Studies In Human Subjects Research Articles

Maternal high-cholesterol diet negatively programs offspring bone development and downregulates hedgehog signaling in osteoblasts

Cholesterol is one of the essential intrauterine factors required for fetal growth and development. Maternal high cholesterol levels are known to be detrimental for offspring health. However, its long-term effect on offspring skeletal development remains to be elucidated. We performed our studies in two strains of mice (C57BL6/J and Swiss Albino) and human subjects (65 mother–female newborn dyads) to understand the regulation of offspring skeletal growth by maternal high cholesterol. We found that mice offspring from high-cholesterol-fed dams had low birth weight, smaller body length, and delayed skeletal ossification at the E18.5 embryonic stage. Moreover, we observed that the offspring did not recover from the reduced skeletal mass and exhibited a low bone mass phenotype throughout their life. We attributed this effect to reduced osteoblast cell activity with a concomitant increase in the osteoclast cell population. Our investigation of the molecular mechanism revealed that offspring from high-cholesterol-fed dams had a decrease in the expression of ligands and proteins involved in hedgehog signaling. Further, our cross-sectional study of human subjects showed a significant inverse correlation between maternal blood cholesterol levels and cord blood bone formation markers. Moreover, the bone formation markers were significantly lower in the female newborns of hypercholesterolemic mothers compared with mothers with normal cholesterolemic levels. Together, our results suggest that maternal high cholesterol levels deleteriously program offspring bone mass and bone quality and downregulate the hedgehog signaling pathway in their osteoblasts.

Oxidative stress-mediated memory impairment during aging and its therapeutic intervention by natural bioactive compounds.

Aging and associated neurodegenerative diseases are accompanied by the decline of several brain functions including cognitive abilities. Progressive deleterious changes at biochemical and physiological levels lead to the generation of oxidative stress, accumulation of protein aggregates, mitochondrial dysfunctions, loss of synaptic connections, and ultimately neurodegeneration and cognitive decline during aging. Oxidative stress that arises due to an imbalance between the rates of production and elimination of free radicles is the key factor for age-associated neurodegeneration and cognitive decline. Due to high energy demand, the brain is more susceptible to free radicals-mediated damages as they oxidize lipids, proteins, and nucleic acids, thereby causing an imbalance in the homeostasis of the aging brain. Animal, as well as human subject studies, showed that with almost no or few side effects, dietary interventions and plant-derived bioactive compounds could be beneficial to recovering the memory or delaying the onset of memory impairment. As the plant-derived bioactive compounds have antioxidative properties, several of them were used to recover the oxidative stress-mediated changes in the aging brain. In the present article, we review different aspects of oxidative stress-mediated cognitive change during aging and its therapeutic intervention by natural bioactive compounds.

A novel self-expanding shape memory polymer coil for intracranial aneurysm embolization: 1 year follow-up in Chile

BackgroundAneurysm recurrence remains a challenge when coiling cerebral aneurysms. Development of next generation coils has focused on accelerating thrombus maturation and increasing coil packing density. Ultra low density shape memory...

Bioequivalence of a biosimilar enoxaparin (Cloti-Xa™) and its innovator (Clexane® ): A single-dose, randomized, double-blind, two-period, two-treatment, two-sequence, crossover, balanced study in healthy human subjects.

Currently, several biosimilars of low‐molecular‐weight heparins (LMWHs) with differing potencies are being developed and marketed globally. Thus, it is important that the potency of each biosimilar LMWH be compared with its innovator's molecule. The present study aimed to determine the bioequivalence of biosimilar (Cloti‐Xa™) and innovator (Clexane®) formulations of enoxaparin sodium (40 mg/0.4 ml) in healthy human volunteers. It was conducted as a single‐dose, randomized, double‐blind, two‐period, two‐treatment, two‐sequence, crossover, balanced, pharmacodynamic study (NCT05265676). The participants were sequentially and randomly administered subcutaneous injections of Cloti‐Xa™ (test) and Clexane® (reference), separated by a one‐week washout period. To assess the Anti‐Xa & Anti‐IIa activities, tissue factor pathway inhibitor (TFPI) release and activated partial thromboplastin time (aPTT), blood samples were obtained at various timepoints upto 24 h after the drug administration. Bioequivalence was concluded if the two‐sided 90% CI for the test to reference ratio of the population is within 80%–125% for each of the Ln‐transformed values of A max and AUECt for Anti‐Xa and Anti‐IIa. TFPI and aPTT data were submitted as supportive evidence. The study sample consisted of twenty‐four male participants. The 90% CIs of A max and AUECt for Anti‐Xa activity were 105.50%–113.90% and 103.97%–112.08%, and for Anti‐IIa activity were 106.56%–117.90% and 107.35%–124.86%, respectively. In addition, the 90% CI of the ratio of Anti‐Xa/Anti‐IIa activity falls within the acceptance criteria. TFPI and aPTT profiles were similar for both products. No serious adverse events were observed during the study. Conclusively, the results showed that Cloti‐Xa™ and Clexane® are bioequivalent and well‐tolerated.

Partner-Aware Algorithms in Decentralized Cooperative Bandit Teams

When humans collaborate with each other, they often make decisions by observing others and considering the consequences that their actions may have on the entire team, instead of greedily doing what is best for just themselves. We would like our AI agents to effectively collaborate in a similar way by capturing a model of their partners. In this work, we propose and analyze a decentralized Multi-Armed Bandit (MAB) problem with coupled rewards as an abstraction of more general multi-agent collaboration. We demonstrate that naive extensions of single-agent optimal MAB algorithms fail when applied for decentralized bandit teams. Instead, we propose a Partner-Aware strategy for joint sequential decision-making that extends the well-known single-agent Upper Confidence Bound algorithm. We analytically show that our proposed strategy achieves logarithmic regret, and provide extensive experiments involving human-AI and human-robot collaboration to validate our theoretical findings. Our results show that the proposed partner-aware strategy outperforms other known methods, and our human subject studies suggest humans prefer to collaborate with AI agents implementing our partner-aware strategy.

Most Pathways Can Be Related to the Pathogenesis of Alzheimer’s Disease

Alzheimer’s disease (AD) is a complex neurodegenerative disorder. The relative contribution of the numerous underlying functional mechanisms is poorly understood. To comprehensively understand the context and distribution of pathways that contribute to AD, we performed text-mining to generate an exhaustive, systematic assessment of the breadth and diversity of biological pathways within a corpus of 206,324 dementia publication abstracts. A total of 91% (325/335) of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways have publications containing an association via at least 5 studies, while 63% of pathway terms have at least 50 studies providing a clear association with AD. Despite major technological advances, the same set of top-ranked pathways have been consistently related to AD for 30 years, including AD, immune system, metabolic pathways, cholinergic synapse, long-term depression, proteasome, diabetes, cancer, and chemokine signaling. AD pathways studied appear biased: animal model and human subject studies prioritize different AD pathways. Surprisingly, human genetic discoveries and drug targeting are not enriched in the most frequently studied pathways. Our findings suggest that not only is this disorder incredibly complex, but that its functional reach is also nearly global. As a consequence of our study, research results can now be assessed in the context of the wider AD literature, supporting the design of drug therapies that target a broader range of mechanisms. The results of this study can be explored at www.adpathways.org.

Construction of sublingual trilaminated Eszopiclone fast dissolving film for the treatment of Insomnia: Formulation, characterization and In vivo clinical comparative pharmacokinetic study in healthy human subjects.

Disturbed sleep can cause to m health problems such as cognitive impairment, depressed mood, and negative effects on cardiovascular, endocrine, and immune function. This study formulates and optimizes Eszopiclone trilaminate fast dissolving film. Prepared Eszopiclone trilaminate fast dissolving film (Eszopiclone TFDF) was characterized by disintegration time, drug release, tensile strength (TS), percentage elongation (EB%), folding endurance, taste masking test, and in vitro dissolution test. The selected formulas were F2 (0.5% xanthan gum, 10% propylene glycol), F4 (3% sodium alginate, 10% propylene glycol) and F6 (1.5% pullulan, 10% propylene glycol) were subjected to in vivo study compared to conventional Lunesta® tablet. The results indicated that disintegration time was in the range of 940 m. Drug release was found to be in the field of 78.51%-99.99%, while TS values and EB% differed from 11.12 to 25.74 (MPa) and 25.38%-36.43%, respectively. The folding endurance went between 200 and 300 times. All formulas exhibited acceptable uniformity content, surface pH, film thickness, and a good taste feeling. F4 had the highest Cmax (39.741 ± 6.785-μg/l) and lower Tmax (1.063 hr) among other formulas and conventional tablets. Therefore, FDFs' technology could increase the therapeutic effect of Eszopiclone.

The Effects of Vinegar/Acetic Acid Intake on Appetite Measures and Energy Consumption: A Systematic Literature Review

ObjectivesResearch suggests the active ingredient in vinegar, acetic acid, may reduce appetite, thereby reducing energy consumption. This systematic review aimed to assess the effect of vinegar or acetic acid on appetite and subsequent food intake in humans in the published literature. MethodsAll human subject studies, regardless of age or health status. A search using MedLine (Ovid), PubMed, CINAHL Plus, Web of Science, and Cochrane Library between January to April 2021 resulted in 12 papers. One of the publications by Darzi et al. combined the findings of two independent studies and was therefore treated as two separate studies in this review (study 1” and “Darzi study 2). Outcomes included appetite, measured using an appetite rating scale or visual analog scale, satiation, measured as food intake of intervention meal, and satiety, measured as the amount of food intake following vinegar or acetic acid consumption. ResultsSeven short-term studies were crossover randomized controlled trials (RCT) investigating the effect of a single vinegar exposure with satiety or appetite as the primary outcome. Six long-term studies were parallel-group RCTs with repeated vinegar exposure, ranging from 4 to 12 weeks. These studies compared energy intake before and after the vinegar/acetic acid intervention. The short-term interventions indicated that vinegar containing at least 24.6 mmol acetic acid when consumed alongside a meal containing solid foods, acutely suppressed appetite up to 120 minutes postprandially, and ad libitum food intake three- and 24-hours after vinegar consumption. However, results from the long-term studies found no effect on appetite suppression. ConclusionsOverall, four of the six short-term studies reported that vinegar suppressed appetite, while none of the long-term studies were able to reproduce these results. Further research is needed to determine whether oral vinegar consumption may result in long-term appetite reduction, decrease energy intake, and potentially aid in weight loss. Funding SourcesNot applicable.

Review of potential psychedelic treatments for PTSD

Post-traumatic stress disorder (PTSD) is a debilitating mental illness with limited treatment options and a high treatment dropout rate. Psychedelics, often in combination with psychotherapy, are now under investigation as a potential treatment option for a variety of psychiatric conditions including PTSD. This paper reviews the proposed mechanism of action for 3,4-Methylenedioxymethamphetamine (MDMA) and classical psychedelics such as psilocybin in treating PTSD, along with available clinical evidence, safety and side effects. MDMA-assisted psychotherapy is in FDA phase III clinical trials for PTSD and is purported to work by way of increased empathy and decreased amygdala activation during the therapeutic encounter and trauma processing. Classical psychedelics may create change by a subjective transformative experience along with an observable process of brain network alterations, though these substances have not been clinically studied in the context PTSD. In recent human-subject studies MDMA-assisted therapy resulted in significant improvement in PTSD symptoms with a good safety and side effect profile. There is not yet direct clinical evidence for classical psychedelics in treating PTSD, but the evidence supports such a trial. The studies to date have been relatively small, and participants are wellscreened for potential co-morbidities which could increase the risks of psychedelic treatment. Nonetheless, the data is promising for psychedelic-assisted treatment to become a much-needed treatment option for PTSD.

A touch-based multimodal and cryptographic bio-human–machine interface

The awareness of individuals’ biological status is critical for creating interactive and adaptive environments that can actively assist the users to achieve optimal outcomes. Accordingly, specialized human–machine interfaces—equipped with bioperception and interpretation capabilities—are required. To this end, we devised a multimodal cryptographic bio-human–machine interface (CB-HMI), which seamlessly translates the user’s touch-based entries into encrypted biochemical, biophysical, and biometric indices. As its central component, the CB-HMI features thin hydrogel-coated chemical sensors and inference algorithms to noninvasively and inconspicuously acquire biochemical indices such as circulating molecules that partition onto the skin (here, ethanol and acetaminophen). Additionally, the CB-HMI hosts physical sensors and associated algorithms to simultaneously acquire the user’s heart rate, blood oxygen level, and fingerprint minutiae pattern. Supported by human subject studies, we demonstrated the CB-HMI’s capability in terms of acquiring physiologically relevant readouts of target bioindices, as well as user-identifying and biometrically encrypting/decrypting these indices in situ (leveraging the fingerprint feature). By upgrading the common surrounding objects with the CB-HMI, we created interactive solutions for driving safety and medication use. Specifically, we demonstrated a vehicle-activation system and a medication-dispensing system, where the integrated CB-HMI uniquely enabled user bioauthentication (on the basis of the user’s biological state and identity) prior to rendering the intended services. Harnessing the levels of bioperception achieved by the CB-HMI and other intelligent HMIs, we can equip our surroundings with a comprehensive and deep awareness of individuals’ psychophysiological state and needs.

Beyond HIV outbreaks: protocol, rationale and implementation of a prospective study quantifying the benefit of incorporating viral sequence clustering analysis into routine public health interventions

IntroductionHIV continues to have great impact on millions of lives. Novel methods are needed to disrupt HIV transmission networks. In the USA, public health departments routinely conduct contact tracing and...

Addressing the social barriers to green stormwater infrastructure in residential areas from a socio-ecological perspective

Despite the well-recognized financial limitations, social aspects can also impact the adoption of green stormwater infrastructure (GSI) as it is ingrained in the socio-ecological system we live in. Thus, this work focuses on gaining an understanding of the public's perceptions of GSI by considering cognitive biases that hinder its adoption. This work is composed of two forms of human-subject studies, including an online-based survey and a series of semi-structured interviews. The survey (n = 510) was conducted to gauge public opinions toward GSI, whereas the interviews with representatives of major local regulatory agencies were to learn about the logistics for GSI implementation in Mecklenburg County, NC. The results were interpreted using the theory of planned behavior of rational actors. Statistical results showed a weak interpretation through this theory to explain the survey participants' intention to adopt GSI measures. This could suggest that the incorporation of irrationality, such as cognitive biases, could further enhance the predictability of the theory. At the same time, an inconsistency between the findings from the survey and the interviews was identified: most survey participants showed an overall uniform positive attitude, intention, and behavior regarding GSI practice adoption, whereas the interviewed experts all suggested a wide diversity on such terms. Suggestions were made based on the findings for better policy-making on public engagement for local regulatory agencies. This research aims to help local stormwater management authorities explore shortcomings in current stakeholder engagement plans to gain sustainable support for GSI implementation in urbanized areas.

Using data about accepted and rejected articles in the Journal of Dental Education to increase authors' chances of article acceptance.

The purpose of our study was to identify trends and compare keywords from titles and methods among articles accepted and rejected for publication in the Journal of Dental Education (JDE). The titles and abstracts of JDE articles submitted between 2010 and 2020 were extracted. We studied the frequencies of keywords in the title and abstracts and used simple descriptive data to present the information. Additionally, keywords from the methods section from JDE articles reviewed between 2015 and 2020 were analyzed by acceptance versus rejection. University of Michigan Medical School's committee on human subject studies provided an exemption (HUM00196884). Articles with the terms "knowledge," "skills," and "attitudes" appear, separately or together, in the titles of submissions to JDE 510 times during the study period-190 in accepted articles and 320 in rejected articles (an acceptance rate of 37.3%). The term "clinical" is in the title of 337 articles submitted to JDE-195 accepted and 142 rejected (an acceptance rate of 57.9%). However, the term "pre-clinical" is associated with only 56 articles in the last 10 years-36 accepts and 20 rejects (64.3%). Studies with cross-sectional study design were accepted at a rate of 72.0% and manuscripts with cohort study designs were accepted at 53.3%. Systematic reviews were accepted at 44.4%, surveys were accepted at 36.7%, meta analyses were accepted at 28%. Questionnaires were accepted at 14%. Higher quality study designs were more likely to be accepted for publication. Studies including a randomizing process and studies that were longitudinal in nature were more likely to be accepted for publication.

Body-Worn IMU-Based Human Hip and Knee Kinematics Estimation during Treadmill Walking.

Traditionally, inertial measurement unit (IMU)-based human joint angle estimation techniques are evaluated for general human motion where human joints explore all of their degrees of freedom. Pure human walking, in contrast, limits the motion of human joints and may lead to unobservability conditions that confound magnetometer-free IMU-based methods. This work explores the unobservability conditions emergent during human walking and expands upon a previous IMU-based method for the human knee to also estimate human hip angles relative to an assumed vertical datum. The proposed method is evaluated () in a human subject study and compared against an optical motion capture system. Accuracy of human knee flexion/extension angle (7.87 absolute root mean square error (RMSE)), hip flexion/extension angle (3.70 relative RMSE), and hip abduction/adduction angle (4.56 relative RMSE) during walking are similar to current state-of-the-art self-calibrating IMU methods that use magnetometers. Larger errors of hip internal/external rotation angle (6.27 relative RMSE) are driven by IMU heading drift characteristic of magnetometer-free approaches and non-hinge kinematics of the hip during gait, amongst other error sources. One of these sources of error, soft tissue perturbations during gait, is explored further in the context of knee angle estimation and it was observed that the IMU method may overestimate the angle during stance and underestimate the angle during swing. The presented method and results provide a novel combination of observability considerations, heuristic correction methods, and validation techniques to magnetic-blind, kinematic-only IMU-based skeletal pose estimation during human tasks with degenerate kinematics (e.g., straight line walking).

The photobiology of the human circadian clock

SignificanceThe function of our biological clock is dependent on environmental light. Rodent studies have shown that there are multiple colors that affect the clock, but indirect measures in humans suggest blue light is key. We performed functional MRI studies in human subjects with unprecedented spatial resolution to investigate color sensitivity of our clock. Here, we show that narrowband blue, green, and orange light were all effective in changing neuronal activity of the clock. While the clock of nocturnal rodents is excited by light, the human clock responds with a decrease in neuronal activity as indicated by a negative BOLD response. The sensitivity of the clock to multiple colors should be integrated in light therapy aimed to strengthen our 24-h rhythms.

Evaluation of vertical and multi-axial suspension seats for reducing vertical-dominant and multi-axial whole body vibration and associated neck and low back joint torque and muscle activity

The primary aim of this laboratory-based human subject study was to evaluate the biomechanical loading associated with mining vehicles’ multi-axial whole body vibration (WBV) by comparing joint torque and muscle activity in the neck and low back during three vibration conditions: mining vehicles’ multi-axial, on-road vehicles’ vertical-dominant, and no vibration. Moreover, the secondary aim was to determine the efficacy of a vertical passive air suspension and a prototype multi-axial active suspension seat in reducing WBV exposures and associated biomechanical loading measures. The peak joint torque and muscle activity in the neck and low back were higher when exposed to multi-axial vibration compared to the vertical-dominant or no vibration condition. When comparing the two suspension seats, there were limited differences in WBV, joint torque, and muscle activity. These results indicate that there is a need to develop more effective engineering controls to lower exposures to multi-axial WBV and related biomechanical loading. Practitioner Summary: This study found that mining vehicles’ multi-axial WBV can increase biomechanical loading in the neck and back more so than on-road vehicles’ vertical-dominant WBV. While a newly-developed multi-axial active suspension seat slightly reduced the overall WBV exposures, the results indicate that more effective engineering controls should be developed. Abbreviation: APDF: amplitude probability density function; Aw: weighted average vibration; BMI: body mass index; C7: The 7th cervical vertebra; EMG: electromyography; ES: erector spinae; IRB: institutional review board; ISO: International Organization for Standardization; L5/S1: the fifth lumbar vertebra (L5)/the first sacral vertebra(S1); MSDs: musculoskeletal disorders; MVC: maximum voluntary contraction; PSD: power spectral density; RVC: reference voluntary contraction; SCM: sternocleidomastoid; SD: standard deviation; SPL: splenius capitis; TRAP: trapezius; VDV: vibration dose value; WBV: whole body vibration

Understanding the Effect of Speed on Human Emotion Perception in Mediated Social Touch Using Voice Coil Actuators

Touch as a modality in social communication has been getting more attention with recent developments in wearable technology and an increase in awareness of how limited physical contact can lead to touch starvation and feelings of depression. Although several mediated touch methods have been developed for conveying emotional support, the transfer of emotion through mediated touch has not been widely studied. This work addresses this need by exploring emotional communication through a novel wearable haptic system. The system records physical touch patterns through an array of force sensors, processes the recordings using novel gesture-based algorithms to create actuator control signals, and generates mediated social touch through an array of voice coil actuators. We conducted a human subject study (N= 20) to understand the perception and emotional components of this mediated social touch for common social touch gestures, including poking, patting, massaging, squeezing, and stroking. Our results show that the speed of the virtual gesture significantly alters the participants' ratings of valence, arousal, realism, and comfort of these gestures with increased speed producing negative emotions and decreased realism. The findings from the study will allow us to better recognize generic patterns from human mediated touch perception and determine how mediated social touch can be used to convey emotion. Our system design, signal processing methods, and results can provide guidance in future mediated social touch design.

Novel Approach to Track the Lifecycle of Inflammation from Chemokine Expression to Inflammatory Proteins in Sweat Using Electrochemical Biosensor

AbstractInflammatory biomarkers are modulated during the course of any infectious disease, and currently, there is no wearable technology that enables patient management through noninvasive monitoring of these markers. This work is the first demonstration of the discovery and quantification of interferon‐inducible protein (IP‐10) and tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), two key prognostic markers of infection in human sweat. The levels of IP‐10 and TRAIL in sweat are quantified, validated, and confirmed using a standard reference method through preclinical human subject studies. Additionally, simultaneous and continuous detection of IP‐10, TRAIL, and C‐reactive protein (CRP), for infection monitoring in sweat using a wearable SWEATSENSER device is demonstrated. The SWEATSENSER is ultrasensitive with a limit of detection of 1 pg mL−1 (IP‐10 and TRAIL), 0.2 ng mL−1 (CRP) with a wide dynamic range. Bland–Altman analysis demonstrates good agreement between SWEATSENSER and standard reference methods through human subject studies. Serum to sweat relationship demonstrates the potential of the SWEATSENSER to track infection etiology.

Accuracy of Optic Nerve Sheath Diameter Measurements in Pocket-Sized Ultrasound Devices in a Simulation Model.

IntroductionTransorbital sonographic measurement of optic nerve sheath diameter (ONSD) is an emerging non-invasive technique for the identification and monitoring of intracranial hypertension. In recent years, new pocket ultrasound devices have become available, and it is uncertain if they have the resolution to measure such small structures appropriately as compared to their predecessors. In this study, we measure the performance of three ultrasound units on a simulation model to establish their precision and accuracy.MethodsONSD was measured by three expert point-of-care sonographers using ultrasound machines three times on each of seven discrete ONS model sizes ranging from 3.5 to 7.9 mm. Two pocket ultrasounds (IVIZ, Sonosite, and Lumify, Philips) and one standard-sized portable ultrasound (M-Turbo, Sonosite) were used. Measurements were analyzed for mean error and variance and tested for significance using blocked covariance matrix regression analyses.ResultsThe devices differed in their variances (Lumify: 0.19 mm2, M-Turbo: 0.26 mm2, IVIZ: 0.34 mm2) and their mean error (Lumify: −0.05 mm, M-Turbo: 0.10 mm, IVIZ: −0.10 mm). The difference in mean error between users is not significant (p = 0.45), but there is a significant difference in mean error between devices (p = 0.02).ConclusionsAccurate ONSD measurement is possible utilizing pocket-sized ultrasound, and in some cases, may be more accurate than larger portable ultrasound units. While the differences in these devices were statistically significant, all three were highly accurate, with one pocket device (Lumify) outperforming the rest. Further study in human subjects should be conducted prior to using pocket ultrasound devices for in vivo diagnosis of intracranial hypertension.

Conceptual Game Expansion

Automated game design is the problem of automatically producing games through computational processes. Traditionally, these methods have relied on the authoring of search spaces by a designer, defining the space of all possible games for the system to author. In this paper, we instead learn representations of existing games from gameplay video and use these to approximate a search space of novel games. In a human subject study we demonstrate that these novel games are indistinguishable from human games in terms of challenge, and that one of the novel games was equivalent to one of the human games in terms of fun, frustration, and likeability.