hydrogel system eliminates subculturing and improves retention of nonsenescent mesenchymal stem cell populations.

Aim: To compare the physiological behavior of mesenchymal stem/stromal cells (MSCs) within an expandable tissue-mimetic 3D system relative to in vitro expansion in a traditional 2D system. Methods: Adipose-derived MSCs (ASCs) were continuously cultured for 6 weeks on either 2D culture plastic or in a 3D hydrogel system that eliminated subculturing. ASCs were assessed for senescence, 'stem-like' MSC markers, and ability for their secretome to augment a secondary cell population. Results: The 3D hydrogel system resulted in an enhanced retention of more regenerative, nonsenescent ASC populations that exhibited increased expression of 'stem-like' MSC surface markers. Conclusion: This study introduces a proof-of-concept design for a novel modular 3D system that can improve in vitro expansion of stem-like cell populations for future regenerative therapies.

Extra-Virgin Olive Oil Enhances the Blood-Brain Barrier Function in Mild Cognitive Impairment: A Randomized Controlled Trial.

Mild cognitive impairment (MCI) and early Alzheimer's disease (AD) are characterized by blood-brain barrier (BBB) breakdown leading to abnormal BBB permeability ahead of brain atrophy or dementia. Previous findings in AD mouse models have reported the beneficial effect of extra-virgin olive oil (EVOO) against AD, which improved BBB and memory functions and reduced brain amyloid-ß (Aß) and related pathology. This work aimed to translate these preclinical findings to humans in individuals with MCI. We examined the effect of daily consumption of refined olive oil (ROO) and EVOO for 6 months in MCI subjects on BBB permeability (assessed by contrast-enhanced MRI), and brain function (assessed using functional-MRI) as the primary outcomes. Cognitive function and AD blood biomarkers were also assessed as the secondary outcomes. Twenty-six participants with MCI were randomized with 25 participants completed the study. EVOO significantly improved clinical dementia rating (CDR) and behavioral scores. EVOO also reduced BBB permeability and enhanced functional connectivity. While ROO consumption did not alter BBB permeability or brain connectivity, it improved CDR scores and increased functional brain activation to a memory task in cortical regions involved in perception and cognition. Moreover, EVOO and ROO significantly reduced blood Aß42/Aß40 and p-tau/t-tau ratios, suggesting that both altered the processing and clearance of Aß. In conclusion, EVOO and ROO improved CDR and behavioral scores; only EVOO enhanced brain connectivity and reduced BBB permeability, suggesting EVOO biophenols contributed to such an effect. This proof-of-concept study justifies further clinical trials to assess olive oil's protective effects against AD and its potential role in preventing MCI conversion to AD and related dementias.

Effectiveness of a Novel ω-3 Krill Oil Agent in Patients With Severe Hypertriglyceridemia: A Randomized Clinical Trial.

Importance: Intense interest exists in novel ω-3 formulations with high bioavailability to reduce blood triglyceride (TG) levels. Objective: To determine the phase 3 efficacy and safety of a naturally derived krill oil with eicosapentaenoic acid and docosahexaenoic acid as both phospholipid esters (PLs) and free fatty acids (FFAs) (ω-3-PL/FFA [CaPre]), measured by fasting TG levels and other lipid parameters in severe hypertriglyceridemia. Design, Setting, and Participants: This study pooled the results of 2 identical randomized, double-blind, placebo-controlled trials. TRILOGY 1 (Study of CaPre in Lowering Very High Triglycerides) enrolled participants at 71 US centers from January 23, 2018, to November 20, 2019; TRILOGY 2 enrolled participants at 93 US, Canadian, and Mexican centers from April 6, 2018, to January 9, 2020. Patients with fasting TG levels from 500 to 1500 mg/dL, with or without stable treatment with statins, fibrates, or other agents to lower cholesterol levels, were eligible to participate. Interventions: Randomization (2.5:1.0) to ω-3-PL/FFA, 4 g/d, vs placebo (cornstarch) for 26 weeks. Main Outcomes and Measures: The primary outcome was the mean percentage of change in TG levels at 12 weeks; persistence at 26 weeks was the key secondary outcome. Other prespecified secondary outcomes were effects on levels of non-high-density lipoprotein cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), HDL-C, and low-density lipoprotein cholesterol (LDL-C); safety and tolerability; and TG level changes in prespecified subgroups. Results: A total of 520 patients were randomized, with a mean (SD) age of 54.9 (11.2) years (339 men [65.2%]), mean (SD) body mass index of 31.5 (5.1), and baseline mean (SD) TG level of 701 (222) mg/dL. Two hundred fifty-six patients (49.2%) were of Hispanic or Latino ethnicity; 275 (52.9%) had diabetes; and 248 (47.7%) were receiving statins. In the intention-to-treat analysis, TG levels were reduced by 26.0% (95% CI, 20.5%-31.5%) in the ω-3-PL/FFA group and 15.1% (95% CI, 6.6%-23.5%) in the placebo group at 12 weeks (mean treatment difference, -10.9% [95% CI, -20.4% to -1.5%]; P = .02), with reductions persisting at 26 weeks (mean treatment difference, -12.7% [95% CI, -23.1% to -2.4%]; P = .02). Compared with placebo, ω-3-PL/FFA had no significant effect at 12 weeks on mean treatment differences for non-HDL-C (-3.2% [95% CI, -8.0% to 1.6%]; P = .18), VLDL-C (-3.8% [95% CI, -12.2% to 4.7%]; P = .38), HDL-C (0.7% [95% CI, -3.7% to 5.1%]; P = .77), or LDL-C (4.5% [95% CI, -5.9% to 14.8%]; P = .40) levels; corresponding differences at 26 weeks were -5.8% (95% CI, -11.3% to -0.3%; P = .04) for non-HDL-C levels, -9.1% (95% CI, -21.5% to 3.2%; P = .15) for VLDL-C levels, 1.9% (95% CI, -4.8% to 8.6%; P = .57) for HDL-C levels, and 6.3% (95% CI, -12.4% to 25.0%; P = .51) for LDL-C levels. Effects on the primary end point did not vary significantly by age, sex, race and ethnicity, country, qualifying TG level, diabetes, or fibrate use but tended to be larger among patients taking statins or cholesterol absorption inhibitors at baseline (mean treatment difference, -19.5% [95% CI, -34.5% to -4.6%]; P = .08 for interaction) and with lower (less than median) baseline blood eicosapentaenoic acid plus docosahexaenoic acid levels (-19.5% [95% CI, -33.8% to -5.3%]; P = .08 for interaction). ω-3-PL/FFA was well tolerated, with a safety profile similar to that of placebo. Conclusions and Relevance: This study found that ω-3 -PL/FFA, a novel krill oil-derived ω-3 formulation, reduced TG levels and was safe and well tolerated in patients with severe hypertriglyceridemia. Trial Registration: ClinicalTrials.gov Identifiers: NCT03398005 and NCT03361501.

Estrogen Signaling Dictates Musculoskeletal Stem Cell Behavior: Sex Differences in Tissue Repair.

Sexual dimorphisms in humans and other species exist in visually evident features such as body size and less apparent characteristics, including disease prevalence. Current research is adding to a growing understanding of sex differences in stem cell function and response to external stimuli, including sex hormones such as estrogens. These differences are proving significant and directly impact both the understanding of stem cell processes in tissue repair and the clinical implementation of stem cell therapies. Adult stem cells of the musculoskeletal system, including those used for development and repair of muscle, bone, cartilage, fibrocartilage, ligaments, and tendons, are no exception. Both in vitro and in vivo studies have found differences in stem cell number, proliferative and differentiation capabilities, and response to estrogen treatment between males and females of many species. Maintaining the stemness and reducing senescence of adult stem cells is an important topic with implications in regenerative therapy and aging. As such, this review discusses the effect of estrogens on musculoskeletal system stem cell response in multiple species and highlights the research gaps that still need to be addressed. The following evidence from investigations of sex-related phenotypes in adult progenitor and stem cells are pieces to the big puzzle of sex-related effects on aging and disease and critical information for both fundamental tissue repair and regeneration studies and safe and effective clinical use of stem cells. Impact Statement This review summarizes current knowledge of sex differences in and the effects of estrogen treatment on musculoskeletal stem cells in the context of tissue engineering. Specifically, it highlights the impact of sex on musculoskeletal stem cell function and ability to regenerate tissue. Furthermore, it discusses the varying effects of estrogen on stem cell properties, including proliferation and differentiation, important to tissue engineering. This review aims to highlight the potential impact of estrogens and the importance of performing sex comparative studies in the field of tissue engineering.

Large-scale North American cancer survivorship surveys: 2011-2019 update.

PURPOSE: There are gaps in our knowledge to provide quality cancer care to the growing numbers of survivors. Leveraging existing data to answer survivorship research questions is one approach to address these gaps. Therefore, the purpose of this paper is to replicate and expand a previous report of existing cancer survivorship survey data. METHODS: We conducted a trifold search strategy for relevant surveys and data sets to (1) determine the extent to which cancer survivors are being surveyed, (2) determine the topics being covered in these surveys, and (3) create a compendium of information about these surveys and data sets, so researchers can conduct additional analyses. RESULTS: Thirty-five surveys were identified and included in this report; most were longitudinal studies (71%) in adult cancer survivors (91%). The domains addressed in these surveys were general medical characteristics, medical conditions, costs, employment, symptoms and/or side effects, psychosocial factors and coping, perceived quality of care, and health behaviors. CONCLUSIONS: Existing data are available for researchers to explore new knowledge to enhance cancer survivorship quality care. This is an opportunity to fully utilize existing data to answer survivorship questions in a cost effective manner. IMPLICATIONS FOR CANCER SURVIVORS: Survivors should be encouraged to participate in research studies as these data can close the gap in our knowledge and care of this growing population.

Integration of clinical perspective into biomimetic bioreactor design for orthopedics.

The challenges to accommodate multiple tissue formation metrics in conventional bioreactors have resulted in an increased interest to explore novel bioreactor designs. Bioreactors allow researchers to isolate variables in controlled environments to quantify cell response. While current bioreactor designs can effectively provide either mechanical, electrical, or chemical stimuli to the controlled environment, these systems lack the ability to combine all these stimuli simultaneously to better recapitulate the physiological environment. Introducing a dynamic and systematic combination of biomimetic stimuli bioreactor systems could tremendously enhance its clinical relevance in research. Thus, cues from different tissue responses should be studied collectively and included in the design of a biomimetic bioreactor platform. This review begins by providing a summary on the progression of bioreactors from simple to complex designs, focusing on the major advances in bioreactor technology and the approaches employed to better simulate in vivo conditions. The current state of bioreactors in terms of their clinical relevance is also analyzed. Finally, this review provides a comprehensive overview of individual biophysical stimuli and their role in establishing a biomimetic microenvironment for tissue engineering. To date, the most advanced bioreactor designs only incorporate one or two stimuli. Thus, the cell response measured is likely unrelated to the actual clinical performance. Integrating clinically relevant stimuli in bioreactor designs to study cell response can further advance the understanding of physical phenomenon naturally occurring in the body. In the future, the clinically informed biomimetic bioreactor could yield more efficiently translatable results for improved patient care.

Risk Patterns and Mortality in Postmenopausal Women Using Latent Class Analysis.

INTRODUCTION: Although risk factors often co-occur, previous studies examining lifestyle or psychosocial factors often treat these factors as individual predictors of health. This study aims to identify the underlying subgroups of women characterized by distinct lifestyle and psychosocial risk patterns and to investigate the prospective associations between risk patterns and mortality among postmenopausal women. METHODS: A total of 64,812 postmenopausal women aged 50-79 years without prevalent diabetes, cardiovascular disease, and cancer at baseline (1993-1998) were followed until 2019 with a mean follow-up duration of 14.6 (SD=6.4) years. Latent class analysis was used to identify the latent classes of women with homogeneous combinations of lifestyle and psychosocial variables and to test whether the classes were prospectively associated with mortality. Analyses were stratified by race/ethnicity and were performed in 2020. RESULTS: A total of 4 latent classes (Healthy Lifestyle and Psychosocial, Risky Psychosocial, Risky Lifestyle, and Risky Lifestyle and Risky Psychosocial) were identified for Hispanic, Black, and White women, and 2 classes (High Risk or Low Risk) were identified for American Indian and Asian women. Women in the Risky Lifestyle and Risky Psychosocial group had the highest hazard ratios for all outcomes studied for all race/ethnicity groups than those in the Healthy Lifestyle and Psychosocial group, followed by those in the Risky Lifestyle group. Risky Psychosocial class was significantly associated with an elevated risk of overall and cardiovascular disease mortality only in Black women. CONCLUSIONS: The class with concurrent risky lifestyle and psychosocial factors conveyed the greatest risk of all types of mortality than a low-risk ref group. Health promotion should address both behavioral and psychosocial risks concurrently.

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.

Effects of menopausal hormone therapy on erythrocyte n-3 and n-6 PUFA concentrations in the Women's Health Initiative randomized trial.

BACKGROUND: The factors other than dietary intake that determine tissue concentrations of EPA and DHA remain obscure. Prior studies suggested that, in women, endogenous estrogen may accelerate synthesis of DHA from ɑ-linolenic acid (ALA), but the effects of exogenous estrogen on RBC n-3 (É·-3) PUFA concentrations are unknown. OBJECTIVE: We tested the hypothesis that menopausal hormone therapy (HT) would increase RBC n-3 PUFA concentrations. METHODS: Postmenopausal women (ages 50-79 y) were assigned to HT or placebo in the Women's Health Initiative (WHI) randomized trial. The present analyses included a subset of 1170 women (ages 65-79 y) who had RBC PUFA concentrations measured at baseline and at 1 y as participants in the WHI Memory Study. HT included conjugated equine estrogens (E) alone for women without a uterus (n = 560) and E plus medroxyprogesterone acetate (P) for those with an intact uterus (n = 610). RBC n-3 and n-6 (É·-6) PUFAs were quantified. RESULTS: Effects of E alone and E+P on PUFA profiles were similar and were thus combined in the analyses. Relative to the changes in the placebo group after 1 y of HT, docosapentaenoic acid (DPA; n-3) concentrations decreased by 10% (95% CI: 7.3%, 12.5%), whereas DHA increased by 11% (95% CI: 7.4%, 13.9%) in the HT group. Like DHA, DPA n-6 increased by 13% from baseline (95% CI: 10.0%, 20.3%), whereas linoleic acid decreased by 2.0% (95% CI: 1.0%, 4.1%; P values at least <0.01 for all). EPA and arachidonic acid concentrations were unchanged. CONCLUSIONS: HT increased RBC concentrations of the terminal n-3 and n-6 PUFAs (DHA and DPA n-6). These findings are consistent with an estrogen-induced increase in DHA and DPA n-6 synthesis, which is consistent with an upregulation of fatty acid elongases and/or desaturases in the PUFA synthetic pathway. The clinical implications of these changes require further study. The Women's Health Initiative Memory Study is registered at clinicaltrials.gov as NCT00685009. Note that the data presented here were not planned as part of the original trial, and therefore are to be considered exploratory.

Neurophysiological Effects of Whole Coffee Cherry Extract in Older Adults with Subjective Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Pilot Study.

Bioactive plant-based compounds have shown promise as protective agents across multiple domains including improvements in neurological and psychological measures. Methodological challenges have limited our understanding of the neurophysiological changes associated with polyphenol-rich supplements such as whole coffee cherry extract (WCCE). In the current study, we (1) compared 100 mg of WCCE to a placebo using an acute, randomized, double-blind, within-subject, cross-over design, and we (2) conducted a phytochemical analysis of WCCE. The primary objective of the study was to determine the neurophysiological and behavioral changes that resulted from the acute administration of WCCE. We hypothesized that WCCE would increase brain-derived neurotrophic factor (BDNF) and glutamate levels while also increasing neurofunctional measures in cognitive brain regions. Furthermore, we expected there to be increased behavioral performance associated with WCCE, as measured by reaction time and accuracy. Participants underwent four neuroimaging scans (pre- and post-WCCE and placebo) to assess neurofunctional/metabolic outcomes using functional magnetic resonance imaging and magnetic resonance spectroscopy. The results suggest that polyphenol-rich WCCE is associated with decreased reaction time and may protect against cognitive errors on tasks of working memory and response inhibition. Behavioral findings were concomitant with neurofunctional changes in structures involved in decision-making and attention. Specifically, we found increased functional connectivity between the anterior cingulate and regions involved in sensory and decision-making networks. Additionally, we observed increased BDNF and an increased glutamate/gamma-aminobutyric acid (GABA) ratio following WCCE administration. These results suggest that WCCE is associated with acute neurophysiological changes supportive of faster reaction times and increased, sustained attention.

Association of Body Mass Index With Colorectal Cancer Risk by Genome-Wide Variants.

BACKGROUND: Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk. METHODS: We tested multiplicative statistical interactions between BMI (per 5 kg/m2) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14 059 colorectal cancer case (53.2% women) and 14 416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided. RESULTS: Each 5 kg/m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 × 10-17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 × 10-24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; Pobserved = .0009; Pthreshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 × 10-10). Each 5 kg/m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 × 10-10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 × 10-8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes. CONCLUSION: These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.

Physical activity and fitness: The feasibility and preliminary effectiveness of wearable activity tracker technology incorporating altruistic motivation in youth.

PURPOSE: The purpose of this study was to examine the feasibility and preliminary effectiveness of using wearable activity tracker technology, integrated with altruistic motivation in children to increase physical activity (PA), fitness, and prosocial behavior. DESIGN AND METHODS: A quasiexperimental design was employed in two 4th grade classrooms in a rural southern state. The intervention was a wearable PA tracker and a web-based curriculum with activities to earn power points redeemable to provide life-saving food to undernourished kids internationally. Seventeen children in the intervention group participated in the 10-week PA program and 18 children were in the wait listed control group. Three measures were assessed in both groups at baseline and postintervention: (a) PA measured with accelerometers, (b) fitness levels measured with shuttle run, and (c) prosocial behavior measured with Strengths and Difficulties questionnaire. RESULTS: Of the 35 children enrolled, the majority were nine years old (n = 28), black (n = 31) and female (n = 23). An overall enrollment rate of 88%, attrition rate of 9%, and an accelerometer noncompliance rate of 25% was determined to assess feasibility. There was no statistical significance between the control and intervention group outcome variables. The average minutes of PA in the control group decreased 8 min from baseline to postintervention (p = .05). In the intervention group, PA decreased by 10 min from baseline to postintervention (p = .12). In both the control and intervention groups, prosocial behavior scores decreased (p = .09 control; p = .62 intervention). The fitness scores, VO2 max, did not significantly change (intervention p = .21; control p = .35). PRACTICE IMPLICATIONS: Developing effective interventions that foster PA and dissuade sedentary behaviors are essential to enhancing PA and fitness levels. The recruitment, retention, and accelerometer wear adherence suggest this setting, with this population is feasible. The intervention is deliverable, however, the potential of wearable activity trackers and the effect of prosocial behavior that benefits others in increasing PA and improving cardiorespiratory fitness, should be further researched by building on the successful elements of this study.

Chemotherapy-induced peripheral neuropathy: Identifying the research gaps and associated changes to clinical trial design.

BACKGROUND: To the authors' knowledge, the empiric identification of agents and interventions to mitigate chemotherapy-induced peripheral neuropathy (CIPN) has resulted in only 1 agent that modestly mitigates it and no agents or interventions that prevent its development. This speaks to the need for a mechanistic understanding of CIPN to develop effective interventions. METHODS: To understand the extent to which mechanistic understanding of CIPN is being translated into the development of interventions, the National Cancer Institute conducted a review of the National Institutes of Health (NIH)'s portfolio of investigator-initiated grants, the literature regarding CIPN mechanisms, and the clinical trials listed in the ClinicalTrials.gov database from January 1, 2011, to May 22, 2019. RESULTS: A total of 69 NIH-supported grants and 95 published articles were identified that evaluated mechanistic pathways of 7 different chemotherapy agents that cause CIPN. The review also identified 35 clinical trials that investigated agents or devices with which to treat CIPN. Only 3 trials incorporated a mechanistic rationale to support the choice of the intervention. CONCLUSIONS: To the authors' knowledge, very little of the mechanistic understanding of the development of CIPN is being translated into intervention rationale in clinical trials that evaluate interventions to mitigate CIPN. Efforts to incentivize this translation are needed.

Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies.

BACKGROUND: De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). METHODS AND FINDINGS: Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. CONCLUSIONS: Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.