How material sensory properties and individual differences influence the haptic aesthetic appeal of visually presented stimuli.

Touch plays a crucial role for humans. Despite its centrality in sensory experiences, the field of haptic aesthetics is underexplored. So far, existing research has revealed that preferences in the haptic domain are related to stimulus properties and the Gestalt laws of grouping. Additionally, haptic aesthetics is influenced by top-down processes, e.g., stimulus familiarity, and is likely to be modulated by personality and expertise. To further our understanding of these influences on haptic aesthetic appraisal, the current study investigated the imagined haptic aesthetic appeal of visually presented material surfaces, considering the role of haptic expertise, Need for touch, personality traits. The results revealed a positive influence of familiarity, simplicity, smoothness, warmth, lightness, dryness, slipperiness and a negative influence of complexity on individuals' aesthetic responses. While the study failed to support the predicted influence of Need for touch and haptic expertise on aesthetic responses, results did reveal an influence of openness to experience, conscientiousness and neuroticism. Despite the limitations related to the indirect stimuli presentation (vision only), the findings contribute to the relatively unexplored role of bottom-up and top-down features in haptic aesthetics that might be incorporated into the design of consumers' products to better meet their preferences.

Drug content determination of low-dosed hot-melt extruded filaments using Raman spectroscopy.

The aim of this study was to evaluate the suitability of a non-disruptive Raman spectroscopic method to quantify drug concentrations below 5 w% within a polymer matrix produced by hot-melt extrusion (HME). For calibration, praziquantel (PZQ)-polyvinylpyrrolidone-vinylacetat-copolymer (PVP-VA) mixtures were extruded. By focusing the laser light of the Raman probe to a diameter of 1 mm and implementing a self-constructed filament holder, the signal-to-noise (S/N) ratio could be reduced considerably. The obtained Raman spectra show quite high fluorescence, which is likely to be caused by dissolved pharmaceutical active ingredient (API) in the polymer matrix. For content determination, HPLC analysis was conducted as a reference method using the same filament segments. A partial least squares (PLS) model, regressing the PZQ concentrations from HPLC method analysis versus the off-line collected Raman spectra, was developed. The linear correlation for a suitable extrusion run for the production of low-dosed filaments (extrusion 1, two kneading zones) is acceptable (R2 = 0.9915) while the correlation for a extrusion set-up with low miscibility (extrusion 2; without kneading zone) is unacceptable (R2 = 0.5349). The predictive performance of the calibration model from extrusion 1 is rated by the root mean square error of estimation (RMSEE), which was 0.08%. This calibration can now be used to validate the content of low-dosed filaments during HME.

The Impact of Nasal Intubation on Feeding Outcomes in Neonates Requiring Cardiac Surgery: A Randomized Control Trial.

Neonates who require surgery for congenital heart disease (CHD) frequently have difficulty with oral feeds post-operatively and may require a feeding tube at hospital discharge. The purpose of this study was to determine the effect of oral or nasal intubation route on feeding method at hospital discharge. This was a non-blinded randomized control trial of 62 neonates who underwent surgery for CHD between 2018 and 2021. Infants in the nasal (25 patients) and oral (37 patients) groups were similar in terms of pre-operative risk factors for feeding difficulties including completed weeks of gestational age at birth (39 vs 38 weeks), birthweight (3530 vs 3100 g), pre-operative PO intake (92% vs 81%), and rate of pre-operative intubation (22% vs 28%). Surgical risk factors were also similar including Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category (3.9 vs 4.1), shunt placement (32% vs 41%), cardiopulmonary bypass time (181 vs 177 min), and cross-clamp time (111 vs 105 min). 96% of nasally intubated patients took full oral feeds by discharge as compared with 78% of orally intubated infants (p = 0.05). Nasally intubated infants reach full oral feeds an average of 3 days earlier than their orally intubated peers. In this cohort of patients, nasally intubated infants reach oral feeds more quickly and are less likely to require supplemental tube feeding in comparison to orally intubated peers. Intubation route is a potential modifiable risk factor for oral aversion and appears safe in neonates. The study was approved by the University of Virginia Institutional Review Board for Health Sciences Research and was retrospectively registered on clinicaltrials.gov (NCT05378685) on May 18, 2022.

3D Printed Mini-Floating-Polypill for Parkinson's Disease: Combination of Levodopa, Benserazide, and Pramipexole in Various Dosing for Personalized Therapy.

Therapy for Parkinson's disease is quite challenging. Numerous drugs are available for symptomatic treatment, and levodopa (LD), in combination with a dopa decarboxylase inhibitor (e.g., benserazide (BZ)), has been the drug of choice for years. As the disease progresses, therapy must be supplemented with a dopamine agonist (e.g., pramipexole (PDM)). Side effects increase, as do the required dose and dosing intervals. For these specific requirements of drug therapy, the 3D printing method fused deposition modelling (FDM) was applied in this study for personalized therapy. Hot melt extrusion was utilized to produce two different compositions into filaments: PDM and polyvinyl alcohol for rapid drug release and a fixed combination of LD/BZ (4:1) in an ethylene-vinyl acetate copolymer matrix for prolonged drug release. Since LD is absorbed in the upper gastrointestinal tract, a formulation that floats in gastric fluid was desired to prolong API absorption. Using the FDM 3D printing process, different polypill geometries were printed from both filaments, with variable dosages. Dosage forms with 15−180 mg LD could be printed, showing similar release rates (f2 > 50). In addition, a mini drug delivery dosage form was printed that released 75% LD/BZ within 750 min and could be used as a gastric retentive drug delivery system due to the floating properties of the composition. The floating mini-polypill was designed to accommodate patients' swallowing difficulties and to allow for individualized dosing with an API release over a longer period of time.

Introducing Fiber-Assisted Colorimetric Measurements as a Quality Control Tool of Hot Melt Extruded Filaments.

Pharmaceutical and medicinal printing technologies allow personalization and on-demand manufacturing of drug and medicinal products. Being able to manufacture patient tailored dosage forms or medical devices in a pharmacy, medical office, dental laboratory, or hospital at the point of care raises new demands on quality control procedures. For Fused Deposition Modeling, for example, it must be ensured that the starting materials, the (drug-loaded) filaments, are not accidentally exchanged by the operator. This study investigated the potential of colorimetric measurements for direct and indirect determination of the identity of extruded filaments consisting of polymer matrix, different API and/or coloring agents. Since reflection measurements were affected by surface properties of the filaments, a self-constructed filament holder was utilized with an optical fiber positioned in a 180° angle to a white light LED to perform transmission measurements. It was possible to distinguish filaments with different API concentrations by their color values, taking into account that transmission partially decreased by increased API concentration. Therefore, the intensity of the light source had to be adjusted depending on the transparency of the filament. It was shown that colorimetry can be used as a quality control tool to detect differences in drug-loading and is able to distinguish various extruded batches. Additionally, if differences in API/polymer concentrations do not lead to significant changes in L*a*b values, coloring agents were used as additives in low concentrations to color code filaments. In future studies, the setup must be supplemented with a standardized light source and obscuring filters for light intensity adjustments.

On the etiology of aesthetic chills: a behavioral genetic study.

Aesthetic chills, broadly defined as a somatic marker of peak emotional-hedonic responses, are experienced by individuals across a variety of human cultures. Yet individuals vary widely in the propensity of feeling them. These individual differences have been studied in relation to demographics, personality, and neurobiological and physiological factors, but no study to date has explored the genetic etiological sources of variation. To partition genetic and environmental sources of variation in the propensity of feeling aesthetic chills, we fitted a biometrical genetic model to data from 14,127 twins (from 8995 pairs), collected by the Netherlands Twin Register. Both genetic and unique environmental factors accounted for variance in aesthetic chills, with heritability estimated at 0.36 ([0.33, 0.39] 95% CI). We found females more prone than males to report feeling aesthetic chills. However, a test for genotype x sex interaction did not show evidence that heritability differs between sexes. We thus show that the propensity of feeling aesthetic chills is not shaped by nurture alone, but it also reflects underlying genetic propensities.

Embedding a Sensitive Liquid-Core Waveguide UV Detector into an HPLC-UV System for Simultaneous Quantification of Differently Dosed Active Ingredients during Drug Release.

Individual dosing of pharmaceutics and personalized medicine have become important with regard to therapeutic safety. Dose adjustments, biorelevant drug release and combination of multiple active substances in one dosage form for the reduction in polymedication are essential aspects that increase the safety and acceptance of the patient's pharmacotherapy. Therefore, not only innovative drug products but also new analytical methods are needed during the drug development phase and for quality control that can simultaneously determine different active ingredients and cover wide concentration ranges. We investigated a liquid-core waveguide UV absorbance flow cell detector coupled to an existing HPLC-UV system. A Teflon AF 2400 capillary tubing of 20 cm length was connected in series to the HPLC flow line and enabled a lower limit of quantification of 1 ng/mL pramipexole (increase in sensitivity by 20 compared to common 0.9 cm flow cells). This allowed the low-concentration of pramipexole and the higher concentrations of levodopa and benserazide occurring during drug release to be determined in a single chromatographic run within 22.5 min.

Dose-independent drug release from 3D printed oral medicines for patient-specific dosing to improve therapy safety.

Fused deposition modelling (FDM) 3D printing provides the ability to address individual patients' therapeutic needs without having to change the formulation every time. This is particularly interesting for dosing and release modelling. In this study, a geometry model was developed that can represent variable dosages while keeping the surface area to volume (SA/V) ratio alike, so the drug release profiles remain similar. The model was tested on three different formulations. Two BCS I active pharmaceutical ingredients (API), pramipexole and levodopa, and one BCS II API, praziquantel, were used. Polyvinyl alcohol (PVA, water soluble) and a combination of vinylpyrrolidone-vinyl acetate copolymer (PVP-VA, water soluble) and ethylene-vinyl acetate (EVA, water insoluble) were used as the polymer matrix. The curves were compared using the similarity factor (f2 value) and mean dissolution time (MDT). Using a hollow cylinder-based (HCb) geometry model, a dose-independent drug release could be realized. For the PVA formulations, an 8-fold dose change could be obtained and for the EVA-PVP-VA formulation a factor of 5.5 could be achieved, with f2 > 50. Due to the layer structure of the printed objects, very fine dose variation of 0.13 mg per layer is possible within these models. This allows variable dosing in small steps with only one basis formulation.

Blind-Watermarking-Proof-of-Concept of a Novel Approach to Ensure Batch Traceability for 3D Printed Tablets.

Falsified medicines are a major issue and a threat around the world. Various approaches are currently being investigated to mitigate the threat. In this study, a concept is tested that encodes binary digits (bits) on the surface of Fused Deposition Modelling (FDM) 3D printed geometries. All that is needed is a computer, a FDM 3D printer and a paper scanner for detection. For the experiments, eleven different formulations were tested, covering the most used polymers for 3D printing in pharma: Ethylene-vinyl acetate (EVA), polyvinyl alcohol (PVA), polylactic acid (PLA), Hypromellose (HPMC), ethyl cellulose (EC), basic butylated-methacrylate-copolymer (EPO), and ammonio-methacrylate-copolymer type A (ERL). In addition, the scanning process and printing process were evaluated. It was possible to print up to 32 bits per side on oblong shaped tablets corresponding to the dimensions of market preparations of oblong tablets and capsules. Not all polymers or polymer blends were suitable for this method. Only PVA, PLA, EC, EC+HPMC, and EPO allowed the detection of bits with the scanner. EVA and ERL had too much surface roughness, too low viscosity, and cooled down too slowly preventing the detection of bits. It was observed that the addition of a colorant or active pharmaceutical ingredient (API) could facilitate the detection process. Thus, the process could be transferred for 3D printed pharmaceuticals, but further improvement is necessary to increase robustness and allow use for more materials.

Precise Dosing of Pramipexole for Low-Dosed Filament Production by Hot Melt Extrusion Applying Various Feeding Methods.

The aim of this research was the production of low-dosed filaments via hot-melt extrusion (HME) with the model drug pramipexole for the treatment of Parkinson's disease. The active pharmaceutical ingredient (API) and one of the polymers polyvinyl alcohol (PVA) or basic butylated methacrylate copolymer (bPMMA) were fed by various dosing techniques with the aim of achieving the smallest deviation (RSD) from the target concentration of 0.1% (w/w) pramipexole. It was found that deviation from target pramipexole concentration occurred due to degradation products in bPMMA formulations. Additionally, material temperature above 120 °C led to the formation of the anhydrous form of pramipexole within the extruded filaments and need to be considered in the calculation of the recovered API. This study clearly shows that even if equilibrium state of the extrusion parameters was reached, equilibrium condition for drug content was reached relatively late in the process. In addition, the RSD calculated by the Stange-Poole equation was proposed by us to predict the final content uniformity considering the sample size of the analyzed filament. The calculated RSD, depending on sample size and drug load, can serve as upper and lower limits of variation from target concentration and can be used to evaluate the deviations of drug content in equilibrium conditions of the HME process. The lowest deviations from target concentration in equilibrium condition for drug content were obtained in filaments extruded from previously prepared granule mixtures (RSD = 6.00%, acceptance value = 12.2). These promising results can be transferred to other API-excipient combinations to produce low-dosed filaments, which can be used for, e.g., fused filament 3D printing. The introduced calculation of the RSD by Stange-Poole equation can be used for precise determination of the homogeneity of an extruded batch.

A dot that went for a walk: People prefer lines drawn with human-like kinematics.

A dominant theory of embodied aesthetic experience (Freedberg & Gallese, 2007, Trends in Cognitive Sciences, 11, 197) posits that the appreciation of visual art is linked to the artist's movements when creating the artwork, yet a direct link between the kinematics of drawing actions and the aesthetics of drawing outcomes has not been experimentally demonstrated. Across four experiments, we measured aesthetic responses of students from arts and non-arts backgrounds to drawing movements generated from computational models of human writing. Experiment 1 demonstrated that human-like drawing movements with bell-shaped velocity profiles (Sigma Lognormal [SL] and Minimum Jerk [MJ]) are perceived as more natural and pleasant than movements with a uniform profile, and in both Experiments 1 and 2 movements that were perceived as more natural were also preferred. Experiment 3 showed that this effect persists if lower-level dynamic stimulus features are fully matched across experimental and control conditions. Furthermore, aesthetic preference for human-like movements were associated with greater perceptual fluency in Experiment 3, evidenced by unbiased estimations of the duration of natural movements. In Experiment 4, line drawings with visual features consistent with the dynamics of natural, human-like movements were preferred, but only by art students. Our findings directly link the aesthetics of human action to the visual aesthetics of drawings, but highlight the importance of incorporating artistic expertise into embodied accounts of aesthetic experience.

Quality of FDM 3D Printed Medicines for Pediatrics: Considerations for Formulation Development, Filament Extrusion, Printing Process and Printer Design.

3d printing is capable of providing dose individualization for pediatric medicines and translating the precision medicine approach into practical application. In pediatrics, dose individualization and preparation of small dosage forms is a requirement for successful therapy, which is frequently not possible due to the lack of suitable dosage forms. For precision medicine, individual characteristics of patients are considered for the selection of the best possible API in the most suitable dose with the most effective release profile to improve therapeutic outcome. 3d printing is inherently suitable for manufacturing of individualized medicines with varying dosages, sizes, release profiles and drug combinations in small batch sizes, which cannot be manufactured with traditional technologies. However, understanding of critical quality attributes and process parameters still needs to be significantly improved for this new technology. To ensure health and safety of patients, cleaning and process validation needs to be established. Additionally, adequate analytical methods for the in-process control of intermediates, regarding their printability as well as control of the final 3d printed tablets considering any risk of this new technology will be required. The PolyPrint consortium is actively working on developing novel polymers for fused deposition modeling (FDM) 3d printing, filament formulation and manufacturing development as well as optimization of the printing process, and the design of a GMP-capable FDM 3d printer. In this manuscript, the consortium shares its views on quality aspects and measures for 3d printing from drug-loaded filaments, including formulation development, the printing process, and the printed dosage forms. Additionally, engineering approaches for quality assurance during the printing process and for the final dosage form will be presented together with considerations for a GMP-capable printer design.

Predicting Drug Release from 3D Printed Oral Medicines Based on the Surface Area to Volume Ratio of Tablet Geometry.

3D printing offers the advantage of being able to modify dosage form geometry, which can be exploited to modify release characteristics. In this study, we investigated the influence of the surface area to volume ratio (SA/V) to change and predict release profiles of 3D printed dosage forms. Geometries with varying SA/V and dosages were designed and printed, and drug dissolution was investigated. Three drug substances were used: pramipexole, levodopa (both BCS I) and praziquantel (BCS II). Two polymers were chosen as matrix formers: polyvinyl alcohol (water-soluble) and ethylene vinyl acetate (inert). Drug release was characterized using the mean dissolution time (MDT) and established equations that describe complete dissolution curves were applied. Predictions were validated with previously un-printed dosage forms. Based on an identified MDT-SA/V correlation, the MDT can be predicted with a deviation of ≤5 min for a given SA/V. Using correlations of fit parameters and SA/V, RMSEP values of 0.6-2.8% and 1.6-3.4% were obtained for the BCS I formulations and RMSEP values of 1.0-3.8% were obtained for the BCS II formulation, indicating accurate prediction over a wide range of dissolution profiles. With this approach, MDT and release profiles of dosage forms with a given SA/V can be precisely predicted without performing dissolution tests and vice versa, the required SA/V can be predicted for a desired release profile.

Freeze-drying in protective bags: Characterization of heat and mass transfer.

During lyophilisation of highly potent Active Pharmaceutical Ingredients (APIs) potential contamination of the freeze-drier is an important safety issue. Since the stoppers are in semistoppered position during the lyophilization process, API may contaminate the chamber and cross-contamination may occur as well. In this study two protective bags, which enclose each tray and their influence on heat and mass transfer during freeze-drying were investigated. Sublimation tests were performed using either purified water or solutions containing trehalose as well as hydroxypropyl-ß-cyclodextrin (HPbCD) as bulking agents. During sublimation tests with purified water both bags clearly influenced heat and mass transfer compared to unpacked reference vials. The bag, which was originally designed to be used for steam sterilization, had a massive impact on drying characteristics. The bag membrane becomes the rate limiting factor, generating a separate compartment within the bag. In this compartment vapor pressure is much higher compared to the chamber pressure during primary drying, leading to altered drying conditions. However, drying was still possible. The other bag, which was specifically designed for lyophilization, also had an impact on drying behavior which could be assigned to the foil between shelf and bottom of the vials. This was detectable as differences in Kv values. Membrane resistance, however, becomes negligible when 10% (w/w) trehalose or HPbCD solutions were dried using the later bag as containment. The data reported in this work demonstrate the relevance and value of sublimation tests to understand the lyophilization process, especially when new components are implemented. The data should be considered, when freeze-drying shall be performed using such bags.

Pharmacy Technicians' Roles and Responsibilities in the Community Pharmacy Sector: A Welsh Perspective.

Background: Healthcare delivery models in Wales are changing in response to unprecedented pressure on the National Health Service UK (NHS). Community pharmacies will be prioritised to address public health and clinical needs at a local level. To support the delivery of the new model, pharmacy technicians must be enabled and developed to optimize their roles. The aim of the study was to establish existing roles of pharmacy technicians working in the community pharmacy sector in Wales and to explore barriers and enablers to development. Methods: A combination of quantitative and qualitative methodologies was used, with the main focus on quantitative methods. A total of 83 participants completed an online questionnaire and additional qualitative data were obtained from four semi-structured telephone interviews. Results: The dispensing and final accuracy checking of medicines were reported as core functions of the community pharmacy technician role, with an average of 43% and 57% of time being spent on these roles, respectively. There was some evidence of engagement in leadership and management roles (average of 19%) and limited evidence of delivery of services (average of 6%). Conclusions: There is scope to enable community pharmacy technicians to optimize and further develop their roles. Enablers include the effective use of delegation, workplace support, improved staffing levels and the prioritisation of extended pharmacy technician roles.

Meta-analytic findings reveal lower means but higher variances in visuospatial ability in dyslexia.

Conflicting empirical and theoretical accounts suggest that dyslexia is associated with either average, enhanced, or impoverished high-level visuospatial processing relative to controls. Such heterogeneous results could be due to the presence of wider variability in dyslexic samples, which is unlikely to be identified at the single study level, due to lack of power. To address this, this study reports a meta-analysis of means and variances in high-level visuospatial ability in 909 non-dyslexic and 956 dyslexic individuals. The findings suggest that dyslexia is associated not only with a lower mean performance on visuospatial tasks but also with greater variability in performance. Through novel meta-analytic techniques, we demonstrate a negative effect size for mean differences (-.457), but a positive effect size for SD differences (+.118; SD ratio = 1.107). In doing so, this is the first study to demonstrate impoverished visuospatial processing of the majority of individuals with dyslexia in addition to greater variance in performance in this group. The findings advocate for further consideration of both the presence of, and reasons for, increased variance in perception, attention, and memory across neurodevelopmental disorders.

The Leuven Embedded Figures Test (L-EFT): measuring perception, intelligence or executive function?

Performance on the Embedded Figures Test (EFT) has been interpreted as a reflection of local/global perceptual style, weak central coherence and/or field independence, as well as a measure of intelligence and executive function. The variable ways in which EFT findings have been interpreted demonstrate that the construct validity of this measure is unclear. In order to address this lack of clarity, we investigated to what extent performance on a new Embedded Figures Test (L-EFT) correlated with measures of intelligence, executive functions and estimates of local/global perceptual styles. In addition, we compared L-EFT performance to the original group EFT to directly contrast both tasks. Taken together, our results indicate that performance on the L-EFT does not correlate strongly with estimates of local/global perceptual style, intelligence or executive functions. Additionally, the results show that performance on the L-EFT is similarly associated with memory span and fluid intelligence as the group EFT. These results suggest that the L-EFT does not reflect a general perceptual or cognitive style/ability. These results further emphasize that empirical data on the construct validity of a task do not always align with the face validity of a task.

Superior Disembedding in Children with ASD: New Tests Using Abstract, Meaningful, and 3D Contexts.

Since its initial development, the embedded figures test (EFT) has been used extensively to measure local-global perceptual style. However, little is known about the perceptual factors that influence target detection. The current study aimed to investigate disembedding in children with and without ASD, aged 8-15 years, using the newly developed, stimulus-controlled L-EFT, M-EFT and D-EFT. Firstly, results revealed superior disembedding for children with ASD, irrespective of the type of target or embedding context, although the ASD group took more time in both the M-EFT and D-EFT. Secondly, the number of target lines continuing into the context proved more of a hindrance for the controls. Taken together, these findings provide strong evidence to support the notion of superior disembedding in ASD.

Perceptual flexibility is coupled with reduced executive inhibition in students of the visual arts.

Artists often report that seeing familiar stimuli in novel and interesting ways plays a role in visual art creation. However, the attentional mechanisms which underpin this ability have yet to be fully investigated. More specifically, it is unclear whether the ability to reinterpret visual stimuli in novel and interesting ways is facilitated by endogenously generated switches of attention, and whether it is linked in turn to executive functions such as inhibition and response switching. To address this issue, the current study explored ambiguous figure reversal and executive function in a sample of undergraduate students studying arts and non-art subjects (N = 141). Art students showed more frequent perceptual reversals in an ambiguous figure task, both when viewing the stimulus passively and when eliciting perceptual reversals voluntarily, but showed no difference from non-art students when asked to actively maintain specific percepts. In addition, art students were worse than non-art students at inhibiting distracting flankers in an executive inhibition task. The findings suggest that art students can elicit endogenous shifts of attention more easily than non-art students but that this faculty is not directly associated with enhanced executive function. It is proposed that the signature of artistic skill may be increased perceptual flexibility accompanied by reduced cognitive inhibition; however, future research will be necessary to determine which particular subskills in the visual arts are linked to aspects of perception and executive function.

Local-global processing bias is not a unitary individual difference in visual processing.

A large body of research reports individual differences in local and global visual processing in relation to expertise, culture and psychopathology. However, recent research has suggested that various different measures of local-global processing are not strongly associated with one another, calling its construct validity into question. The current study sought to further explore the validity of local-global processing biases in perception by developing three tasks based on two existing paradigms: the Embedded Figures Test (EFT) and the Navon hierarchical letters task. The newly developed tasks aimed to control for stimulus and response factors that may have impacted upon the reliability of previous research. They were administered to a large sample of undergraduate students (N>100). The results of two new versions of the EFT indicated that disembedding performance is influenced by the structure of the embedding context. In addition, global precedence and interference in the Navon task remained present even when local attentional approaches to global hierarchical stimuli were restricted. Inter-task correlations within the EFT were high but low between the EFT and the Navon task, lending support to the notion that local-global processing is not a monolithic construct, but representative of a number of distinct perceptual abilities and biases. Future research may use these task distinctions to pinpoint more precisely which aspects of perceptual processing characterise specific (clinical) participant populations.