Mechanistic Factors Research Articles

Homogeneous Catalysis in N-Formylation/N-Methylation Utilizing Carbon Dioxide as the C1 Source.

The growing emphasis on sustainable chemistry has driven research into utilizing carbon dioxide (CO2) as a nontoxic, abundant, and cost-effective C1 building block. CO2 offers a promising avenue for direct conversion into valuable chemicals ranging from fuels to pharmaceuticals. This review focuses on the utilization of CO2 for reductive N-formylation/N-methylation reactions of various amines, providing advantages over conventional methods involving toxic CO and other methylating reagents. The approach employs readily available reductants such as silane, borane reagents, and hydrogen (H2). The discussion encompasses recent developments in transition metal and organocatalyst systems for these reactions, highlighting mechanistic interpretations and factors influencing product selectivity.

Acute ergogenic effects of repetitive maximal breath-holding maneuvers on hematological and physiological responses: a graded exercise test investigation.

Repetitive maximal breath-holds (BHs or apneas) have been noted to induce advantageous hematological and blood buffering changes. Building on this, the hypothesis was formulated that the execution of repeated maximal BH efforts might lead to subsequent enhancements in performance during a time-to-exhaustion test. This study investigated the acute effects of five static maximal breath-holding maneuvers conducted with face immersion in cold water (10°C) on subsequent graded exercise test (GET) performance. Seventeen well-trained participants completed a GET on a motorized treadmill under two randomized cross-over conditions: baseline measurement (CON) and after five repeated maximal breath-holding efforts (EXP). The GET protocol consists of incremental increases in speed until exhaustion. After the fifth breath-hold, participants in the EXP condition exhibited significant (P < 0.05) increases in hematocrit, hemoglobin concentration, red blood cell count, and muscle deoxygenation, accompanied by a reduction in blood lactate concentration (4.09 ± 2.21%, 3.9 ± 1.76%, 3.96 ± 2.1%, 81.48 ± 23.83%, and 15.22 ± 17.64%, respectively), compared to CON. During GET, the EXP condition showed a significantly (P < 0.05) delayed onset time of the second ventilatory threshold (3.14 ± 5.85%) and (P < 0.05) increased time to exhaustion (0.75 ± 1.02%). This evidence suggests that repeated maximal static breath-holding maneuvers enhance the oxygen delivery system by increasing the circulation of reserve red blood cells, heightened muscle oxygen deoxygenation, enhanced aerobic metabolism utilization, and postponing the transition from aerobic to anaerobic metabolism, implying a potential ergogenic effect. While pre-exercise breath-holding shows promise for improving time-to-exhaustion and optimizing subsequent distance running performance, further in-depth investigation is essential to fully elucidate the underlying mechanistic factors.

Influence of Anisotropic Consolidation on the Instability of Loose Granular Soils Under Undrained and Drained Loading

Previous studies, mostly experimental, have reported conflicting observations on the effect of the initial anisotropic consolidation stress ratio (η&lt;sub&gt;0&lt;/sub&gt;) on the stress ratio at the onset of instability (η&lt;sub&gt;f&lt;/sub&gt;) for drained and undrained loading that involve static liquefaction. They indicate that as η&lt;sub&gt;0&lt;/sub&gt; increases, η&lt;sub&gt;f&lt;/sub&gt; could decrease, increase, or remain invariant, albeit without providing potential mechanistic factors. In this study, the anisotropic critical state theory (ACST) is used to investigate potential factors, including compressibility, state, and fabric anisotropy, that can explain the influence of η&lt;sub&gt;0&lt;/sub&gt; on η&lt;sub&gt;f&lt;/sub&gt; under undrained and drained loading. The assessments consider numerical simulations with the ACST-based SANISAND-F model, insights from SANISAND-F based instability criteria, the instability surface concept, and available experimental observations. Our findings show that compressibility and fabric anisotropy (and its evolution) are key factors in explaining the influence of η&lt;sub&gt;0&lt;/sub&gt; on η&lt;sub&gt;f&lt;/sub&gt;. In particular, the results show that if fabric evolution is not substantial, an increase in η&lt;sub&gt;0&lt;/sub&gt; decreases η&lt;sub&gt;f&lt;/sub&gt; for materials with significant compressibility, whereas the effect of η&lt;sub&gt;0&lt;/sub&gt; in low compressibility materials is minimal. On the other hand, for materials that promote fabric evolution, the results suggest that the effect of fabric changes counteract compressibility effects, potentially increasing η&lt;sub&gt;f&lt;/sub&gt;.

Cu-Catalyzed Three-Component Alkene Carboamination: Mechanistic Insights and Rational Design to Overcome Limitations.

Herein, we report mechanistic investigations into the Cu-catalyzed three-component carboamination of alkenes with α-halo carbonyls and aryl amines via an oxocarbenium intermediate. Monitoring the reaction reveals the formation of transient atom transfer radical addition (ATRA) intermediates with both electron-neutral and deficient vinyl arenes as well as unactivated alkenes. Based on our experimental studies and density functional theory calculations, the oxocarbenium is generated through atom transfer and subsequent intramolecular substitution. Further, mechanistic factors that dictate the regioselectivity of the nucleophilic attack onto the oxocarbenium to afford the γ-amino ester, γ-iminolactone, or γ-lactone are discussed. A strategy to overcome scope limitation with respect to unactivated alkenes is developed using the mechanistic insights gained herein. Finally, we demonstrate that under modified conditions, our Cu catalyst enables the ATRA reaction between a variety of alkyl halides and vinyl arenes/α-olefins, and we present a one-pot, two-step carbofunctionalization with an array of nucleophiles through ATRA/SN2.

Ion Transfer Kinetics at the Tungsten Oxide Interface

Investigating the kinetics of interfacial ion transfer is imperative for the enhancement of electrochemical energy storage technologies, such as cation batteries. Consequently, we study the enigmatic proton transfer mechanisms that occur at solid-liquid interfaces to evaluate parameters that may modulate the optimization of battery efficiency. Utilizing electrochemical techniques, our objective is to deconvolute the mechanistic and rate-limiting factors associated with proton insertion from an acidic aqueous electrolyte into a thin film of tungsten trioxide (WO3). While WO3 has been investigated as a battery anode, the kinetics of cation insertion remain inadequately explored despite their effects on system efficiency. Through the Potentiostatic Intermittent Titration Technique (PITT), a developed application of chronoamperometry, along with Butler-Volmer equation fitting, our research endeavors to define the exchange current density and activation energy pertinent to cation insertion. The broader implications of exploring interfacial ion transfer phenomena manifest in advancing the fundamental understanding of energy storage processes.

Swelling of cellulosic fibers in aqueous systems: A Review of chemical and mechanistic factors

Swelling of cellulosic fibers in aqueous systems: A Review of chemical and mechanistic factors

EEG Ictal Power Dynamics, Function-Structure Associations, and Epilepsy Surgical Outcomes.

Postoperative seizure control in drug-resistant temporal lobe epilepsy (TLE) remains variable, and the causes for this variability are not well understood. One contributing factor could be the extensive spread of synchronized ictal activity across networks. Our study used novel quantifiable assessments from intracranial EEG (iEEG) to test this hypothesis and investigated how the spread of seizures is determined by underlying structural network topological properties. We evaluated iEEG data from 157 seizures in 27 patients with TLE: 100 seizures from 17 patients with postoperative seizure control (Engel score I) vs 57 seizures from 10 patients with unfavorable surgical outcomes (Engel score II-IV). We introduced a quantifiable method to measure seizure power dynamics within anatomical regions, refining existing seizure imaging frameworks and minimizing reliance on subjective human decision-making. Time-frequency power representations were obtained in 6 frequency bands ranging from theta to gamma. Ictal power spectrums were normalized against a baseline clip taken at least 6 hours away from ictal events. Electrodes' time-frequency power spectrums were then mapped onto individual T1-weighted MRIs and grouped based on a standard brain atlas. We compared spatiotemporal dynamics for seizures between groups with favorable and unfavorable surgical outcomes. This comparison included examining the range of activated brain regions and the spreading rate of ictal activities. We then evaluated whether regional iEEG power values were a function of fractional anisotropy (FA) from diffusion tensor imaging across regions over time. Seizures from patients with unfavorable outcomes exhibited significantly higher maximum activation sizes in various frequency bands. Notably, we provided quantifiable evidence that in seizures associated with unfavorable surgical outcomes, the spread of beta-band power across brain regions is significantly faster, detectable as early as the first second after seizure onset. There was a significant correlation between beta power during seizures and FA in the corresponding areas, particularly in the unfavorable outcome group. Our findings further suggest that integrating structural and functional features could improve the prediction of epilepsy surgical outcomes. Our findings suggest that ictal iEEG power dynamics and the structural-functional relationship are mechanistic factors associated with surgical outcomes in TLE.

Microstructural and mechanistic insights into the Tension–Compression asymmetry of rapidly solidified Fe–Cr alloys: A phase field and strain gradient plasticity study

Rapid solidification in Additively Manufactured (AM) metallic materials results in the development of significant microscale internal stresses, which are attributed to the printing induced dislocation substructures. The resulting backstress due to the Geometrically Necessary Dislocations (GNDs) is responsible for the observed Tension–Compression (TC) asymmetry. We propose a combined Phase Field (PF)-Strain Gradient J2 Plasticity (SGP) framework to investigate the TC asymmetry in such microstructures. The proposed PF model is an extension of Kobayashi’s dendritic growth framework, modified to account for the orientation-based anisotropy and multi-grain interaction effects. The SGP model has consideration for anisotropic temperature-dependent elasticity, dislocation strengthening, solid solution strengthening, along with GND-induced directional backstress. This model is employed to predict the solute segregation, dislocation substructure and backstress development during solidification and the post-solidification anisotropic mechanical properties in terms of the TC asymmetry of rapidly solidified Fe–Cr alloys. It is observed that higher thermal gradients (and hence, cooling rates) lead to higher magnitudes of solute segregation, GND density, and backstress. This also correlates with a corresponding increase in the predicted TC asymmetry. The results presented in this study point to the microstructural factors, such as dislocation substructure and solute segregation, and mechanistic factors, such as backstress, which may contribute to the development of TC asymmetry in rapidly solidified microstructures.

The role of victimisation and sleep quality in self-harm and depression among sexual minority adolescents. A prospective cohort study.

Sexual minority adolescents (SMA) have a disproportionately high prevalence of victimisation, self-harm, and depressed mood, relative to the general population. Yet, the contributing and mechanistic factors are unclear. We aim to explore the directional relationship between victimisation and self-harm and depressed mood, with poor sleep quality as a possible mediator. A secondary data analysis was conducted using a nationally representative birth cohort in the United Kingdom, where participants self-identified as sexual minority (N = 1922, aged 11-13, 67.1% female) and their parents completed questionnaires and interviews when the participants were aged 11, 14 and 17. Logistic and linear regression were used to test whether victimisation prospectively predicted self-harm and depressed mood with mediation analyses conducted to assess if sleep onset latency and nocturnal awakening mediated their relationships. After adjusting for demographic factors and baseline self-harm and depressed mood, victimisation at age 11 significantly predicted self-harm (OR = 1.40, p < .01) and depressed mood (B = 0.024, SE = 0.01, p < .05) at age 17. In the mediation analyses, frequent nocturnal awakening at age 14, but not sleep onset latency, significantly mediated the effect of victimisation at age 11 on self-harm (indirect effect B = 0.008, SE = 0.004, 95%CI = 0.001-0.017) and depressed mood (indirect effect B = 0.005, SE = 0.002 95%CI = 0.001-0.010) at age 17. Our findings supported that victimisation contributed to negative mental health among SMA. Poor sleep quality could be an indicator of maladjustment with victimisation, which further increased vulnerability to negative mental health. Victimisation and sleep quality could be important assessment targets in mental health campaign among sexual minority adolescents.

The causes and consequences of trained immunity in myeloid cells.

Conventionally, immunity in humans has been classified as innate and adaptive, with the concept that only the latter type has an immunological memory/recall response against specific antigens or pathogens. Recently, a new concept of trained immunity (a.k.a. innate memory response) has emerged. According to this concept, innate immune cells can exhibit enhanced responsiveness to subsequent challenges, after initial stimulation with antigen/pathogen. Thus, trained immunity enables the innate immune cells to respond robustly and non-specifically through exposure or re-exposure to antigens/infections or vaccines, providing enhanced resistance to unrelated pathogens or reduced infection severity. For example, individuals vaccinated with BCG to protect against tuberculosis were also protected from malaria and SARS-CoV-2 infections. Epigenetic modifications such as histone acetylation and metabolic reprogramming (e.g. shift towards glycolysis) and their inter-linked regulations are the key factors underpinning the immune activation of trained cells. The integrated metabolic and epigenetic rewiring generates sufficient metabolic intermediates, which is crucial to meet the energy demand required to produce proinflammatory and antimicrobial responses by the trained cells. These factors also determine the efficacy and durability of trained immunity. Importantly, the signaling pathways and regulatory molecules of trained immunity can be harnessed as potential targets for developing novel intervention strategies, such as better vaccines and immunotherapies against infectious (e.g., sepsis) and non-infectious (e.g., cancer) diseases. However, aberrant inflammation caused by inappropriate onset of trained immunity can lead to severe autoimmune pathological consequences, (e.g., systemic sclerosis and granulomatosis). In this review, we provide an overview of conventional innate and adaptive immunity and summarize various mechanistic factors associated with the onset and regulation of trained immunity, focusing on immunologic, metabolic, and epigenetic changes in myeloid cells. This review underscores the transformative potential of trained immunity in immunology, paving the way for developing novel therapeutic strategies for various infectious and non-infectious diseases that leverage innate immune memory.

The role of working conditions in educational differences in all-cause and ischemic heart disease mortality among Swedish men.

This study aims to investigate the extent to which low job control and heavy physical workload in middle age explain educational differences in all-cause and ischemic heart disease (IHD) mortality while accounting for important confounding factors. The study is based on a register-linked cohort of men who were conscripted into the Swedish military at around the age of 18 in 1969/1970 and were alive and registered in Sweden in 2005 (N=46 565). Cox proportional hazards regression models were built to estimate educational differences in all-cause and IHD mortality and the extent to which this was explained by physical workload and job control around age 55 by calculating the reduction in hazard ratio (HR) after adjustments. Indicators of health, health behavior, and other factors measured during conscription were accounted for. We found a clear educational gradient for all-cause and IHD mortality (HR 2.07 and 2.47, respectively, for the lowest compared to the highest education level). A substantial part was explained by the differential distribution of the confounding factors. However, work-related factors, especially high physical workload, also played important explanatory roles. Even after accounting for earlier life factors, low job control and especially high physical workload seem to be important mechanistic factors in explaining educational inequalities in all-cause and IHD mortality. It is therefore important to find ways to reduce physical workload and increase job control in order to decrease inequalities in mortality.

Mechanisms of Waterflood Inefficiency: Analysis of Geological, Petrophysical and Reservoir History, a Field Case Study of FWU (East Section)

The petroleum reservoir represents a complex heterogeneous system that requires thorough characterization prior to the implementation of any incremental recovery technique. One of the most commonly utilized and successful secondary recovery techniques is waterflooding. However, a lack of sufficient investigation into the inherent behavior and characteristics of the reservoir formation in situ can result in failure or suboptimal performance of waterflood operations. Therefore, a comprehensive understanding of the geological history, static and dynamic reservoir characteristics, and petrophysical data is essential for analyzing the mechanisms and causes of waterflood inefficiency and failure. In this study, waterflood inefficiency was observed in the Morrow B reservoir located in the Farnsworth Unit, situated in the northwestern shelf of the Anadarko Basin, Texas. To assess the potential mechanisms behind the inefficiency of waterflooding in the east half, geological, petrophysical, and reservoir engineering data, along with historical information, were integrated, reviewed, and analyzed. The integration and analysis of these datasets revealed that several factors contributed to the waterflood inefficiency. Firstly, the presence of abundant dispersed authigenic clays within the reservoir, worsened by low reservoir quality and high heterogeneity, led to unfavorable conditions for waterflood operations. The use of freshwater for flooding exacerbated the adverse effects of sensitive and migratory clays, further hampering the effectiveness of the waterflood. In addition to these factors, several reservoir engineering issues played a significant role in the inefficiency of waterflooding. These issues included inadequate perforation strategies due to the absence of detailed hydraulic flow units (HFUs) and rock typing, random placement of injectors, and uncontrolled injected fresh water. These external controlling parameters further contributed to the overall inefficiencies observed during waterflood operations in the east half of the reservoir. A detailed understanding of the mechanistic factors of inefficient waterflood operation will provide adequate insights into the development of the improved recovery technique for the field.

Comparative Analysis of the Two Innovative Vaccines

Multiple sclerosis (MS), one of the most prevalent autoimmune diseases, poses a significant challenge for therapeutic advancements. Among these, antigen-specific therapies (ASTs) utilizing therapeutic vaccines have emerged as highly promising. Designed to induce antigen-specific tolerance without compromising the overall immune system, these vaccines offer a glimmer of hope for MS patients, despite many still being in the preclinical trial phase. This research provides an elaborate comparison of two distinct vaccine types: m1Ψ mRNA vaccines and ROS-scavenging CeNP MSN vaccines. As AST vaccines targeting MS, they exhibit notable similarities across various facets, ranging from superficial aspects such as the models employed to evaluate therapeutic effects to deeper considerations like their anti-inflammatory characteristics and key mechanistic factors. Beneath these similarities, significant differences are identified and analyzed within this article. Additionally, the advantages, disadvantages, and noteworthy features of each vaccine are thoroughly compared, accompanied by corresponding suggestions for improvement. Through this comparative analysis of the two innovative vaccines, the paper aims to enhance readers' comprehension of MS treatments. By offering humble insights, it aspires to make a positive impact on related research, ultimately contributing to the advancement of MS therapeutic approaches.

Effects of Multicomponent Home-Based Intervention on Muscle Composition, Fitness, and Bone Density After Hip Fracture.

Mechanistic factors on the pathway to improving independent ambulatory ability among hip fracture patients by a multicomponent home-based physical therapy intervention that emphasized aerobic, strength, balance, and functional training are unknown. The aim of this study was to determine the effects of 2 different home-based physical therapy programs on muscle area and attenuation (reflects muscle density) of the lower extremities, bone mineral density (BMD), and aerobic capacity. Randomized controlled trial of home-based 16 weeks of strength, endurance, balance, and function exercises (PUSH, n = 19) compared to seated active range-of-motion exercises and transcutaneous electrical neurostimulation (PULSE, n = 18) in community-dwelling adults >60 years of age within 26 weeks of hip fracture. In PUSH and PULSE groups combined, the fractured leg had lower muscle area and muscle attenuation and higher subcutaneous fat than the nonfractured leg (p < .001) at baseline. At 16 weeks, mean muscle area of the fractured leg was higher in the PUSH than PULSE group (p = .04). Changes in muscle area were not significantly different when compared to the comparative PULSE group. There was a clinically relevant difference in change in femoral neck BMD between groups (p = .05) that showed an increase after PULSE and decrease after PUSH. There were generally no between-group differences in mean VO2peak tests at 16-week follow-up, except the PUSH group reached a higher max incline (p = .04). The treatment effects of a multicomponent home-based physical therapy intervention on muscle composition, BMD, and aerobic capacity were not significantly different than an active control intervention in older adults recovering from hip fracture. ClinicalTrials.gov Identifier: NCT01783704.

Effective engineering of a ketoreductase for the biocatalytic synthesis of an ipatasertib precursor

Semi-rational enzyme engineering is a powerful method to develop industrial biocatalysts. Profiting from advances in molecular biology and bioinformatics, semi-rational approaches can effectively accelerate enzyme engineering campaigns. Here, we present the optimization of a ketoreductase from Sporidiobolus salmonicolor for the chemo-enzymatic synthesis of ipatasertib, a potent protein kinase B inhibitor. Harnessing the power of mutational scanning and structure-guided rational design, we created a 10-amino acid substituted variant exhibiting a 64-fold higher apparent kcat and improved robustness under process conditions compared to the wild-type enzyme. In addition, the benefit of algorithm-aided enzyme engineering was studied to derive correlations in protein sequence-function data, and it was found that the applied Gaussian processes allowed us to reduce enzyme library size. The final scalable and high performing biocatalytic process yielded the alcohol intermediate with ≥ 98% conversion and a diastereomeric excess of 99.7% (R,R-trans) from 100 g L−1 ketone after 30 h. Modelling and kinetic studies shed light on the mechanistic factors governing the improved reaction outcome, with mutations T134V, A238K, M242W and Q245S exerting the most beneficial effect on reduction activity towards the target ketone.

Experimental study of mechanistic factors influencing solvent-driven fractional crystallization of calcium sulfate

To advance dimethyl ether-driven fractional crystallization (DME-FC), a more sustainable method of water treatment and mineral recovery, a range of chemical equilibria were measured. These include varying concentrations of miscible organic solvents (MOS) used to experimentally measure the solvent-induced solid-liquid equilibrium (SLE) of calcium sulfate (CaSO4) in water. Seven MOS, including dimethyl ether (DME), acetonitrile (MeCN), 1,4-dioxane, tetrahydrofuran (THF), acetone, ethanol, and diethylamine, were screened to establish trends associated with molecular volume, functional groups, and physical properties. The effect of MOS on CaSO4 removal differed at concentrations <0.15 mol fraction MOS; MOS with greater molecular volume (THF, 1,4-dioxane, and diethylamine) induced greater CaSO4 precipitation on a per mole basis. The solvent-induced SLE for all MOS converged between 0.15 and 0.2 mol fraction MOS, reaching a CaSO4 concentration consistent with a water to MOS hydration ratio of 5:1 to 6:1, which may correspond to the solvent generating a solution-based pseudo-clathrate structure with continuity within the solution. Solution pseudo-clathrate structures provide a mechanistic basis for DME-FC.

Predicting Clinical Pharmacokinetics/Pharmacodynamics and Impact of Organ Impairment on siRNA-Based Therapeutics Using a Mechanistic Physiologically-Based Pharmacokinetic-Pharmacodynamic Model.

Approved and emerging siRNA therapeutics are primarily designed for targeted delivery to liver where the therapeutic gene silencing effects occurs. Impairment of hepatic/renal function and its impact on siRNA pharmacokinetics/pharmacodynamics (PKs/PDs) are yet to be mechanistically evaluated to describe the unanticipated clinical observations for this novel modality. We developed pathophysiologically relevant models for organ impairment within a physiologically-based PK-PD (PBPK-PD) modeling framework focusing on modality-specific mechanistic factors to evaluate impact on siRNA PKs and PDs. PBPK-PD models for two US Food and Drug Administration (FDA) approved siRNAs inclisiran and vutrisiran were developed as case studies leveraging available tissue-specific data and translated to humans. Key determinants of the clinical PK and PD of N-acetylgalactosamine conjugated siRNAs (GalNAc-siRNAs) with varying sequences were also identified to inform effective clinical translation strategies for emerging GalNAc-siRNA candidates. A 30-70% reduction in hepatic asialoglycoprotein receptors concentrations still allowed for sufficient amount of free cytoplasmic siRNA for RISC-loading to produce PD effects comparable in extent and duration to normal liver function. This included severe hepatic impairment for which no clinical data are available. Inclusion of other modality agnostic physiological changes relevant to organ impairment did not alter the findings. Changes in renal physiologies, including changes in GFR across various degrees of impairment, well predicted minimal changes in PD for inclisiran and vutrisiran. This work provides a quantitative mechanistic framework and insights on modality-specific factors that drive clinical translation and patient/disease-related factors that impact specific dosing considerations and clinical outcomes to help accelerate the optimal development of siRNA therapeutics.

HEARING AND VISION LOSS: EPIDEMIOLOGIC AND INTERVENTION IMPLICATIONS FOR SOCIAL ISOLATION, LONELINESS, AND MOOD DISORDERS

Abstract This session will discuss hearing loss and vision impairment as modifiable risk factors for social isolation, loneliness, and mood disorders from both epidemiologic and intervention perspectives. Prevalence of hearing and vision loss is high; two-thirds of older adults have hearing loss and over one-quarter have vision impairment. Hearing loss and vision impairment have been linked to poor cognitive and physical health but remain understudied in the context of social and mental health in large, population-based studies. Research gaps remain in measurement (findings typically based on subjective assessments) and generalizability. This session will investigate associations between objectively measured hearing, vision, and dual sensory loss on social isolation and mood disorders using a sample nationally representative of older adults in the US. This session will also describe potential mechanistic and environmental factors, such as fatigue and exclusion of hearing loss and vision impairment in health care settings that may explain observed associations. Whether treatment of hearing loss and vision impairment is an effective intervention for improving social and mental health is unknown. We will conclude by presenting findings from a randomized controlled trial designed to test whether a hearing intervention consisting of provision of hearing aids and related technologies, counseling, and education could reduce cognitive decline in older adults with untreated hearing loss. We focus on the effect of hearing intervention on social isolation and loneliness, both pre-specified outcomes of this trial. This is a Loneliness and Social Isolation Interest Group Sponsored Symposium. This is a collaborative symposium between the Loneliness and Social Isolation and Sensory Health Interest Groups.

Developing a theory-driven framework for a web-based intervention to improve transition in childhood cancer survivors: a protocol of realist synthesis

Backgrounds and purposeChildhood cancer survivors (CCSs) who transition through adolescence and enter young adulthood may suffer psychological, cognitive, social, fertility, and sexual issues and concerns. There is an urgent need...

Mechanistic, participant, and movement-related factors that contribute to low-flow-mediated constriction.

Endothelial function is commonly determined via the ultrasound-based flow-mediated dilation (FMD) technique which assesses arterial dilation in response to a hyperemia response following distal cuff occlusion. However, the low-flow-mediated constriction (L-FMC) response during cuff-induced ischemia is often overlooked. L-FMC provides unique information regarding endothelial function, but vascular researchers may be unclear on what this metric adds. Therefore, the objective of this review was to examine the mechanistic determinants and participant-level factors of L-FMC. Existing mechanistic studies have demonstrated that vasoreactivity to low flow may be mediated via non-nitric oxide vasodilators (i.e., endothelial hyperpolarizing factors and/or prostaglandins), inflammatory markers, and enhancement of vasoconstriction via endothelin-1. In general, participant-level factors such as aging and presence of cardiovascular conditions generally are associated with attenuated L-FMC responses. However, the influence of sex on L-FMC is unclear with divergent results between L-FMC in upper versus lower limb vessels. The ability of aerobic exercise to augment L-FMC (i.e., make more negative) is well supported, but there is a major gap in the literature concerning the mechanistic underpinnings of this observation. This review summarizes that while larger L-FMC responses are generally healthy, the impact of interventions to augment/attenuate L-FMC has not included mechanistic measures that would provide insight into non-nitric oxide-based endothelial function. Clarifications to terminology and areas of further inquiry as it relates to the specific pharmacological, individual-level factors, and lifestyle behaviors that impact L-FMC are highlighted. A greater integration of mechanistic work alongside applied lifestyle interventions is required to better understand endothelial cell function to reductions in local blood flow.