Human Subjects Research Articles

Anthropocentrism and Inheritance in Our Mutual Friend: Return, Recognition, Reanimation

Abstract In decentering “Man,” a category long rhetorically constructed as the privileged species of a divine creator, Charles Darwin’s theory of natural selection necessitated a reexamination of how human subjectivity should be represented in fiction. This article uses the example of Charles Dickens’s Our Mutual Friend (1864) to track and scientifically contextualize how anthropocentrism is constructed and interrogated in fiction after publication of On the Origin of Species (1859). Competing nineteenth-century theories of species transmutation recognized physiological fluidity and variation within species and type, yet unlike Darwin, they sought to define uniquely human qualities of mind. Literary narratives, such as Dickens’s final completed novel, engaged this intellectual project—attempting to stabilize a dominant form of human subjectivity while recognizing shifting varieties of being. Protagonist John Harmon is oddly vacant as an imagined human consciousness; his actions create or resolve conflict within the story, but he fails to demonstrate any stable motivation. Depicting the initial misrecognition, and eventual recognition, of an English heir newly returned from abroad, Our Mutual Friend articulates cultural anxieties about the potential mutability of identity and type and the origins and durability of English dominance. Its post-Darwinian model of consciousness challenges traditional realist valorization of the individualistic, agential subject.

Carbon Nanotubes: A Targeted Drug Delivery against Cancer Cell

Abstract: Drug delivery in human subjects has been the most difficult task since the ancient time of the medical sector. An ideal drug delivery system is, one that minimizes the adverse effects and maximizes the desired effects of the drug candidate. Various drug delivery systems have been developed that may have some kind of advantages and disadvantages, among them targeted drug delivery system is more preferable and convenient which may employ various nanoparticles or other materials for the drug delivery at the specified site of action. In this, the authors elaborately and comprehensively explained the role of recent carbon nanotubes (CNTs) in targeted drug delivery systems (specifically for targeting cancerous cells). The authors also described the methods of preparation of CNTs, characterization techniques for CNTs, cellular penetration of, CNTs, and the associated toxicities with CNTs. Carbon nanotubes are preferable to other nanoparticles because they are more electrically, mechanically, and organically stable than others, they can carry more amount of drug in comparison to other nanoparticles and their functionalization property makes them more attractive as a carrier molecule for targeting any root cause of the disease.

Is There an Association between 5a Reductase Inhibitors and Metabolic Syndrome? A Narrative Review of the Literature.

Finasteride and dutasteride are 5a Reductase Inhibitors (5a-RIs) and comprise the mainstay of treatment for the management of patients with benign prostatic hyperplasia. 5a-RIs are expressed in a variety of tissues, such as adipose tissues and liver, resulting in a reduction of glucocorticoid levels and affecting androgen regulation and metabolic function. As a result, the administration of these regimens may generate adverse metabolic events, such as liver disease, hyperglycemia, hyperlipidemia, and diabetes mellitus. Although several studies have tried to record these adverse metabolic events both in human subjects and animal models, the exact mechanisms of these actions have not been well described yet in the literature. Further well-designed clinical trials are needed to elucidate the exact role of 5a reductase inhibitors in the progression of the metabolic syndrome. The aim of this study was to systematically review the literature concerning the role of dutasteride or finasteride in the progression of metabolic adverse events and further investigate possible pathophysiologic mechanisms.

Novel Approaches for the Early Detection of Glaucoma Using Artificial Intelligence

Background: If left untreated, glaucoma—the second most common cause of blindness worldwide—causes irreversible visual loss due to a gradual neurodegeneration of the retinal ganglion cells. Conventional techniques for identifying glaucoma, like optical coherence tomography (OCT) and visual field exams, are frequently laborious and dependent on subjective interpretation. Through the fast and accurate analysis of massive amounts of imaging data, artificial intelligence (AI), in particular machine learning (ML) and deep learning (DL), has emerged as a promising method to improve the early detection and management of glaucoma. Aims: The purpose of this study is to examine the current uses of AI in the early diagnosis, treatment, and detection of glaucoma while highlighting the advantages and drawbacks of different AI models and algorithms. In addition, it aims to determine how AI technologies might transform glaucoma treatment and suggest future lines of inquiry for this area of study. Methods: A thorough search of databases, including Web of Science, PubMed, and Scopus, was carried out to find pertinent papers released until August 2024. The inclusion criteria were limited to research published in English in peer-reviewed publications that used AI, ML, or DL to diagnose or treat glaucoma in human subjects. Articles were chosen and vetted according to their quality, contribution to the field, and relevancy. Results: Convolutional neural networks (CNNs) and other deep learning algorithms are among the AI models included in this paper that have been shown to have excellent sensitivity and specificity in identifying glaucomatous alterations in fundus photos, OCT scans, and visual field tests. By automating standard screening procedures, these models have demonstrated promise in distinguishing between glaucomatous and healthy eyes, forecasting the course of the disease, and possibly lessening the workload of physicians. Nonetheless, several significant obstacles remain, such as the requirement for various training datasets, outside validation, decision-making transparency, and handling moral and legal issues. Conclusions: Artificial intelligence (AI) holds great promise for improving the diagnosis and treatment of glaucoma by facilitating prompt and precise interpretation of imaging data and assisting in clinical decision making. To guarantee wider accessibility and better patient results, future research should create strong generalizable AI models validated in various populations, address ethical and legal matters, and incorporate AI into clinical practice.

Comparative effects of ranolazine and trimetazidine on cardiac structure and exercise capacity in a healthy rat model: a new doping agent?

Abstract Background/Introduction Anti-anginal drugs that have been shown to improve myocardial energy use include ranolazine and trimetazidine [1]. An inquiry is warranted into their ability to impact cardiac functions and exercise capacity. Purpose This study aims to evaluate the effects of ranolazine; and trimetazidine as a positive control group on cardiac structure and exercise capacity in a rodent model in comparison with the control group. Methods In a randomized, controlled trial, 24 Sprague-Dawley rats were divided into three groups: control, ranolazine, and trimetazidine. Rats were given daily doses of ranolazine (50 mg/kg/1 ml) [2], trimetazidine (10 mg/kg/1 ml) [3], or saline (control) via gastric gavage for 30 days. At the beginning of the trial, as well as on the 15th and 30th days, the rats were weighed, placed on rotarod, and assessed using transthoracic echocardiography (Figure 1). The rats underwent 21 days of forced swimming testing. According to the guidelines for rat exercise testing [4], signs of exhaustion, lack of coordinated movements, and failure to surface for three seconds following submersion in the water were designated as grounds for terminating the test. Weight, rotarod durations, M-mode and Doppler measurements, and forced swimming test durations were recorded on the 0th, 15th, and 30th days. Results No discernible differences were found between the groups in the initial evaluations. By using echocardiography, the left ventricular masses expanded in all three, indicating the emergence of an athlete's heart. In comparison to the control group, the ranolazine and trimetazidine groups showed considerable increases in their ability to exercise. In particular, the swimming times of the trimetazidine group and the ranolazine group improved to a mean of 1889 seconds by the 21st session, 1700 seconds in the trimetazidine group, and 1548 seconds in the control group (Figure 2), respectively, indicating enhanced cardiac performance. Conclusion(s) Ranolazine exhibits significant potential to enhance exercise capacity and cardiac efficiency in rats, surpassing the effects observed with trimetazidine. Trimetazidine is already registered as a doping agent in WADA [5]. These findings highlight the potential use of ranolazine as a performance enhancing agent in healthy subjects for a malicious purpose of creating unfair advantages in professional sports. Further studies in human subjects are needed.Figure 1Figure 2

Simulating Pelvis Kinematics from Belt and Seat Loading in Frontal Car Crash Scenarios: Important Boundary Conditions that Influence the Outcome.

The risk of submarining during automotive crashes, defined by the lap belt sliding off the pelvis to load the abdomen, is predicted to increase in future autonomous vehicles as greater variation in seating position is enabled. Biofidelic tools are required to efficiently design and evaluate new and/or improved safety systems. This study aims to evaluate the pelvis response sensitivity to variations in boundary conditions that directly influence the pelvis loads, deemed important for the submarining outcome, to facilitate a more precise comparison between finite element human body models (FE-HBMs) and post-mortem human subjects (PMHSs). A parameter study, using a one-variable-at-a-time analysis (low/high) of belt friction, seat friction, seat stiffness, and (on/off) for added belt bending stiffness, was performed using a state-of-the-art FE-HBM in four different test scenarios; one stationary, two sleds with upright occupant posture, and one sled with reclined occupant posture. In the stationary scenario, both belt friction and belt bending stiffness influenced the belt folding behavior, which consequently affected the belt-to-pelvis angle at submarining. In the sled scenarios, only seat friction was found to influence the pelvis kinematics and submarining outcome, with the most biofidelic response resulting from both the low (0.2) and high (0.5) friction coefficient depending on the scenario. To reduce uncertainty in boundary conditions affecting the external pelvis loads and increase confidence in FE-HBM to PMHS comparisons, it is recommended that future experiments evaluate the PMHS to seat friction coefficient and that new belt modeling methods that accurately capture belt folding when interacting with soft tissues are developed.

Comparison of 600 mg VS 300 mg clopidogrel loading dose for patients with ischemic heart disease: a meta-analysis of randomized controlled trials

Abstract Background While a 600-mg loading dose (LD) of clopidogrel has demonstrated superior inhibition of platelet function compared to 300-mg LD, the clinical evidence supporting this superiority is limited. The debate centers on whether a higher clopidogrel LD regimen in primary percutaneous coronary intervention outperforms the standard 300 mg LD, with potential benefits being more pronounced in higher-risk patients. Balancing enhanced platelet inhibition to reduce ischemic events against the associated risk of increased bleeding remains a critical consideration in determining the optimal loading dose of clopidogrel for patients with ischemic heart disease. Purpose The objective of this meta-analysis is to validate current randomized trials that investigate the efficacy and safety of two clopidogrel loading regimens (600 mg vs 300 mg) in patients with ischemic heart disease treated with primary percutaneous coronary intervention. Method A systematic literature search for randomized controlled trials was performed comparing 600 mg with 300 mg LD of clopidogrel using PubMed, MEDLINE, Embase, Cochrane, Clinicaltrials.gov. and Herdin PH. Studies included those between 2010 - 2023 involving human subjects. The primary efficacy endpoint was a 1-month rate of major adverse cardiac event (MACE) and the primary safety outcome was bleeding adverse effects. Result Nine randomized control studies involving 29,827 patients were included in the efficacy analysis. Mean duration of follow-up was 30 days. Only 8 studies were eligible for safety analysis. Compared with standard LD clopidogrel, high LD significantly reduced incidence of overall MACE (OR:0.82, 95% CI:0.74-0.91, p=0.0002), nonfatal myocardial infarction (OR:0.56; 95% CI:0.32-0.99, p = 0.15) and target vessel revascularization (OR 0.63; 95% CI 0.41 to 0.95, p = 0.03 ), without significant difference in terms of cardiac death (OR:0.89; 95% CI:0.76-1.04, p=0.15) and stroke (OR 0.92; 95% CI 0.67 to 1.26, p = 0.61). However, major bleeding risk was higher in the 600 mg LD (1.9%; 261/13288) compared with 300 mg LD (2.4%; 328/13242) [OR:1.27; 95% CI:1.08-1.49, p=0.005] without significant difference in minor bleeding (OR:1.05; 95% CI:0.94-1.17, p=0.35). Conclusion The administration of 600 mg of clopidogrel LD reduces the overall risk of MACE with an associated increased risk of major bleeding in patients with ischemic heart disease undergoing primary percutaneous coronary intervention.MACE OUTCOMES

Study protocol for a multicenter non-inferiority randomized controlled trial to assess functional outcomes and cost-effectiveness of a primarily non-operative treatment strategy with cast immobilization versus immediate operative treatment followed by cast immobilization for patients with complete ulnar collateral ligament ruptures, including Stener lesions: MUSCAT study

BackgroundGuidelines recommend operative treatment followed by cast immobilization for acute complete ulnar collateral ligament (UCL) ruptures, including Stener lesions. This recommendation is based on expert opinion, anatomic theories, and low-quality observational case series. High-quality studies comparing non-operative treatment to operative treatment are lacking. We hypothesize that primarily non-operative treatment with cast immobilization (cast immobilization) is non-inferior regarding functional outcome and carries concomitant lower costs compared with immediate operative treatment followed by cast immobilization (operative treatment) for complete UCL ruptures, including Stener lesions.MethodsThis is a multicenter randomized controlled non-inferiority trial (RCT) including patients of 18 years and above, requiring treatment for an acute complete UCL rupture, including Stener lesions. Patients are randomized to cast immobilization or operative treatment followed by cast immobilization. Immobilization consists of 4 weeks of a non-removable cast around the metacarpophalangeal (MCP) and carpometacarpal (CMC) joint of the thumb in a neutral position, followed by a removable cast for 4 weeks for both groups. Patients in the cast immobilization group are re-evaluated 2 to 3 weeks after the start of cast immobilization to examine thumb stability and determine if secondary surgery is required. In case of persistent laxity, secondary surgery is required. The primary outcome is hand function expressed as the Michigan Hand outcome Questionnaire (MHQ) at 6 months (from injury to 6 months after).DiscussionIf cast immobilization is non-inferior to operative treatment, the proposed treatment strategy will reduce patient burden by preventing surgery. It is expected that about one in ten patients who started with cast immobilization will need secondary surgery during re-evaluation. As a result, completion of the treatment will take longer for these patients compared to patients who received immediate operative treatment.Trial registrationCentral Committee on Research Involving Human Subjects (CCMO), NL78886.100.21; registered on 4 October 2021. Medical Research Ethics Committees United (MEC-U), R21.006; registered on 09 December 2021. Clinical Trial register, identifier: NCT05291260; retrospectively registered on 22 March 2022.

Combined SK and K2P channel block cardioverts atrial fibrillation in 82% of cases, doubling the efficacy of single channel block

Abstract Background Inhibiting the atrial-selective SK and K2P channels represents a promising strategy for cardioverting atrial fibrillation (AF), but its efficacy has not been evaluated in a large human cohort. Objectives This study employed in-silico trials in 1000 virtual patients (i.e., clinical trials conducted in a population of virtual human subjects through modelling and simulation) to estimate the efficacy and safety of three pharmacological interventions: single and combined SK and K2P channel block. Methods A large cohort of 1000 virtual patients was developed based on human data, to cover the electrophysiological, anatomical and structural variability encountered in clinical practice. The subset of virtual patients with AF maintenance underwent pharmacological cardioversion (Figure). Results Sustained AF was observed in 654 (65%) virtual patients. In this cohort, cardioversion efficacies of 33% (213 of 654), 43% (278 of 654) and 82% (534 of 654) were obtained for single SK, single K2P and combined channel block, respectively (Figure). The cardioversion efficacy was proportional to an increase in tissue refractoriness (increase of 45.2±43.0, 71.0±55.3 and 133.0±48.4 ms in the atrial refractory period) and depended on the ionic current profile. Virtual patients cardioverted by SK channel block presented lower K2P densities (0.008±0.002 vs. 0.006±0.002 S/mF; non-cardioverted vs. cardioverted virtual patients, respectively). Similarly, a lower SK density favoured the success of K2P channel inhibition (1.87±0.24 vs. 1.46±0.5 S/mF; non-cardioverted vs. cardioverted virtual patients, respectively). Both ionic currents had a crucial role on atrial repolarization, and thus, a synergism resulted from the polypharmacological strategy (i.e., higher efficacy than the additive effects of single channel block). All three interventions, including the multi-channel block, preserved the atrial electrophysiological function (i.e., conduction velocity and calcium transient dynamics) and thus, the atrial contractile properties (safety). Conclusion In-silico trials identify the polypharmacological SK+K2P channel block as an effective and safe strategy for AF management.

The orchestration of coding and non-coding genes at the CDH13 locus in coronary artery disease

Abstract Background The CDH13 locus was associated with coronary artery disease (CAD) by genome-wide association studies (GWAS). However, the causal gene(s) and underlying disease mechanisms at this locus remain undetermined. Purpose We intended to pinpoint and functionally validate the causal coding and non-coding genes at the CDH13 locus and delineate the underlying mechanisms for CAD. Methods and results We conducted the transcriptome-wide association analysis (TWAS) using nine types of CAD-relevant tissues from Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) and Genotyped Tissue Expression (GTEx) projects and identified CDH13 (T-cadherin) and four long non-coding RNA (lncRNA) genes as candidate causal genes at The CDH13 locus. One of the antisense(AS) lncRNAs, CDH13-AS2, was predicted to bind on the 3’ untranslated region (UTR) of CDH13 using LncRRIsearch and RNAup servers. The binding interaction was validated by dCas13-medicated RNA immunoprecipitation. Weighted correlation network analysis (WGCNA) using transcriptomic data from CAD-relevant tissues of ~600 human subjects suggested a positive expression correlation between CDH13 and CDH13-AS2 in artery tissues. CRISPR/Cas9-based knockout (KO) of CDH13 or CDH13-AS2 in human umbilical vein endothelial cells (HUVECs) indicated synergistically atherogenic phenotypes, including reduced proliferation and migration, and increased apoptosis and monocyte adhesion. The data matched with the downregulation of CDH13 in artery samples of atherosclerosis patients. The cellular phenotypes were also in line with our in vivo data of Cdh13 and Apoe double-KO (Cdh13-/-/Apoe-/-) mice, which showed increased aortic lesion areas when fed on a high-fat diet compared to Apoe-/- mice. Furthermore, prediction using TargetScan, miRWalk, and scanMiRApp databases identified the potential binding of several EC-expression microRNAs (mir) on 3’UTR of CDH13. Several disease-associated variants were mapped to the predicted binding sites of a few microRNAs, including mir-let7, mir-30, and mir-125. The dual luciferase-based RNA interference (RNAi) assay confirmed the binding of mir-let7 on 3’UTR of CDH13. Transcriptional activation of CDH13-AS2 by the enzymatically inactivated Cas9 (dCas9) system diminished the binding of mir-let7 and increased CDH13 expression. Conclusions At the CDH13 locus, CDH13 and CDH13-AS2 are two causal genes, whose downregulation likely contributes to CAD. CDH13-AS2 bound and stabilized CDH13 partially by preventing mir-let7 mediated degradation of CDH13 mRNA, suggesting therapeutic potentials.

Safety and efficacy of aspiration thrombectomy with intracoronary tirofiban VS aspiration thrombectomy alone in patients undergoing primary PCI: a systematic review and meta-analysis

Abstract Background Primary percutaneous coronary intervention (PPCI) may be complicated by intracoronary thrombus accumulation in ST elevation myocardial infarction (STEMI) leading to decrease in myocardial perfusion and increase in infarct size. The utilization of aspiration thrombectomy and intracoronary tirofiban in STEMI patients undergoing PPCI hold clinical relevance by removal of thrombus burden, potentially reducing distal embolization and improving myocardial perfusion and by targeting platelet aggregation to mitigate thrombotic complications, respectively. Given the paramount importance of achieving rapid and effective reperfusion in STEMI, the evaluation of these interventions is warranted to assess overall impact on patient outcomes in terms of safety and efficacy. Purpose The current meta-analysis aims to investigate the clinical outcomes of aspiration thrombectomy (AT) with intracoronary tirofiban versus AT alone during PPCI. Methods A systematic search for randomized controlled trials that evaluate the safety and efficacy of aspiration thrombectomy with intracoronary tirofiban in STEMI patients who underwent PPCI was done using PubMed, MEDLINE, Embase, Cochrane, Clinicaltrials.gov. and Herdin PH. Studies included those between 2010 - 2023 and involved human subjects. Search terms included "Aspiration Thrombectomy", "Intracoronary Tirofiban", "Primary Percutaneous Coronary Intervention" and "STEMI patients". Results Four RCTs (n: 490 participants) were included in this meta-analysis comparing aspiration thrombectomy with intracoronary tirofiban versus aspiration thrombectomy alone in STEMI patients undergoing PPCI. The results revealed no statistically significant difference in ST segment resolution (RR 1.02, 95%, CI: 0.97 - 1.08, P = 0.41, I2 = 0%), myocardial blush grade 2-3, (risk ratio of 1.04, 95%, CI: 0.97 – 1.12, P = 0.22, I2 = 62%) and TIMI 3 flow (risk ratio of 1.0, 95% CI: 0.95 - 1.04, P = 0.87). The occurrence of major adverse cardiovascular events did not significantly differ between the two groups (RR 0.46, 95% CI: 0.19 – 1.09, P = 0.08, I2 = 0%). There was no statistically significant difference in terms of bleeding when combining intracoronary tirofiban to standard medical therapy (RR 1.35, 95% CI: 0.64 – 2.84, P= 0.78, 4 trials [490 patients]). Conclusion In primary percutaneous coronary intervention, MACE outcomes of aspiration thrombectomy with intracoronary tirofiban were similar to that for aspiration thrombectomy alone in terms of improving myocardial perfusion in STEMI patients without increasing the risk for bleeding. Our meta-analysis suggests that AT alone may be the more acceptable standard during PPCI when encountering heavy thrombus burden. Future validated studies may help further investigate the strategy of adding tirofiban during aspiration thrombectomy.1. Primary Outcomes2. Secondary Outcomes

Potential Effects of Soccer Ball Characteristics on Ball-to-Head Contact: A Systematic Review

Background: The aim of this study was to systematically review research on the effect of soccer ball characteristics on ball-to-head contact. Methods: This systematic review was conducted using electronic databases, which included PubMed, Cochrane, and Web of Science. The search strategy combined keywords related to soccer, the ball and its characteristics, heading, and kinematics variables. Studies analyzing the impact of soccer ball characteristics on heading biomechanics were included. The review included studies using mathematical models, simulations, and human subjects. Results: A total of nine studies were included, highlighting the lack of evidence on this topic. The following ball characteristics were investigated: inflation pressure (n = 7), mass (n = 4), structure/material properties (n = 3), size/diameter (n = 3), and stiffness (n = 3). Most studies used non-human subjects, such as mathematical, simulated, or head-form models. Key findings were as follows: (a) reducing inflation pressure may decrease impact magnitude; (b) ball size may not directly relate to impact magnitude, but one study found that a smaller size resulted in a shorter impact time; (c) lower impact observed with decreasing ball mass; (d) lowering stiffness showed a tendency to lower impact; (e) two studies on water absorption found that wet balls were heavier and had greater impact forces than dry balls; and (f) ball structure and cover material directly influenced impulsive forces. Conclusions: Modifying soccer ball characteristics may reduce heading forces, but the available research has limitations. More controlled studies are needed to determine optimal ball properties for mitigating injury risk during soccer heading. Standardized testing methods can further clarify the biomechanics of heading, supporting ongoing innovations to enhance player experience.

Phytochemical Compounds as Promising Therapeutics for Intestinal Fibrosis in Inflammatory Bowel Disease: A Critical Review

Background/Objective: Intestinal fibrosis, a prominent consequence of inflammatory bowel disease (IBD), presents considerable difficulty owing to the absence of licensed antifibrotic therapies. This review assesses the therapeutic potential of phytochemicals as alternate methods for controlling intestinal fibrosis. Phytochemicals, bioactive molecules originating from plants, exhibit potential antifibrotic, anti-inflammatory, and antioxidant activities, targeting pathways associated with inflammation and fibrosis. Compounds such as Asperuloside, Berberine, and olive phenols have demonstrated potential in preclinical models by regulating critical signaling pathways, including TGF-β/Smad and NFκB, which are integral to advancing fibrosis. Results: The main findings suggest that these phytochemicals significantly reduce fibrotic markers, collagen deposition, and inflammation in various experimental models of IBD. These phytochemicals may function as supplementary medicines to standard treatments, perhaps enhancing patient outcomes while mitigating the adverse effects of prolonged immunosuppressive usage. Nonetheless, additional clinical trials are necessary to validate their safety, effectiveness, and bioavailability in human subjects. Conclusions: Therefore, investigating phytochemicals may lead to crucial advances in the formulation of innovative treatment approaches for fibrosis associated with IBD, offering a promising avenue for future therapeutic development.

Exosomes for Treating Hair Loss: A Review of Clinical Studies.

The regenerative properties of exosomes make them especially appealing to treat skin and hair diseases. Preclinical studies suggest that exosomes may fuel hair growth by stimulating dermal papilla cells, activating hair follicle stem cells, and promoting angiogenesis. However, very limited data are available on the safety and efficacy of exosome use in human subjects. To review the published literature on exosome use in human subjects with a focus on safety and the challenges facing clinical implementation in the treatment of androgenetic and nonscarring alopecias. A review was conducted of PubMed, EMBASE, and Cochrane databases and included 48 studies. Twenty-five studies were clinical trials, 14 case reports, 4 case series, 1 retrospective review, and 4 conference abstracts. Nine clinical studies were found relevant to alopecia. One hundred twenty-five patients received an exosome treatment for hair loss. Side effects were rare. However, in the broader field of dermatology, at least 10 serious adverse events have been reported. Although exosomes have many promising therapeutic applications, there is demand for larger well-designed clinical trials with extended follow-up periods to prove efficacy and a need for consistent manufacturing standards and regulatory oversight to ensure product safety.

Underpowered Studies in Muscle Metabolism Research: Determinants and Considerations

Biomedical research frequently employs null hypothesis testing to determine whether an observed difference in a sample is likely to exist in the broader population. Null hypothesis testing generally assumes that differences between groups or interventions are non-existent, unless proven otherwise. Because biomedical studies with human subjects are often limited by financial and logistical resources, they tend to have low statistical power, i.e. a low probability of statistically confirming a true difference. As a result, small but potentially clinically important differences may be overseen or ignored simply due to the absence of a statistically significant difference. This absence is often misinterpreted as ‘equivalence’ of treatments. In this educational paper, we will use practical examples related to the effects of exercise and nutrition on muscle protein metabolism to illustrate the most important determinants of statistical power, as well as their implications for both investigators and readers of scientific articles.Changes in muscle mass occur at a relatively slow rate, making it practically challenging to detect differences between treatment groups in a long-term setting. One way to make it ‘easier’ to differentiate between groups and hence increase statistical power is to have a sufficiently long study duration to allow treatment effects to become apparent. This is especially relevant when comparing treatments with relatively small expected differences such as the effect of modest changes in daily protein intake. Secondly, one could try to minimize the variance and response heterogeneity within groups, for example by using strict inclusion criteria and standardization protocols (e.g., meal provision), by using cross-over designs, or even within-subject designs where two interventions are compared simultaneously (e.g., studying an exercised limb vs a contralateral control limb) although this might limit the generalizability of the findings (e.g. such single-limb exercise training is not common in practice). In terms of data interpretation, investigators should obviously refrain from drawing strong conclusions from underpowered studies. Yet, such studies still provide valuable data for meta-analyses. Finally, because muscle protein synthesis rates are highly responsive to anabolic stimuli, acute metabolic studies are more sensitive to detect potentially clinically relevant differences in the anabolic response between treatments. Apart from further elaborating on these topics, this educational article encourages readers to more critically question null findings and scientists to more clearly discuss limitations that may have compromised statistical power.

Vagus nerve stimulation in Parkinson’s disease: a scoping review of animal studies and human subjects research

Parkinson’s Disease (PD) is a prevalent, progressive neurodegenerative disease with motor and non-motor symptoms. Vagus Nerve Stimulation (VNS) has emerged as a potential therapeutic approach for PD, but published research on this topic varies widely. This scoping review maps existing literature on VNS for PD, highlighting stimulation methods, operational parameters, safety profiles, neurophysiological mechanisms, and clinical outcomes in human and animal models. Online databases were used to identify 788 papers published between 2013 and 2023, from which 17 publications on invasive and non-invasive VNS in PD were selected. Studies showed high variability in VNS parameters and study design. Evidence in animal models and human subjects suggests potential neurophysiological effects on PD-related pathology and motor function improvements. However, significant gaps in the literature remain. Future research should include rigorous reporting of study design, standardization of stimulation parameters, and larger sample sizes to ultimately facilitate translation of VNS into clinical practice.

Behavioral and Neurophysiological Signatures of Cognitive Control in Humans and Rats.

Deficits in cognitive control are implicated in numerous neuropsychiatric disorders. However, relevant pharmacological treatments are limited, likely due to weak translational validity of applicable preclinical models used. Neural indices derived from electroencephalography (EEG) may prove useful in comparing and translating the effects of cognition-enhancing drugs between species. In the current study, we aimed to extend our previous cross-species results by examining if methylphenidate (MPH) modulates behavioral and neural indices of cognitive control in independent cohorts of humans and rats. We measured continuous EEG data from healthy adults (n=25; 14 female) and Long Evans rats (n=22; 8 female) and compared both stimulus- and response-locked event-related potentials (ERPs) and spectral power measures across species, and their MPH-related moderation following treatment with vehicle (placebo) or one of two doses of MPH. Across both species, linear mixed effects modeling confirmed the expected Flanker interference effect on behavior (e.g., accuracy) and response-related ERPs. Unexpectedly, in contrast to past work, we did not observe any task-related effects on the spectral power of rodents. Moreover, MPH generally did not modulate cognitive control of either species, although some species-specific patterns offer insight for future research. Collectively, these findings in independent human and rodent subjects replicate some of our previously reported behavioral and neurophysiological patterns partly consistent with the notion that similar neural mechanisms may regulate cognitive control in both species. Nonetheless, these results showcase an approach to accelerate translation using a coordinated between-species platform to evaluate pro-cognitive treatments.

Ventilatory response to head-down-tilt in healthy human subjects.

Postural fluid shifts may directly affect respiratory control via a complex interaction of baro- and chemo-reflexes, and cerebral blood flow. Few data exist concerning the steady state ventilatory responses during head-down tilt. We examined the cardiorespiratory responses during acute 50° head-down tilt (HDT) in 18 healthy subjects (mean [SD] age 27 [10] years). Protocol 1 (n=8, two female) was 50° HDT from 60° head-up posture sustained for 10min, while exposed to normoxia, normoxic hypercapnia (5% CO2), hypoxia (12% inspired O2) or hyperoxic hypercapnia (95% O2, 5% CO2). Protocol 2 (n=10, four female) was 50° HDT from supine, sustained for 10min, while breathing either medical air or normoxic hypercapnic (5% CO2) gas. Ventilation ( , pneumotachograph), end-tidal O2 and CO2 concentration and blood pressure (Finapres) were measured continuously throughout each protocol. Middle cerebral artery blood flow velocity (MCAv; transcranial Doppler) was also measured during protocol 2. Ventilation increased significantly (P<0.05) compared to baseline during HDT in both hyperoxic hypercapnia (protocol 1 by mean [SD] 139 [26]%) and normoxic hypercapnia (protocol 1 by mean [SD] 131 [21]% and protocol 2 by 129 [23]%), despite no change in or from baseline. No change in was observed during HDT with medical air or hypoxia, and there was no significant change in MCAv during HDT compared to baseline. The absence of change in cerebral blood flow leads us to postulate that the augmented ventilatory response during steep HDT may involve mechanisms related to cerebral venous pressure and venous outflow.

Cell Population-resolved Multi-Omics Atlas of the Developing Lung.

The lung is a vital organ that undergoes extensive morphological and functional changes during postnatal development. To disambiguate how different cell populations contribute to organ development, we performed proteomic and transcriptomic analyses of four sorted cell populations from the lung of human subjects aged 0 to 8 years-old with a focus on early life. The cell populations analyzed included epithelial, endothelial, mesenchymal, and immune cells. Our results revealed distinct molecular signatures for each of the sorted cell populations that enable the description of molecular shifts occurring in these populations during post-natal development. We confirmed that the proteome of the different cell populations was distinct regardless of age and identified functions specific to each population. We identified a series of cell population protein markers, including those located at the cell surface, that show differential expression and distribution on RNA in situ hybridization and immunofluorescence imaging. We validated the spatial distribution of AT1 and endothelial cell surface markers. Temporal analyses of the proteomes of the four populations revealed processes modulated during postnatal development and clarified the findings obtained from whole tissue proteome studies. Finally, the proteome was compared to a transcriptomics survey performed on the same lung samples to evaluate processes under post-transcriptional control.

Sensitivity improvement of a deuterium-deuterium neutron generator based in vivo neutron activation analysis (IVNAA) system.

Our lab has been developing a deuterium-deuterium (DD) neutron generator-based neutron activation analysis (NAA) system to quantify metals and elements in the human body in vivo. The system has been used to quantify metals such as manganese, aluminum, sodium in bones of a living human. The technology provides a useful way to assess metal exposure and to estimate elemental deposition, storage and biokinetics. It has great potential to be applied in the occupational and environmental health fields to study the association of metal exposure and various health outcomes, as well as in the nutrition field to study the intake of essential elements and human health. However, the relatively low sensitivity of the system has greatly limited its applications. Neutron moderation plays an important role in designing an IVNAA facility, as it affects thermal neutron flux in irradiation cave and radiation exposure to the human subject. This study aims to develop a novel thermal neutron enhancement method to improve the sensitivity of the in vivo neutron activation analysis (IVNAA) system for elemental measurement but still maintain radiation dose. Utilizing a compact DD neutron source, we propose a new and practical moderator design that combines high density polyethylene with heavy water to enhance thermal neutrons by reducing thermal neutron absorption. All material dimensions are calculated by PHITS, a general-purpose Monte Carlo simulation program. The improvement of the new design predicted by the Monte Carlo simulation for the quantification of one of the elements, manganese was verified by experimental irradiation of manganese-doped bone equivalent phantoms. For the same radiation dose, a 67.9% thermal neutron flux enhancement is reached. With only 4.2% increase of radiation dose, the simulated thermal neutron flux and activation can be further increased by 84.2%. A 100% thermal neutron enhancement ratio is also achievable with a 20% dose increase. The experimental results clearly show higher manganese activation gamma ray counts for each specific phantom, with a significantly reduced minimum detection limit. Additionally, the photon dose was suppressed. The thermal neutron enhancement method can increase the number of useful neutrons significantly but maintain the radiation dose. This greatly decreased the detection limit of the system for elemental quantification at an acceptable dose, which will broadly expand the application of the technology in research and clinical use. The method can also be applied to other neutron medical applications, including neutron imaging and radiotherapy.