Healthy Human Volunteers Research Articles

Known mechanisms cannot account for a third of reduced susceptibility in non-aureus staphylococci

Non-aureus staphylococci (NAS) are implicated in many healthcare-acquired infections and an understanding of the genetics of antimicrobial resistance is important in relation to both clinical intervention and the role of NAS as a reservoir of resistance genes. Gap statement: The burden of antimicrobial resistance in NAS, particularly to clinically relevant antimicrobials, is under-recognised. We sourced 394 NAS isolates from clinical samples, healthy human volunteers, animals and type cultures and subjected them to minimum inhibitory concentration (MIC) testing by agar dilution using eight antimicrobials. Cefoxitin was used to screen for methicillin resistance, as it stimulates the expression of mecA in S. aureus. We performed whole genome sequencing on 366 isolates and analysed these genotypically for the presence of genetic mechanisms responsible for the phenotypic levels of reduced antimicrobial susceptibility. We observed 175 sequenced isolates with a MIC ≥ 4 µg/ml to cefoxitin, of which 50% did not harbour a known mec homologue. Eight clinical NAS isolates displayed high daptomycin MICs (>4 µg/ml), with no known mechanism identified. Differences in MICs against erythromycin were attributable to the presence of different resistance genes (msrA and ermC). In total, 49% of isolates displayed reduced susceptibility to three or more of the antimicrobials tested. The widespread presence of reduced antimicrobial susceptibility in NAS is concerning. An increased likelihood of harder-to-treat infections caused directly by NAS with acquired resistance genes has clinical implications for AMR detection, the horizontal resistance gene pool and the management of patients.

Electrical auricular tragus stimulation induces release of circulating cardioprotective factors in healthy human volunteers

Abstract Background Vagal activation during remote ischemic conditioning (RIC) with subsequent release of cardioprotective factors from the spleen into the circulation reduces infarct size. These humoral cardioprotective factors can be transferred with plasma-dialysate from human donors undergoing RIC to isolated recipient hearts where they reduce infarct size. Electrical auricular tragus stimulation (ATS) has been demonstrated to reduce the release of cardiac injury biomarkers and ventricular arrhythmias and to improve contractile function in patients with acute myocardial infarction. Purpose To determine whether ATS, as RIC, induces release of cardioprotective factors into the circulation. Methods Healthy volunteers (3 females, 7 males, 26±5 years) were randomized to receive ATS or RIC, respectively, with an interval of at least two weeks between protocols. ATS was induced by bipolar electrical rectangular pulses of 200 µs width and a frequency of 30 Hz. The amplitude (5.5 ± 0.81 mA) was set for each volunteer to not be perceived as uncomfortable. A microprocessor-controlled circuit periodically interrupted the stimulation signal after 5 s of stimulation for 5 s. ATS was continued over 30 min. RIC served as a reference to induce the release of cardioprotective factors by 3 x 5 min blood pressure cuff inflation at 200 mmHg on the left upper arm/ 5 min deflation. Venous blood samples were taken before and 60 min after ATS or RIC, respectively, and used to prepare plasma-dialysates (1:10 dialysis against buffer for 24 h, cut-off 12-14 kDa). Male Lewis rats were sacrificed and their hearts isolated and perfused at constant pressure with buffer. Plasma-dialysates from samples taken before and 60 min after ATS or RIC, respectively, were infused for 8 min into rat hearts followed by 2 min washout before global 30 min ischemia/ 120 min reperfusion. Infarct size was demarcated by triphenyl tetrazolium chloride staining and calculated as percent of ventricular mass. Results With infusion of plasma-dialysate before ATS, infarct size was 30.9 ± 4.5% of ventricular mass and not different from that with infusion of plasma-dialysate before RIC (35.8 ± 5.8 %). Infusion of plasma-dialysate after ATS reduced infarct size to 18.3 ± 3.9 %. This cardioprotective effect was similar to that seen with infusion of plasma-dialysate after RIC (20.1 ± 3.5 %). Conclusion ATS induces the release of cardioprotective factors into the circulation of healthy volunteers. Plasma-dialysates after ATS or RIC, respectively, reduce myocardial infarct size by the same magnitude in ex vivo isolated perfused rat hearts with global ischemia/ reperfusion.

Disrupted interoceptive awareness by auditory distractor: Difficulty inferring the internal bodily states?

Recent studies have associated interoceptive awareness, the perception of internal bodily sensations, with a predictive mechanism of perception across all sensory modalities. According to the framework, volitional attention plays a pivotal role in interoceptive awareness by prioritizing interoceptive sensations over exteroceptive ones. Consequently, it is hypothesized that the presence of irrelevant stimuli would disrupt the attentional modulation and interoceptive awareness, which remains untested. In this study, we investigated if interoceptive awareness is diminished by unrelated auditory distractors to validate the proposed perceptual framework. A total of 30 healthy human volunteers performed the heartbeat counting task both with and without auditory distractors. Additionally, we measured participant’s psychophysiological traits related to interoception, including the high-frequency component of heart rate variability (HF-HRV) and trait interoceptive sensibility. The results showed that interoceptive accuracy, confidence, and heartbeat intensity decreased in the presence of distractor sound. Moreover, individuals with higher HF-HRV and a greater tendency to worry about bodily states experienced a more pronounced distractor effect on interoceptive awareness. These results provide support for the perceptual mechanism of interoceptive awareness in terms of the predictive process, highlighting the impact of relative precision across interoceptive and exteroceptive signals on perceptual experiences.

Infra-slow fluctuations in cortical potentials and respiration drive fast cortical EEG rhythms in sleeping and waking states

ObjectiveInfra-slow fluctuations (ISF, 0.008–0.1 Hz) characterize hemodynamic and electric potential signals of human brain. ISFs correlate with the amplitude dynamics of fast (>1 Hz) neuronal oscillations, and may arise from permeability fluctuations of the blood–brain barrier (BBB). It is unclear if physiological rhythms like respiration drive or track fast cortical oscillations, and the role of sleep in this coupling is unknown. MethodsWe used high-density full-band electroencephalography (EEG) in healthy human volunteers (N = 21) to measure concurrently the ISFs, respiratory pulsations, and fast neuronal oscillations during periods of wakefulness and sleep, and to assess the strength and direction of their phase-amplitude coupling. ResultsThe phases of ISFs and respiration were both coupled with the amplitude of fast neuronal oscillations, with stronger ISF coupling being evident during sleep. Phases of ISF and respiration drove the amplitude dynamics of fast oscillations in sleeping and waking states, with different contributions. ConclusionsISFs in slow cortical potentials and respiration together significantly determine the dynamics of fast cortical oscillations. SignificanceWe propose that these slow physiological phases play a significant role in coordinating cortical excitability, which is a fundamental aspect of brain function.

The study of tryptophol containing emulgel on fungal reduction and skin irritation

Tryptophol (TOH), a fungal quorum-sensing molecule, that possesses anti-fungal activities for controlling the growth of human pathogenic fungi. In the present study, we developed TOH-containing emulgel formulations and examined the antifungal activities and potential use as topical treatments on the skin. The results showed that TOH-containing emulgel at 1000 μM has excellent physical characteristics as homogenous, stability, and inhibits the growth of 30 species of human pathogenic fungi in vitro. TOH-containing emulgel did not cause skin irritation in mouse model of irritation and in healthy human volunteers. Moreover, an increase in skin hydration and a decrease in trans-epidermal water loss (TEWL) were observed after TOH-containing emulgel treatment on human skin. Our findings indicated that TOH-containing emulgel can be utilize as an antifungal agent for topical treatment against fungal infections on the skin.

Gelled Liquid Crystal Nanocarriers for Improved Antioxidant Activity of Resveratrol.

As many natural origin antioxidants, resveratrol is characterized by non-suitable physicochemical properties for its topical application. To allow its benefits to manifest on human skin, resveratrol has been entrapped within liquid crystal nanocarriers (LCNs) made up of glyceryl monooleate, a penetration enhancer, and DSPE-PEG 750. The nanosystems have been more deeply characterized by using dynamic light scattering and Turbiscan Lab® Expert optical analyzer, and they have been tested in vitro on NCTC 2544. The improved antioxidant activity of entrapped resveratrol was evaluated on keratinocyte cells as a function of its concentration. Finally, to really propose the resveratrol-loaded LCNs for topical use, the systems were gelled by using two different gelling agents, poloxamer P407 and carboxymethyl cellulose, to improve the contact time between skin and formulation. The rheological features of obtained gels were evaluated using two important methods (microrheology at rest and dynamic rheology), before testing their safety profile on human healthy volunteers. The obtained results showed the ability of LCNs to improve antioxidant activity of RSV and the gelled LCNs showed good rheological profiles. In conclusion, the results confirmed the potentiality of gelled resveratrol-loaded nanosystems for skin disease, mainly related to their antioxidant effects.

Sex Differences in the Efficacy of Mediterranean Diet Treatment: A Nutrigenomics Pilot Study.

The Mediterranean diet (MedD) has been shown to have beneficial effects on health, well-being, and mental status. It potentially modulates gene expressions linked to oxidative stress, contributing to its beneficial effects on overall health. The aim of this study was to assess the effects of MedD treatment in healthy human volunteers on the expression of ten genes related to oxidative stress and inflammation in women and men. Of 30 enrolled subjects, 17 were eligible, 10 women and 7 men. All of them received the same MedD treatment. Before and after 8 weeks of MedD treatment, an evaluation of body composition, blood tests, and anthropometric and clinical parameters was performed. Furthermore, 10 genes were amplified and analyzed. The study showed significant differences between females and males in body composition and biochemical parameters before and after MedD treatment. Significant differences between females and males in Resistance Force (p < 0.009) and Diastolic Blood Pressure (p < 0.04) before MedD treatment, and in High-Density Lipoprotein (p < 0.02) after MedD treatment, were observed. Moreover, a significant upregulation of Apolipoprotein E and Angiotensin I-Converting Enzyme in females has been shown. Sex differences impact MedD treatment response, and influence the genetic expression of genes related to oxidative stress; our findings may help to personalize diet therapy and contribute to overall health and well-being.

Examination of the Rate and Extent of Drug Released from Commercial Topical Delivery Systems During Wear: An Example with Lidocaine Topical Systems.

This study aimed to determine the extent and rate of lidocaine released in vivo from two bioequivalent topical delivery systems (TDS) by using complementary assessments: pharmacokinetic analysis in healthy human volunteers, and residual lidocaine in TDS following 12h of wear. The goal was to explore a potentially more clinically meaningful strength presentation than percent active pharmaceutical ingredient loaded in topical systems. A three-arm, open-label, crossover clinical study was conducted in 23 human subjects, with 5% lidocaine topical systems from two manufacturers, and intravenous lidocaine administration. Residual drug and LC-MS/MS analyses were performed on worn TDS and serum samples. The rate and extent of drug released from the TDS during wear were determined through (1) calculations of consumed lidocaine via analysis of residual drug in worn TDS, and (2) a pharmacokinetic approach via derivation of the absolute clearance and serum lidocaine concentration at steady state. Overall the pharmacokinetic approach underestimated the amount transferred to the subject and exhibited greater variability, which may relate to natural inter-subject variability in pharmacokinetic parameters. Further, lidocaine TDS are intended for localized, not systemic, delivery and this may also explain some of the variability seen in the systemic serum concentrations. The residual drug and pharmacokinetic approaches align well for transdermal formulations, but the differences in administration route (topical versus transdermal) all but eliminates the potential use of the pharmacokinetic approach unless additional compartmental modeling is explored.

De novo assembly of Roseomonas mucosa isolates from healthy human volunteers used to treat atopic dermatitis.

Roseomonas mucosa is a bacterium that is found in the natural microbiota of human skin. Here, we present de novo sequence assemblies from R. mucosa isolated from the skin microflora of three healthy human volunteers that were used to treat atopic dermatitis patients.

Flexible array coil for cervical and extraspinal (FACE) MRI at 3.0 Tesla.

Objective.High-resolution MRI of the cervical spine (c-spine) and extraspinal neck region requires close-fitting receiver coils to maximize the signal-to-noise ratio (SNR). Conventional, rigid C-spine receiver coils do not adequately contour to the neck to accommodate varying body shapes, resulting in suboptimal SNR. Recent innovations in flexible surface coil array designs may provide three-dimensional (3D) bendability and conformability to optimize SNR, while improving capabilities for higher acceleration factors.Approach.This work describes the design, implementation, and preliminaryin vivotesting of a novel, conformal 23-channel receive-only flexible array for cervical and extraspinal (FACE) MRI at 3-Tesla (T), with use of high-impedance elements to enhance the coil's flexibility. Coil performance was tested by assessing SNR and geometry factors (g-factors) in a phantom compared to a conventional 21-channel head-neck-unit (HNU).In vivoimaging was performed in healthy human volunteers and patients using high-resolution c-spine and neck MRI protocols at 3T, including MR neurography (MRN).Main results.Mean SNR with the FACE was 141%-161% higher at left, right, and posterior off-isocenter positions and 4% higher at the isocenter of the phantom compared to the HNU. Parallel imaging performance was comparable for an acceleration factor (R) = 2 × 2 between the two coils, but improved forR= 3 × 3 with meang-factors ranging from 1.46-2.15 with the FACE compared to 2.36-3.62 obtained with the HNU. Preliminary human volunteer and patient testing confirmed that equivalent or superior image quality could be obtained for evaluation of osseous and soft tissue structures of the cervical region with the FACE.Significance.A conformal and highly flexible cervical array with high-impedance coil elements can potentially enable higher-resolution imaging for cervical imaging.

Illuminating Insights: Clinical Study Harnessing Pharmacoscintigraphy for Permeation Study of Radiolabeled Nimesulide Topical Formulation in Healthy Human Volunteers.

An alternative to oral administration for the delivery of therapeutic substances is the topical route, which frequently has comparable efficacy but may have a better tolerability profile. Gamma scintigraphy is a noninvasive technique that involves the application of radioactive substances to conduct biodistribution studies of therapeutic substances delivered through various routes. Nimesulide (NSD) was radiolabeled with technetium pertechnetate (Technetium99m [99mTc]) and this radiolabeled drug complex (99mTc-NSD) was used to prepare a topical gel formulation. The permeation of the radiolabeled drug from the topical gel was determined by gamma scintigraphy on human volunteers. The region of interest was calculated for the quantification of permeated radiolabeled drugs. This was observed that the mean percentage permeation of 99mTc-NSD was found to be 0.32 ± 0.22 to 36.37 ± 2.86 at 5 and 240 min. It was demonstrated that gamma scintigraphy may be a noninvasive and reliable technique for the determination of drug permeation through topical routes.

Hematinic Potential of Olive Leaf Extract: Evidence from an In Vivo Study in Mice and a Pilot Study in Healthy Human Volunteers.

Natural resources have recently received considerable attention as complementary or alternative hematinic agents. In this regard, olive leaf extract, which is rich in bioactive phenolic compounds, has been reported to induce erythroid differentiation in human hematopoietic stem cells. Therefore, in the present study, we aimed to explore the potential hematinic properties of aqueous olive leaf extract (WOL) in vivo. After 24 days of administering WOL to healthy mice orally, red blood cell (RBC), hematocrit, reticulocyte, and reticulocyte hemoglobin content (CHr) showed a significant increase. Additionally, WOL promoted plasma iron levels and the expression of splenic ferroportin (Fpn), an iron transporter. Additionally, a single-arm pilot study involving a limited number of healthy volunteers was conducted to assess WOL's feasibility, compliance, and potential benefits. Following an 8-week intervention with WOL, RBC count and hemoglobin level were significantly increased. Notably, there were no significant changes in the safety measures related to liver and kidney functions. Furthermore, we identified oleuropein and oleuroside as the active components in WOL to induce erythroid differentiation in the K562 cell line. Altogether, our study presents evidence of the hematinic potential of WOL in the in vivo studies, opening up exciting possibilities for future applications in preventing or treating anemia.

TRPA1 Antagonist LY3526318 Inhibits the Cinnamaldehyde-Evoked Dermal Blood Flow Increase: Translational Proof of Pharmacology.

Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose-dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose-dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde-induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross-species differences in potency of the compound at TRPA1. Exposure-response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde-evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.

Where in the brain do internally generated and externally presented visual information interact?

Conscious experiences normally result from the flow of external input into our sensory systems. However, we can also create conscious percepts independently of sensory stimulation. These internally generated percepts are referred to as mental images, and they have many similarities with real visual percepts. Consequently, mental imagery is often referred to as “seeing in the mind’s eye”. While the neural basis of imagery has been widely studied, the interaction between internal and external sources of visual information has received little interest. Here we examined this question by using fMRI to record brain activity of healthy human volunteers while they were performing visual imagery that was distracted with a concurrent presentation of a visual stimulus. Multivariate pattern analysis (MVPA) was used to identify the brain basis of this interaction. Visual imagery was reflected in several brain areas in ventral temporal, lateral occipitotemporal, and posterior frontal cortices, with a left-hemisphere dominance. The key finding was that imagery content representations in the left lateral occipitotemporal cortex were disrupted when a visual distractor was presented during imagery. Our results thus demonstrate that the representations of internal and external visual information interact in brain areas associated with the encoding of visual objects and shapes.

Main urinary biomarkers of golden berries (Physalis peruviana) following acute and short-term nutritional intervention in healthy human volunteers

The metabolites entering the bloodstream and being excreted in urine as a result of consuming golden berries are currently unidentified. However, these metabolites potentially underlie the health benefits observed in various in vitro, animal, and human models. A nutritional intervention with 18 healthy human volunteers was performed, and urine was collected at baseline and after acute and short-term fruit consumption for 19 days. After UPLC-ESI/QToF-MS analysis, untargeted metabolomics was performed on the urine samples, and from the 50 most discriminant ions (VIP > 2) generated by a validated PLS-DA model (CV-ANOVA = 3.7e-35; R^2Y = 0.86, Q^2Y = 0.62 and no overfitting), 22 compounds were identified with relatively high confidence. The most discriminant metabolites confirmed by DHS/GC-MS2 analysis of volatiles in urine were sesquiterpenes (C15H22): 3 stereoisomers, β-vatirenene, β-vetivenene, and β-vetispirene, and 2 isomers, eremophila-1(10),8,11-triene and α-curcumene. Another major urinary biomarker was 4β-hydroxywithanolide E and its phase II derivatives, which were observed in urine for all individual up to 24 h after the fruit was consumed; thus, the bioavailability of this biomarker in humans was demonstrated for the first time. Additionally, the excretion of certain acylcarnitines and hypoxanthine in urine increased after golden berry consumption, which may be associated with a detoxifying effect and may occur because fats were utilized rather than carbohydrates to meet the body’s energy needs. The main biomarkers of golden berry consumption are specific to this fruit, confirming its potential for the functional food market.

BCG vaccination induces innate immune memory in γδ T cells in humans.

Bacillus Calmette-Guérin vaccine is well known for inducing trained immunity in myeloid and natural killer cells, which can explain its cross-protective effect against heterologous infections. Although displaying functional characteristics of both adaptive and innate immunity, γδ T-cell memory has been only addressed in a pathogen-specific context. In this study, we aimed to determine whether human γδ T cells can mount trained immunity and therefore contribute to the cross-protective effect of the Bacillus Calmette-Guérin vaccine. We investigated in vivo induction of innate memory in γδ T cells by Bacillus Calmette-Guérin vaccination in healthy human volunteers by combining single-cell RNA sequencing technology with immune functional assays. The total number of γδ T cells and membrane markers of activation was not influenced by Bacillus Calmette-Guérin vaccination. In contrast, Bacillus Calmette-Guérin changed γδ T cells' transcriptional programs and increased their responsiveness to heterologous bacterial and fungal stimuli, including lipopolysaccharide and Candida albicans, as simultaneously characterized by higher tumor necrosis factor and interferon γ production, weeks after vaccination. Human γδ T cells in adults display the potential to develop a trained immunity phenotype after Bacillus Calmette-Guérin vaccination.

Bio-evaluation of poly(lactic-co-glycolic) acid nanoparticles loaded with radiolabelled rifampicin.

The poly(lactic-co-glycolic) acid (PLGA) nanoparticles of tubercular drugs have been demonstrated to have a sustained release profile over 7 days. There is no information on the location or mode of release of these nanoparticles in living systems. Therefore, we have planned the study to explore the pharmacokinetics and biodistribution of PLGA rifampicin nanoparticles in healthy human volunteers. We aim to study the distribution pattern of PLGA-loaded nano-formulation of radiolabelled rifampicin in humans. Rifampicin was labelled with 99m Tc by indirect method and nanoparticles were prepared by a single emulsion evaporation method. To investigate the pharmacokinetics and biodistribution of nanoparticles, a single dose of 450 mg of rifampicin was administered orally to healthy human volunteers divided into two different groups. Following a single oral dosage of the rifampicin nanoformulation, the pharmacokinetic (PK) parameters were significantly different between the nanoparticle and conventional groups: area under the concentration-time curve (AUC = 113.8 vs. 58.6; P < .001), mean residence time (MRT = 16.2 vs. 5.8; P < .01) and elimination rate constant (Ke = 0.04 vs. 0.10; P < .05). Also, Single-photon emission computed tomography/computed tomography (SPECT/CT) images revealed biodistribution of nanoparticles in the distal portions of the intestine, which is consistent with our dosimetry analysis. Significant difference in PK parameters and biodistribution of nanoparticles in spleen and lymph nodes with maximum deposition were observed in the large intestine. The nanoparticle distribution pattern may be advantageous for the treatment of intestinal or lymph node tuberculosis (TB) and has the potential to result in a lower dose of rifampicin nanoformulation for the treatment of pulmonary TB.

Connectivity by the Frontal Aslant Tract (FAT) Explains Local Functional Specialization of the Superior and Inferior Frontal Gyri in Humans When Choosing Predictive over Reactive Strategies: A Tractography-Guided TMS Study.

Predictive and reactive behaviors represent two mutually exclusive strategies in a sensorimotor task. Predictive behavior consists in internally estimating timing and features of a target stimulus and relies on a cortical medial frontal system [superior frontal gyrus (SFG)]. Reactive behavior consists in waiting for actual perception of the target stimulus and relies on the lateral frontal cortex [inferior frontal gyrus (IFG)]. We investigated whether SFG-IFG connections by the frontal aslant tract (FAT) can mediate predictive/reactive interactions. In 19 healthy human volunteers, we applied online transcranial magnetic stimulation (TMS) to six spots along the medial and lateral terminations of the FAT, during the set period of a delayed reaction task. Such scenario can be solved using either predictive or reactive strategies. TMS increased the propensity toward reactive behavior if applied to a specific portion of the IFG and increased predictive behavior when applied to a specific SFG spot. The two active spots in the SFG and IFG were directly connected by a sub-bundle of FAT fibers as indicated by diffusion-weighted imaging (DWI) tractography. Since FAT connectivity identifies two distant cortical nodes with opposite functions, we propose that the FAT mediates mutually inhibitory interactions between SFG and IFG to implement a "winner takes all" decisional process. We hypothesize such role of the FAT to be domain-general, whenever competition occurs between internal predictive and external reactive behaviors. Finally, we also show that anatomic connectivity is a powerful factor to explain and predict the spatial distribution of brain stimulation effects.SIGNIFICANCE STATEMENT We interact with sensory cues adopting two main mutually-exclusive strategies: (1) trying to anticipate the occurrence of the cue or (2) waiting for the GO-signal to be manifest and react to it. Here, we showed, by using noninvasive brain stimulation [transcranial magnetic stimulation (TMS)], that two specific cortical regions in the superior frontal gyrus (SFG) and the inferior frontal gyrus (IFG) have opposite roles in facilitating a predictive or a reactive strategy. Importantly these two very distant regions but with highly interconnected functions are specifically connected by a small white matter bundle, which mediates the direct competition and exclusiveness between predictive and reactive strategies. More generally, implementing anatomic connectivity in TMS studies strongly reduces spatial noise.

Effects of donation frequency on U.S. source plasma donor health.

Plasma-derived medicinal products (PDMPs) are essential, life-saving medicines manufactured from plasma donated by healthy human volunteers. PDMPs are used to treat a range of rare, serious, and chronic conditions, often genetic in origin. Approximately 70% of the Source Plasma (SP) used for PDMP manufacturing comes from United States (US). The hypothesis of the study is that US donation frequency does not impair donor self-reported functional health and well-being. A total of 5608 SP donors from 14 US SP centers were enrolled in a cross-sectional study to assess self-reported health related quality of life (HRQoL) and well-being. By sex, donors were assigned to one of four groups, according to their frequency of SP donation in the 12 months before enrollment. The SF-36v2® Health Survey (SF-36v2) and a survey assessing the frequency of various health conditions that may be associated with impaired immune function over different time periods were used. There were no statistically significant differences in SF-36v2 scores between any of the donor frequency groups, compared with new donors after controlling for potential confounding and accounting for multiple comparisons among males and females. Cough, cold, occasional fatigue, and sore throat were the most reported health conditions or symptoms, but there was no clear difference among sex or frequency groups. The self-reported data in this study support the hypothesis that compensated donations at US FDA permitted frequencies and volumes are consistent with maintaining donor health. Compared with the general population, SP donors have comparable or better health than the general population.

Numerical analysis of airflow and particle deposition in multi-fidelity designs of nasal replicas following nasal administration

Background and ObjectiveAn improved understanding of flow behaviour and particle deposition in the human nasal airway is useful for optimising drug delivery and assessing the implications of pollutants and toxin inhalation. The geometry of the human nasal cavity is inherently complex and presents challenges and manufacturing constraints in creating a geometrically realistic replica. Understanding how anatomical structures of the nasal airway affect flow will shed light on the mechanics underpinning flow regulation in the nasal pharynx and provide a means to interpret flow and particle deposition data conducted in a nasal replica or model that has reduced complexity in terms of their geometries. This study aims to elucidate the effects of sinus and reduced turbinate length on nasal flow and particle deposition efficiencies. MethodsA complete nasal airway with maxillary sinus was first reconstructed using magnetic resonance imaging (MRI) scans obtained from a healthy human volunteer. The basic model was then modified to produce a model without the sinus, and another with reduced turbinate length. Computational fluid dynamics (CFD) was used to simulate flow in the nasal cavity using transient flow profiles with peak flow rates of 15 L/min, 35 L/min and 55 L/min. Particle deposition was investigated using discrete phase modelling (DPM). ResultsResults from this study show that simplifying the nasal cavity by removing the maxillary sinus and curved sections of the meatus only has a minor effect on airflow. By mapping the spatial distribution of monodisperse particles (10 μm) in the three models using a grid map that consists of 30 grids, this work highlights the specific nasal airway locations where deposition efficiencies are highest, as observed within a single grid. It also shows that lower peak flow rates result in higher deposition differences in terms of location and deposition quantity, among the models. The highest difference in particle deposition among the three nasal models is ∼10%, and this is observed at the beginning of the middle meatus and the end of the pharynx, but is only limited to the 15 L/min peak flow rate case. Further work demonstrating how the outcome may be affected by a wider range of particle sizes, less specific to the pharmaceutical industries, is warranted. ConclusionA physical replica manufactured without sections of the middle meatus could still be adequate in producing useful data on the deposition efficiencies associated with an intranasal drug formulation and its delivery device.