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Eamon P McCarron,1 Dominic P Williams,1 Daniel J Antoine,1 Anja Kipar,2 Jana Lemm,3 Sebastian Stehr,3 Ingeborg D Welters,4 1Department of Clinical and Molecular Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, 2Department of Veterinary Pathology, University of Liverpool, Liverpool, UK; 3Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany; 4Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK Background: Inflammation forms an important part of the human innate immune system and is largely dependent on the activation of the "classical" NF-κB pathway through Toll-like receptors (TLRs). Understanding this has allowed researchers to explore roles of therapeutic targets in managing conditions such as sepsis. Recapitulating an inflammatory response using lipopolysaccharide (LPS), a "sterile" technique, can provide information that is dissimilar to the clinical condition. By examining NF-κB activation (through immunoblotting of the p65 subunit) in two separate cell lines (murine and human) and analyzing two murine models of sepsis (intraperitoneal [IP] LPS and IP stool inoculation), an evaluation of the translational disconnect between experimental and clinical sepsis can be made. Methods: THP-1 (human) cells and RAW 264.7 (murine) cells were dosed with concentrations of LPS (human, 1 pg/mL to 100 ng/mL; murine, 30 pg/mL to 1,000 ng/mL) and nuclear actin and p65 were immunoblotted to measure changes in nuclear density. In vivo, C57BL/6 mice received either IP injection of stool suspension (5 µL/g ) or LPS (25 mg/kg) or saline (1 mL/kg). Animals were culled at 6 hours and tissues were analyzed. Results: An increase in basal p65:actin density in THP-1 cells (mean 0.214, standard error of the mean 0.024) was seen at doses as small as 0.1 ng/mL (0.519±0.064). In contrast to RAW 264.7 cells, basal increases (0.170±0.025) were only seen when a dose of 3 ng/mL (0.387±0.078) was used. Dose–response analysis of p65:actin ratio showed that THP-1 cells respond to lower doses of LPS than RAW 264.7 cells and lower doses produce a greater fold increase in the nuclear p65 density. Both in vivo models showed evidence of neutrophil (NL) recruitment into tissues (which was more intense after LPS treatment). IP stool inoculation resulted in an acute suppurative peritonitis and more substantial evidence of NL recruitment into adipose tissue and skeletal muscle. Conclusion: Our results support previous observations that translation of murine models into the human clinical setting suffers from considerable limitations including species-associated differences in LPS response seen at a molecular level. Furthermore, the histopathological changes during clinical sepsis cannot be adequately reproduced by injection of LPS. Therefore, the so-called translational disconnect that exists between murine LPS models and human sepsis involves NF-κB activation at a molecular level and is further augmented by the use of LPS as a stimulus for infectious responses in vivo. Keywords: NF-κB, p65, LPS, murine, sepsis, inflammation, leukocyte, monocyte, macrophage

The Marshallese immigrant population, part of a growing Asian American and Pacific Islander population in the United States, has adverse health conditions and disparities that are mainly attributed to their pre-migration health status. Little is known about the perceived and real barriers Marshallese experience in accessing and utilizing health services in the United States. Because of these barriers, their health status is known to exacerbate. This formative study used qualitative methods, using an ethnographic approach, to identify the ethnocultural and socioeconomic barriers to existing health services as perceived by immigrant Marshallese living in Northwest Arkansas. Recommendations were made to improve timely, culturally competent, and appropriate health services. [ABSTRACT FROM AUTHOR]

This study examined risk factors for osteoporosis in Hispanic women. Factors examined included ethnicity, gender, age, height, weight, family and personal history of fractures, height loss, exercise, diet, time since menopause or hysterectomy, hormone replacement therapy (HRT), calcium supplementation, hypertension, thyroid disease, diabetes, arthritis, chemotherapy, family history of breast cancer, use of water pills, fosamax, steroids, alcohol, and smoking. Most results found parallel those found in the Caucasian population. Heavier patients had greater bone density, as well as patients who exercised and those using HRT. Older patients had lower bone density as did diabetic patients. Results not anticipated were higher bone density in patients not taking calcium supplements, and in patients who consumed alcohol. [ABSTRACT FROM AUTHOR]

Evaluates the scattering of incident plane elastic waves by a variety of different defects that lie upon a fluid-solid interface using matched asymptotic expansions. Three examples illustrating the occurrences of three different canonical situations; Identification of the leading-order contribution of the defect to the acoustic field in the far field.

Background: Both low vagally-mediated heart rate variability (HRV) and depression have been shown to be risk factors for cardiovascular disease (CVD). We recently identified an HRV cutpoint below which persons have an increased risk for several cardiometabolic disorders. However, no cutpoint exists to identify those at risk for depression., Methods: The association between daytime HRV and diagnostically validated depression cutoffs using the five-item World Health Organization Well-being Index (WHO-5) was examined in adults from the Mannheim Industrial Cohort Study (n = 9973; M age  = 41.9[10.9]; 20 % women [n = 1934]). The aim was to identify HRV cutpoints for individuals who may have clinical depression., Results: Regression adjusting for age, sex, and linear trend showed a significant quadratic association between depression, indexed by WHO-5 scores and HRV, indexed by the root mean square successive differences (RMSSD) in milliseconds (ms) (p < 0.001). Logistic regression models adjusting for age, sex, and heart period (i.e., inter-beat intervals) compared the clinically depressed (WHO-5 ≤ 28) and those with a screening diagnosis of depression (WHO-5 ≤ 50) to the rest of the population. Significant odds ratios suggested two RMSSD values 25 ± 2 ms (OR = 1.39 [1.17, 1.64]) and 35 ± 2 ms (OR = 1.17 [1.02, 1.34]) that may be used to identify those with an elevated risk for depression., Limitations: The sample was primarily German men. Fitness and anti-depressant use were not available., Conclusions: As HRV is a brief measure that can be used in clinical settings, our HRV cutpoints have implications for the early detection of those at risk for psychological and cardiometabolic disorders., Competing Interests: Declaration of competing interest The authors declare that there are no financial/personal interests or beliefs that could affect their objectivity and that no potential competing interests exist., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

This paper describes a synthetic aperture sonar (SAS) dataset collected in-air consisting of four types of targets in four environments of different complexity. The in-air laboratory based experiments produced data with a level of fidelity and ground truth accuracy that is not easily attainable in data collected underwater. The range of complexity, high level of data fidelity, and accurate ground truth provides a rich dataset with acoustic features on multiple scales. It can be used to develop new signal-processing and image reconstruction algorithms, as well as machine learning models for object detection and classification. It may also find application in model verification and validation for acoustic simulators. The dataset consists of raw acoustic time series returns, associated environmental conditions, hardware configuration, array motion, as well as the reconstructed imagery., (© 2024. The Author(s).)

Higher self-reported rumination, a common form of trait perseverative cognition, is linked with lower resting heart rate variability (HRV), which indicates poorer cardiac function and greater disease risk. A meta-analysis and systematic review indicated that in samples with fewer European Americans, the association of rumination with both heart rate and blood pressure was stronger. Thus, trait rumination may be more strongly associated with resting HRV among ethnically minoritized populations. The current study investigated whether differences in the association of self-reported rumination with resting HRV varied by ethnicity in a sample (N = 513; M age  = 19.41; 226 Women) of self-identified African Americans (n = 110), Asian Americans (n = 84), and European Americans (n = 319). Participants completed a five-minute baseline period to assess resting HRV, followed by the Ruminative Responses Scale, which contains three facets of rumination including brooding, depressive, and reflective rumination. On average, Asian Americans reported higher levels of rumination relative to European Americans. African Americans had higher resting HRV than Asian Americans. Adjusting for covariates, higher self-reported rumination was significantly associated with lower resting HRV in both African and Asian Americans, but not significantly so in European Americans. This finding was consistent for brooding and reflective, but not depressive rumination. Overall, this study lends insight into a psychological mechanism-rumination-that may impact health disparities among ethnically minoritized individuals, contributing to an understanding of how stress gets under the skin among such minoritized populations., (© 2024 John Wiley & Sons Ltd.)

As of 2020, penetrating injuries became the leading cause of death among children and adolescents ages 1-19 in the United States. For the patients who initially survive and receive advanced medical care, vascular injuries are a significant cause of morbidity and additionally trigger notable trauma team angst. Moreover, penetrating injuries can lead to life-threatening hemorrhage and/or limb-threatening ischemia if not addressed promptly. Vascular injury management demands timely and unique expertise, particularly for pediatric patients. As the frequency of vascular injuries requiring operative management increases, it becomes clear that an ad hoc approach is not ideal. An integrated team would provide the best approach for rapid hemorrhage control and revascularization, but the structure of vascular response teams at children's hospitals is highly variable. In part 1 of this review, we will evaluate the scope and extent of the epidemic of traumatic vascular injuries in pediatric patients, review current evidence and outcomes, discuss various challenges and advantages of different team structures, and outline potential outcome targets and pediatric vascular trauma response solutions. LEVEL OF EVIDENCE: n/a., Competing Interests: Conflicts of interest Authors have no relevant financial conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Drug-induced liver injury (DILI) has been significant challenge in drug discovery, often leading to clinical trial failures and necessitating drug withdrawals. The existing suite of in vitro proxy-DILI assays is generally effective at identifying compounds with hepatotoxicity. However, there is considerable interest in enhancing in silico prediction of DILI because it allows for the evaluation of large sets of compounds more quickly and cost-effectively, particularly in the early stages of projects. In this study, we aim to study ML models for DILI prediction that first predicts nine proxy-DILI labels and then uses them as features in addition to chemical structural features to predict DILI. The features include in vitro (e.g., mitochondrial toxicity, bile salt export pump inhibition) data, in vivo (e.g., preclinical rat hepatotoxicity studies) data, pharmacokinetic parameters of maximum concentration, structural fingerprints, and physicochemical parameters. We trained DILI-prediction models on 888 compounds from the DILIst dataset and tested on a held-out external test set of 223 compounds from DILIst dataset. The best model, DILIPredictor, attained an AUC-ROC of 0.79. This model enabled the detection of top 25 toxic compounds compared to models using only structural features (2.68 LR+ score). Using feature interpretation from DILIPredictor, we were able to identify the chemical substructures causing DILI as well as differentiate cases DILI is caused by compounds in animals but not in humans. For example, DILIPredictor correctly recognized 2-butoxyethanol as non-toxic in humans despite its hepatotoxicity in mice models. Overall, the DILIPredictor model improves the detection of compounds causing DILI with an improved differentiation between animal and human sensitivity as well as the potential for mechanism evaluation. DILIPredictor is publicly available at https://broad.io/DILIPredictor for use via web interface and with all code available for download and local implementation via https://pypi.org/project/dilipred/., Competing Interests: Conflicts of Interest The authors declare no conflict of interest.

Study Objective: African Americans (AAs) show early signs of vascular dysfunction paired with elevated blood pressure (BP) and total peripheral resistance (TPR), which is thought to underlie their increased rates of cardiovascular health complications relative to European Americans (EAs). AAs paradoxically have higher cardiac vagal tone, indexed by heart rate variability (HRV), which is cardio-protective. This paradox has been termed the Cardiovascular Conundrum . The physiological mechanism underlying this phenomenon is not well understood. We examined race differences in baroreflex function, which might be an important mechanism underlying the Cardiovascular Conundrum ., Design: Participants completed a 5-minute baseline period where resting cardiac metrics were assessed., Setting: Laboratory., Participants: 130 college-aged individuals (54 women, 57 AAs)., Main Outcome Measures: Baroreflex function was indexed as baroreflex sensitivity (BRS; the magnitude of changes in cardiovascular activity in accordance with BP changes) and effectiveness (BEI; the ratio of BP changes that elicit changes in cardiovascular activity) in the cardiac, vascular, and myocardial limbs., Results and Conclusions: Results showed AAs to have higher HRV and cardiac BRS in comparison to EAs, suggesting the baroreflex is more sensitive to correcting the heart period for changes in BP among AAs compared to EAs. However, AAs showed lower vascular BEI relative to EAs, suggesting less effective control of TPR. In sum, lower BEI in the vascular branch might be an important mechanism underlying the Cardiovascular Conundrum (i.e., higher HRV and BP) and by extension, health disparities in cardiovascular diseases between AAs and EAs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Previous literature demonstrated that long-term memory representations guide spatial attention during visual search in real-world pictures. However, it is currently unknown whether memory-guided visual search is affected by the emotional content of the picture. During functional magnetic resonance imaging (fMRI), participants were asked to encode the position of high-contrast targets embedded in emotional (negative or positive) or neutral pictures. At retrieval, they performed a visual search for targets presented at the same location as during encoding, but at a much lower contrast. Behaviorally, participants detected more accurately targets presented in negative pictures compared to those in positive or neutral pictures. They were also faster in detecting targets presented at encoding in emotional (negative or positive) pictures than in neutral pictures, or targets not presented during encoding (i.e., memory-guided attention effect). At the neural level, we found increased activation in a large circuit of regions involving the dorsal and ventral frontoparietal cortex, insular and parahippocampal cortex, selectively during the detection of targets presented in negative pictures during encoding. We propose that these regions might form an integrated neural circuit recruited to select and process previously encoded target locations (i.e., memory-guided attention sustained by the frontoparietal cortex) embedded in emotional contexts (i.e., emotional contexts recollection supported by the parahippocampal cortex and emotional monitoring supported by the insular cortex). Ultimately, these findings reveal that negative emotions can enhance memory-guided visual search performance by increasing neural activity in a large-scale brain circuit, contributing to disentangle the complex relationship between emotion, attention, and memory., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Asian Americans and European Americans differ in emotion regulation (ER), particularly regarding strategies utilized to adaptively engage in ER. Resting heart rate variability (HRV), a biomarker of ER ability, is suggested to differ between Asian Americans and European Americans, but evidence for such differences has been inconsistent. Yet, research has not considered how Asian Americans and European Americans might differ in the well-established link between resting HRV and ER difficulties, which might lend a better understanding of such inconsistencies. In 374 college-aged individuals (66 Asian Americans; 311 European Americans; 190 women; mean age = 19.3 years [Min. 18, Max 38]), we examined if ethnicity moderated the link between resting HRV and self-reported ER difficulties. Resting HRV was obtained during a 5-min resting-baseline period, and ER difficulties were assessed using the Difficulties in ER Scale, which contained six facets of ER difficulties. Adjusting for gender and body mass index, moderation analyses showed a stronger association between resting HRV and ER difficulties in Asian Americans compared to European Americans. When examining facets of ER, ethnicity moderated only the link between resting HRV and difficulties in accessing ER strategies when facing negative emotions. At lower levels of HRV, Asian Americans reported greater difficulties in ER relative to European Americans. This effect diminished and trended in the opposite direction among those with higher HRV. In sum, these results provide novel evidence that higher resting HRV might be particularly important for adaptive ER among Asian Americans - a marginalized ethnic group - in the U.S., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Psychological and physical factors are robustly associated with perceived social support. Drawing from the literature on attachment style in adults and psychophysiology, we examined the possibility that the interaction of attachment insecurity and resting heart rate variability (HRV) was associated with perceived social support in a diverse sample of young adults living in the U.S ( N  = 145, M age  = 20.45) that was majority Latino ( n  = 77). Analyses revealed three key findings. First, in the overall sample, attachment avoidance and attachment anxiety were negatively associated with perceived social support, but in the Latino sample, only attachment avoidance was negatively associated with perceived social support. Second, HRV was not associated with perceived social support in the overall sample nor in the Latino sample. Third, attachment insecurity and HRV interacted to predict perceived social support only in the Latino sample such that, for those with lower levels of HRV, attachment anxiety was positively associated with perceived social support. This study underscores the importance of examining both psychological and physiological processes with careful consideration of ethnicity/culture in order to better understand perceived social support., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pourmand, Froidevaux, Williams, Yim and Campos.)

Objective: This study assessed whether different types of childhood maltreatment (i.e., abuse versus neglect) had differential relationships with heart rate variability (HRV) and baroreflex sensitivity. In addition, this study tested the indirect effect of maltreatment subtypes on adult mood-related psychopathology via HRV, and whether these relationships differed in those with HRV above and below established clinical cutoffs., Methods: Secondary analysis was performed using the Midlife Development in the United States data set ( N = 967; Mage = 55; 58.4% female; 75.9% White). In a single study visit, autonomic measurements were captured at rest, during two cognitive stressors (Stroop and MATH tasks), and during recovery after the tasks. Structural equation modeling was used to assess the relationships between key variables during all three measurement periods., Results: Resting pathways from abuse and neglect to baroreflex sensitivity were nonsignificant, as was the pathway from HRV to mood-related pathology. Notably, greater abuse was significantly predictive of lower HRV (standardized β = -0.42, p = .009), whereas greater neglect was significantly predictive of higher HRV (standardized β = 0.32, p = .034). In addition, higher abuse was significantly predictive of greater adult symptoms (standardized β = 0.39, p < .001), but neglect was not found to be related to adult mood-related pathology. Significant relationships between variables were only found in those with low HRV., Conclusions: Although cross-sectional, our findings provide further evidence that low HRV may be a transdiagnostic endophenotype for mood-related pathology and suggest that greater differentiation between abuse and neglect is appropriate when investigating the impact of childhood maltreatment on adult health outcomes., (Copyright © 2023 by the American Psychosomatic Society.)

Aims: This study aims to report the medium term outcomes of circumferential periosteal release of the distal femur and distal tibia in treating paediatric leg length discrepancy (LLD)., Materials and Methods: A retrospective case series was performed on all patients undergoing circumferential periosteal release of the distal femur and/or tibia between 2006 and 2019. Data collected included demographics, surgical indications, post-operative leg lengths, and complications. Leg length discrepancy was calculated as actual values and percentages of the longest limb length. Final actual and percentage discrepancies were compared to initial discrepancies using a paired t -test. Patterns of discrepancy over time were analysed using linear mixed models., Results: Eighteen patients (11 males) were identified, who underwent 25 procedures. The mean age at first surgery was 5.8 (range, 2-13). The commonest indication was congenital limb deficiency (7 patients). Five patients underwent repeat periosteal release, and one patient had three releases. The mean follow-up was 63 months [standard deviation (SD), 33.9]. Fifteen patients had sufficient data for statistical analysis.The mean actual discrepancy decreased from 2.07 cm (SD, 1.07) to 1.12 cm (SD, 1.62), and the mean relative discrepancy from 4.3% (SD, 2.8) to 1.5% (SD, 2.4). Significant mean reductions were seen in both actual discrepancies [0.61 cm (95% CI: 0.05-1.16; p = 0.034)], and percentage discrepancy [2.10% (95% CI: 1.0-3.1, p = <0.001]). In five patients, the operated limb overgrew the contralateral limb. Patients whose operated limb overgrew still had a reduction in LLD, with a mean residual discrepancy less than 1 cm (mean 0.7 cm, 95% CI: From -0.9 to 2.4)., Conclusion: Circumferential periosteal release produces a significant decrease in both actual and percentage LLD. We believe this procedure is best indicated in younger patients with congenital LLD in whom the discrepancy is predicted to increase as they age., Clinical Significance: Circumferential periosteal release produces a significant decrease in LLD. This procedure can be used to manage symptoms during growth, particularly at the point where orthotic usage may become problematic, and to potentially reduce the magnitude of surgery needed at an older age., How to Cite This Article: Chatterton BD, Kuiper JH, Williams DP. Circumferential Periosteal Release to Treat Paediatric Leg Length Discrepancy: Medium Term Outcomes. Strategies Trauma Limb Reconstr 2023;18(2):67-72., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2023; The Author(s).)

Background: Members of the dietetics profession have been discussing and confronting the lack of diversity within the profession. The Academy of Nutrition and Dietetics is committed to diversity and inclusion efforts., Objective: Our aim was to determine current admission criteria and practices used by Dietetic Internships (DIs) across the United States., Design: This was a cross-sectional study using electronic survey with open and close-ended items conducted in the fall of 2020., Participants: The electronic survey was distributed to 261 DI directors. Statistical analysis performed Descriptive statistics were calculated for each variable using SPSS software. Six topically related open-ended items were analyzed through a qualitative thematic approach., Results: DI directors (n = 89) were primarily female (n = 76) and White (n = 77). Most admissions process and criteria decisions were made by committees. Directors (n = 79) reported using a predefined rubric/scoring system for candidate evaluation. Many (n = 60) indicated not using Graduate Record Examination scores. All reported considering Didactic Program in Dietetics' grade point average; personal statement quality; professional interests and goals; and type and quantity of previous dietetics-related work and volunteer experience. The admission factors rated (on a 7-point scale) most important were quality of interview (mean = 6.03), Didactic Program in Dietetics' grade point average (mean = 5.67), type of work and volunteer experience (mean = 5.62), quality of personal statement (mean = 5.5), recommender comments (mean = 5.41), and quantity of work and volunteer experience (mean = 5.40). Most (n = 80) indicated that they were satisfied with their selection processes., Conclusions: Educators should continue refining admissions processes as professional gatekeepers, consider reducing application fees, diversifying and training selection committees, re-evaluating admission criteria, and assessing how criteria weights., (Copyright © 2023 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

The present study aimed to investigate sex differences in measures of cardiac chronotropy and heart rate variability (HRV) in 132 young adult wild-type Groningen rats ( n = 45 females). Electrocardiographic signals were recorded for 48 h in freely moving rats to quantify heart rate (HR) and inter-beat interval (IBI) as measures of cardiac chronotropy, and time- and frequency-domain HRV parameters as physiological readouts of cardiac vagal modulation. Females showed greater vagally-mediated HRV despite having higher HR and shorter IBI than males during undisturbed conditions. Such differences were evident i) at any given level of HRV, and ii) both during the 12-h light/inactive and 12-h dark/active phase of the daily cycle. These findings replicate the paradoxical cardiac chronotropic control reported by human meta-analytic findings, since one would expect greater vagally-mediated HRV to be associated with lower HR and longer IBI. Lastly, the association between some HRV measures and HR was stronger in female than male rats. Overall, the current study in young adult rats provides data illustrating a sex-dependent association between vagally-mediated HRV and indexes of cardiac chronotropy. The current results i) are in line with human findings, ii) suggest to always consider biological sex in the analysis and interpretation of HRV data in rats, and iii) warrant the use of rats for investigating the neuro-hormonal basis and temporal evolution of the impact of sex on the association between vagally-mediated HRV and cardiac chronotropy, which could inform the human condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Carnevali, Barbetti, Statello, Williams, Thayer and Sgoifo.)

In response to the COVID-19 pandemic, the University of Leicester introduced a blended teaching model to continue delivery of their undergraduate Chemistry courses in 2020/21. The transition from in-person to blended provided a good opportunity to investigate student engagement in the blended environment, along with the attitudes of faculty members adapting to this mode of delivery. Data from 94 undergraduate students and 13 staff members was collected using surveys, focus groups, and interviews and analyzed using the community of inquiry framework. Analysis of the collected data found that, while some students felt unable to always engage and focus with the remote material, they were pleased with the University's response to the pandemic. Staff members commented on the challenges of gauging student engagement and understanding in synchronous contact sessions because students did not make use of cameras or microphones but praised the array of digital tools available that helped to facilitate some degree of student interaction. This study suggests there is scope for continuation and wider implementation of blended learning environments to provide additional contingency for further disruption to on-campus teaching and to provide new teaching opportunities, and it also presents recommendations as to how to reinforce the community of inquiry presences in blended learning., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society and Division of Chemical Education, Inc.)

Measures of heart rate variability (HRV) as a predictor of risk of disease and mortality have been investigated from various perspectives for more than six decades. The aim of the present comprehensive meta-analysis is to examine eight different HRV parameters to determine their association with all-cause and cardiac mortality. A total of 32 studies and two individual participant datasets (IPD) with 37 samples and 38,008 participants were included. Lower HRV parameter values were significant predictors of higher mortality across different ages, sex, continents, populations and recording lengths. Most of the examined parameters showed comparable hazard ratios (HR). IPD sub-analysis for heart rate corrected HRV parameters confirmed the strong association between HRV and all-cause mortality. Meta-regressions revealed no effect modifier for HRs extracted from covariate-adjusted studies. Sub-analyses of studies comparing the lowest quartile of 5-min root mean square of successive differences (RMSSD) vs. the other quartiles yielded a combined HR of 1.56 (95% CI: 1.32-1.85). The applicability of HRV measurement in preventive settings is discussed., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Childhood adversity (CA) is associated with increased risk for physical and mental health problems, with alterations in vagal regulation (an aspect of autonomic functioning indexed by vagally-mediated heart rate variability [vmHRV]) implicated as a mechanism. Three-level meta-analyses were conducted to synthesize research on the relationship between CA and 1) baseline vagal activity, and 2) vagal reactivity to challenges including stress tests, emotion-eliciting tasks and cognitive tasks. No significant overall association was found between CA and vagal activity (r = -.015; p = .11) or vagal reactivity (r = -.017; p = .13). However, analyses controlling for moderator interrelatedness revealed an association between CA and lower baseline vagal activity in samples including participants diagnosed with a psychiatric disorder, and for direct adversities such as maltreatment. For vagal reactivity, CA was associated with lower reactivity if the adversity was experienced less recently, and for studies operationalizing reactivity using task mean levels of vmHRV. These findings indicate that small alterations in vagal functioning occur for specific CA subtypes and subgroups of individuals., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: Coronavirus (COVID-19) disproportionately affects people of color (e.g., Black and Latinx individuals) in the U.S., increasing their morbidity and mortality relative to White people. Despite this greater threat to their well-being, the mental health impact of COVID-19 on people of color remains poorly understood. Perseverative cognition (PC; i.e., excessive worry and/or rumination), is a common psychological response to such threats that independently associates with poor mental and physical health., Objective: To examine patterns of PC across race/ethnicity when the COVID-19 pandemic began., Methods: This study surveyed 6,514 respondents from the NORC AmeriSpeak panel, a probability-based representative national sample of U.S. adults between 3/18/20-4/18/20. We employed traditional statistical analyses and natural language processing of open-ended data to examine pandemic-related worries., Results: Weighted regression analyses with relevant covariates revealed group differences across specific domains of COVID-related worry. Relative to White respondents, Hispanic/Latino respondents reported more worries about social disarray, meeting basic needs, experiencing economic impacts, obtaining healthcare, and contracting COVID-19. Black respondents reported more worry about economic impacts relative to Whites. Additional group differences in worry emerged in open-ended data: Black respondents perseverated about death from COVID-19, whereas Hispanic/Latino respondents reported concerns about COVID-19 spread, and people refusing to uphold mitigation mandates. In contrast, White respondents expressed worry over compromised immune systems and economic collapse., Conclusions: Results identify significant group differences in COVID-19 related PC, suggesting that people of color faced greater threat to mental well-being at the onset of the pandemic, and may be at greater risk for downstream PC-related physical health consequences., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Identification of individual differences in drug use is warranted, as a history of use is associated with future drug problems. Such drug use is thought to disrupt inhibitory and motivation networks involved in emotion regulation (ER). Higher resting heart rate variability (HRV), a biomarker of effective inhibitory abilities, is associated with less substance (e.g., alcohol, opioid) use. Higher HRV is associated with lower perceived ER difficulties, and this link is stronger in women relative to men. Evidence suggests women might engage in drug use primarily to reduce stress, and men primarily to induce feelings of elation. Research has yet to examine associations among individuals' difficulties in ER, resting HRV, and a recent history of drug use; the current study explored this, in addition to how these associations might differ as a function of gender. Young and healthy college students ( N = 190; 88 women) completed a 5-min baseline to assess resting HRV, followed by the 36-item difficulties in ER Scale and 10-item Drug Abuse Screening Test. Higher difficulties in ER, but not resting HRV, were associated with a greater history of "low-risk" drug use in the full sample and moderation tests confirm this link was stronger in women. Moderated-mediation results confirmed an indirect association between resting HRV and drug use, mediated by self-reported difficulties among women only. A significant association between resting HRV and Difficulties in Emotion Regulation Scale (DERS) emerged only among women without a history of drug use. These results indicate that difficulties in ER are both associated with a low-risk history of drug use and underlie an indirect link between resting HRV and drug use history in women only. Among these women with a history of drug use relative to women without, there was no link between resting HRV and self-reported difficulties in ER, suggesting a disrupted inhibitory-motivational pathway. Additional work is needed to understand the psychophysiological correlates of a history of low-risk drug use in young men. These data are in line with research suggesting gender differences in the motivation to engage in recreational drug use and ER interventions might be important in women who engage in low-risk recreational drug use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kwon, Kittaneh, Gerardo, Koenig, Thayer and Williams.)

The present study tested whether cardiac vagal activity-which is known to play a vital role in social cognition and engagement-predicted the impact of faces of other ethnicity on selective attention under load. Based on the neurovisceral integration theory, we hypothesized that participants with higher resting heart rate variability (HRV) would exhibit better task performance of a target detection task in trials with face distractors of other ethnicity than participants with lower resting HRV, when cognitive resources were scarce under high load. Caucasian participants were instructed to detect a target letter among letter strings superimposed on Black or White male distractor faces under high and low perceptual load. Consistent with the prediction, under high load, HRV was positively correlated with accuracy in trials with Black distractor faces, but not in trials with White distractor faces. The current research demonstrated that individual differences in cardiac vagal tone predicted successful inhibition of an ethnicity-related distractor with limited cognitive resources, which allowed for completing goal-directed behavior more successfully., (Copyright © 2022 Elsevier B.V. All rights reserved.)

There is a continuing debate concerning "adjustments" to heart period variability [i.e., heart rate variability (HRV)] for the heart period [i.e., increases inter-beat-intervals (IBI)]. To date, such arguments have not seriously considered the impact a demographic variable, such as gender, can have on the association between HRV and the heart period. A prior meta-analysis showed women to have greater HRV compared to men despite having shorter IBI and higher heart rate (HR). Thus, it is plausible that men and women differ in the association between HRV and HR/IBI. Thus, the present study investigates the potential moderating effect of gender on the association between HRV and indices of cardiac chronotropy, including both HR and IBI. Data from 633 participants (339 women) were available for analysis. Cardiac measures were assessed during a 5-min baseline-resting period. HRV measures included the standard deviation of inter-beat-intervals, root mean square of successive differences, and autoregressive high frequency power. Moderation analyses showed gender significantly moderated the association between all HRV variables and both HR and IBI (each p < 0.05). However, results were not consistent when using recently recommended HRV variables "adjusted" for IBI. Overall, the current investigation provides data illustrating a differential association between HRV and the heart period based on gender. Substantial neurophysiological evidence support the current findings; women show greater sensitivity to acetylcholine compared to men. If women show greater sensitivity to acetylcholine, and acetylcholine increases HRV and the heart period, then the association between HRV and the heart period indeed should be stronger in women compared to men. Taken together, these data suggest that routine "adjustments" to HRV for the heart period are unjustified and problematic at best. As it relates to the application of future HRV research, it is imperative that researchers continue to consider the potential impact of gender., (© 2021. The Author(s).)

An in vitro/in silico method that determines the risk of human drug induced liver injury in relation to oral doses and blood concentrations of drugs was recently introduced. This method utilizes information on the maximal blood concentration (C max ) for a specific dose of a test compound, which can be estimated using physiologically-based pharmacokinetic modelling, and a cytotoxicity test in cultured human hepatocytes. In the present study, we analyzed if the addition of an assay that measures the inhibition of bile acid export carriers, like BSEP and/or MRP2, to the existing method improves the differentiation of hepatotoxic and non-hepatotoxic compounds. Therefore, an export assay for 5-chloromethylfluorescein diacetate (CMFDA) was established. We tested 36 compounds in a concentration-dependent manner for which the risk of hepatotoxicity for specific oral doses and the capacity to inhibit hepatocyte export carriers are known. Compared to the CTB cytotoxicity test, substantially lower EC 10 values were obtained using the CMFDA assay for several known BSEP and/or MRP2 inhibitors. To quantify if the addition of the CMFDA assay to our test system improves the overall separation of hepatotoxic from non-hepatotoxic compounds, the toxicity separation index (TSI) was calculated. We obtained a better TSI using the lower alert concentration from either the CMFDA or the CTB test (TSI: 0.886) compared to considering the CTB test alone (TSI: 0.775). In conclusion, the data show that integration of the CMFDA assay with an in vitro test battery improves the differentiation of hepatotoxic and non-hepatotoxic compounds in a set of compounds that includes bile acid export carrier inhibitors., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Higher vagally mediated heart rate variability (vmHRV), reflecting vagal activity as indexed by heart function and lower stress vulnerability, is associated with higher perceived social support. Seeking social support is an adaptive stress response, and evolutionary theories suggest that females use this strategy more than males. The current study investigated the hypothesis that higher vmHRV is related to higher perceived social support under conditions of higher, relative to lower, stress, and that this association is most prominent in females. A healthy student sample ( n  = 143; 82 males, 61 females; mean age 19.9) completed the short version of the Medical outcomes study social support survey (MOS) and the Perceived stress scale (PSS). Activity in the high frequency band of heart rate variability (HF-HRV), deducted from five-minute resting electrocardiogram (ECG) recordings, indexed vmHRV. A moderation analysis was conducted, with PSS and sex as moderators of the association between vmHRV and MOS. Statistical effects were adjusted for age, education, physical activity, body mass index (BMI), alcohol and drug use, ECG-derived respiration (EDR), and mean heart rate. Higher PSS scores moderated the association between vmHRV and MOS in females but not males. Lower PSS scores did not moderate the relation between vmHRV and MOS. This suggests that higher vmHRV is associated with higher perceived social support under conditions of higher stress in females but not males, consistent with evolution of different stress management strategies in the sexes. The results may have implications for individualized intervention strategies for increasing vmHRV and perceived social support.

Background: Tissue hypoxia is a key feature of several endemic hepatic diseases, including alcoholic and non-alcoholic fatty liver disease, and organ failure. Hypoxia imposes a severe metabolic challenge on the liver, potentially disrupting its capacity to carry out essential functions including fuel storage and the integration of lipid metabolism at the whole-body level. Mitochondrial respiratory function is understood to be critical in mediating the hepatic hypoxic response, yet the time-dependent nature of this response and the role of the respiratory chain in this remain unclear., Results: Here, we report that hepatic respiratory capacity is enhanced following short-term exposure to hypoxia (2 days, 10% O 2 ) and is associated with increased abundance of the respiratory chain supercomplex III 2 +IV and increased cardiolipin levels. Suppression of this enhanced respiratory capacity, achieved via mild inhibition of mitochondrial complex III, disrupted metabolic homeostasis. Hypoxic exposure for 2 days led to accumulation of plasma and hepatic long chain acyl-carnitines. This was observed alongside depletion of hepatic triacylglycerol species with total chain lengths of 39-53 carbons, containing palmitic, palmitoleic, stearic, and oleic acids, which are associated with de novo lipogenesis. The changes to hepatic respiratory capacity and lipid metabolism following 2 days hypoxic exposure were transient, becoming resolved after 14 days in line with systemic acclimation to hypoxia and elevated circulating haemoglobin concentrations., Conclusions: The liver maintains metabolic homeostasis in response to shorter term hypoxic exposure through transient enhancement of respiratory chain capacity and alterations to lipid metabolism. These findings may have implications in understanding and treating hepatic pathologies associated with hypoxia., (© 2021. The Author(s).)

Elevated callous-unemotional (CU) traits have been repeatedly identified in a subgroup of offenders that displays severe antisocial behavior; establishing physiological markers may help improve early identification and treatment efforts. This study examines to what extent baseline-resting heart rate (HR) and heart rate variability (HRV) can be used as markers of CU in incarcerated juvenile and adult offenders. CU traits were assessed using the Inventory of Callous-Unemotional traits. Results of the multiple hierarchical regression tests indicated that there was a small yet significant positive association between baseline HR and CU and negative association between HRV and CU in juvenile offenders with medium model effect sizes (R 2  = 0.115 for HR-CU; R 2  = 0.126 for HRV-CU). The cardiac markers were unrelated to CU in adult offenders. These findings are important because they demonstrate that impaired cardiac autonomic activity is related to CU traits in juveniles, suggesting that socioemotional processing difficulties should be considered in understanding these deficits. Future research should be conducted in large samples, under reactive and static conditions, while including cardiac covariates, to get more clarity on the interplay between biological systems and behavioral expression., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: Migraine headaches are a prevalent and burdening disorder for the public worldwide. Both traditional preventive drugs and behavioral-based interventions have been used as treatment in the prevention of migraine attacks. However, benefits of alternative interventions in patients with primary headache disorders have not yet been fully explored. The present investigation sought to examine the impact of a patient controlled music intervention (MUSIC CARE) on episodic migraine headache., Design: A sample of 20 episodic migraine patients (17 females, mean age of 42 years) was included in the pilot trial. Patients completed a pre-treatment assessment on headache severity, associated psychopathological distress (anxiety and depression) and functional impairment, and provided reports on their medication intake. During the 3-months intervention period, patients required 1-2 music sessions (based on the "U" sequence) per day with a minimum of 15 per month., Results: Following the intervention, patients reported a significant reduction in the frequency of migraine attacks (M Diff = -2.8, p = .01). Ten patients reported a 50% reduction in the frequency of migraine attacks. Additionally, there was a significant reduction in medication intake (M Diff = -2.85, p = .02), the duration of migraine attacks (M Diff = -5.45, p = .002), anxiety (M Diff = -1.65 (2.88), p = .02) and depression (M Diff = -2.45 (3.5), p = .002)., Conclusion: These data provide evidence that music intervention may significantly prevent migraine attacks. Moreover, this method is easily accessible and administered. Future well-controlled clinical trials are necessary to further explore the efficiency of the intervention., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Elevated blood pressure is a risk factor for increased cardiovascular morbidity and mortality. Decreased vagally-mediated heart rate variability has previously been prospectively linked with increased blood pressure; however, to date, no such prospective data exist regarding this relationship among Blacks., Materials and Methods: We examined this association in 387 normotensive young adults (mean age, 23 years, 52% female, 54% Black) who participated in two laboratory evaluations spanning approximately six years. Blood pressure was measured at both timepoints with a non-invasive oscillometric device and heart rate variability was assessed via bio-impedance., Results: In the total sample, heart rate variability significantly predicted systolic ( p = .022) and diastolic ( p < .001) blood pressure increases six years into the future. However, this pattern varied as a function of ethnicity and sex with the effect of heart rate variability on Time 2 systolic blood pressure only significant among White males ( p = .007). Heart rate variability was also predictive of Time 2 diastolic blood pressure in White males ( p  = .038) as well as among both White ( p  = .032) and Black ( p  = .015) females, but was not related to blood pressure among Black males., Conclusion: We report for the first time significant ethnic and sex differences in the prospective relationship between heart rate variability and blood pressure change. These findings may give clues as to the underlying mechanisms that are involved in the well-known health disparities in blood pressure and hypertension-related cardiovascular diseases.

Background: A paradoxical profile of greater elevated sympathetic vasoconstriction (increased total peripheral resistance, TPR) and increased vagally-mediated heart rate variability (HRV) -the so-called Cardiovascular Conundrum- has been reported in African Americans (AAs) both at rest and in response to orthostasis. Whereas some authors have attributed this pattern to genetic factors, others have pointed to the potential role of coping with repeated racial discrimination. Objective: To disentangle between these alternative explanations, we have examined the hemodynamic profile of another population that is likely to be exposed to episodes of discrimination, i.e., sexual minorities. Methods: The first study was conducted on a sample of AAs and European Americans (EAs) with the aim of replicating previous results on the Cardiovascular Conundrum. In the second study, lesbian, gay, and bisexual (LGB) people, matched by age and sex with heterosexual participants, underwent a hemodynamic and autonomic assessment at rest and during an emotional (in the experimental group, both LGB-related and non LGB related), and a cognitive stressor. Results: The first study confirmed a pattern of higher resting HRV, paired with higher TPR, in AAs compared to EAs. In the second study, compared to heterosexuals, the LGB group showed the Cardiovascular Conundrum pattern, characterized by greater HRV and higher TPR at baseline and a more vascular hemodynamic profile and prominent compensation deficit in response to both tasks, and particularly during the LGB-related emotional task. However, in LGB only, the vascular response was negatively correlated with perceived discrimination. Conclusion: Present preliminary results are discussed in terms of maladaptive physiological consequences of exposure to chronic stress and the chronic use of dysfunctional emotion regulation strategies such as suppression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SB declared a past publication with one of the author JT to the handling editor., (Copyright © 2021 Rosati, Williams, Juster, Thayer, Ottaviani and Baiocco.)

Vagally mediated heart rate variability (vmHRV), a measure of the parasympathetic nervous system's control over the heart, is often negatively related to maladaptive emotional outcomes. Recent work suggests that quadratic relationships involving these factors may be present; however, research has not investigated gender differences in these nonlinear functions. To address this gap, the current study tested for quadratic relationships between resting vmHRV and depression and positive affect while investigating gender differences in these relationships. Significant quadratic effects were found between resting vmHRV and reports of both depression symptoms and positive affect in women but not men. Specifically, the lowest levels of depression and the highest levels of positive affect were found at moderate vmHRV in women. These results suggest that examinations of vmHRV's nonlinear associations require the consideration of gender. Our findings are interpreted based on proposed differential neuropsychological mechanisms of vmHRV in men versus women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Spangler, Dunn, Aldao, Feeling, Free, Gillie, Vasey, Williams, Koenig and Thayer.)

African American (AA) individuals are at a greater risk for the development of cardiovascular complications, such as hypertension, compared with European Americans (EAs). Higher vagally mediated heart rate variability (HRV) is typically associated with lower blood pressure (BP) and total peripheral resistance (TPR). However, research has yet to examine the differential impact of HRV on longitudinal hemodynamic activity between AAs and EAs. We sought to rectify this in a sample of 385 normotensive youths (207 AAs, 178 EAs; mean age 23.16 ± 2.9 yr). Individuals participated in two laboratory evaluations spanning approximately 6 yr. Bioimpedance was used to assess HRV at time 1 and cardiac output at both time 1 and time 2 . Mean arterial pressure (MAP) was measured at both time points via an automated BP machine. TPR was calculated as MAP divided by cardiac output. Results showed AAs to have higher BP and higher TPR at time 2 compared with EAs, independent of several important covariates. Also, higher HRV at time 1 significantly predicted both lower TPR and BP at time 2 among EAs only; these associations were attenuated and not significant in AAs. HRV did not significantly predict cardiac output at time 2 in the full sample or split by ethnicity. Our findings highlight that AAs show TPR mediated long-term increases in BP irrespective of resting HRV, providing a physiological pathway linking AAs with a greater risk for mortality and morbidity from hypertension and potentially other cardiovascular disease. NEW & NEWSWORTHY African Americans and European Americans differ in hemodynamics underlying long-term blood pressure regulation. Over 6 yr, African Americans show total peripheral resistance-mediated increases in blood pressure compared with European Americans. Higher heart rate variability predicts lower blood pressure and total peripheral resistance 6 yr later in European Americans but not African Americans.