Multimodal imaging of a liver-on-a-chip model using labelled and label-free optical microscopy techniques.

A liver-on-a-chip model is an advanced complex in vitro model (CIVM) that incorporates different cell types and extracellular matrix to mimic the microenvironment of the human liver in a laboratory setting. Given the heterogenous and complex nature of liver-on-a-chip models, brightfield and fluorescence-based imaging techniques are widely utilized for assessing the changes occurring in these models with different treatment and environmental conditions. However, the utilization of optical microscopy techniques for structural and functional evaluation of the liver CIVMs have been limited by the reduced light penetration depth and lack of 3D information obtained using these imaging techniques. In this study, the potential of both labelled as well as label-free multimodal optical imaging techniques for visualization and characterization of the cellular and sub-cellular features of a liver-on-a-chip model was investigated. (1) Cellular uptake and distribution of Alexa 488 (A488)-labelled non-targeted and targeted antisense oligonucleotides (ASO and ASO-GalNAc) in the liver-on-a-chip model was determined using multiphoton microscopy. (2) Hyperspectral stimulated Raman scattering (SRS) microscopy of the C-H region was used to determine the heterogeneity of chemical composition of circular and cuboidal hepatocytes in the liver-on-a-chip model in a label-free manner. Additionally, the spatial overlap between the intracellular localization of ASO and lipid droplets was explored using simultaneous hyperspectral SRS and fluorescence microscopy. (3) The capability of light sheet fluorescence microscopy (LSFM) for full-depth 3D visualization of sub-cellular distribution of A488-ASO and cellular phenotypes in the liver-on-a-chip model was demonstrated. In summary, multimodal optical microscopy is a promising platform that can be utilized for visualization and quantification of 3D cellular organization, drug distribution and functional changes occurring in liver-on-a-chip models, and can provide valuable insights into liver biology and drug uptake mechanisms by enabling better characterization of these liver models.

Technical note: Determination of C Q $C_{Q}$ for a miniature x-ray source using a soft x-ray ionization chamber calibrated in NIST reference beam qualities.

BACKGROUND: The C Q $C_Q$ formalism proposed by Watson et al. allows users of the INTRABEAM (Carl Zeiss Medical AG, Jena, Germany) electronic brachytherapy system to accurately determine the absorbed dose to water, in the absence of a primary dosimetry standard. However, all published C Q $C_Q$ values are for PTW 34013 ionization chambers calibrated in a TW30 reference beam, traceable to PTB (Germany). For North American users, it would be advantageous to have C Q $C_Q$ data for chambers calibrated in a kV reference beam maintained by the National Institute of Standards and Technology (NIST). PURPOSE: In this work, we determine C Q $C_Q$ for a PTW 34013 chamber calibrated in three NIST-traceable reference beams: M30, L40, and L50. METHODS: Using available photon spectra data for M30, L40, and L50 reference beam qualities, Monte Carlo simulations using EGSnrc were performed to calculate the ratio of the absorbed dose to the PTW 34013 chamber air cavity to air-kerma ( D gas / K a $D_{\textrm {gas}}/K_a$ ) for these beams. From this ratio, C Q $C_Q$ as a function of depth in water was determined. The effect of the use of a buildup foil was also investigated. An uncertainty analysis considering both the Type A and Type B uncertainties in the calculation of C Q $C_Q$ was performed. RESULTS: The largest difference in C Q $C_Q$ was found between L50 and TW30, with a relative decrease of 1.4% (no buildup) to 1.6% (buildup). For M30 and L40, the differences were minimal compared with measurement uncertainties. CONCLUSIONS: We report C Q $C_Q$ values for three NIST-traceable kV reference beams. This study reinforces the feasibility of adapting the Watson et al. methodology using different kV reference beams, facilitating the use of INTRABEAM in North America and ensuring the continuity and accuracy of dosimetry standards in intraoperative radiation therapy.

Finite element analysis of feeding in red and gray squirrels (Sciurus vulgaris and Sciurus carolinensis).

Invasive gray squirrels (Sciurus carolinensis) have replaced the native red squirrel (Sciurus vulgaris) across much of Great Britain over the last century. Several factors have been proposed to underlie this replacement, but here we investigated the potential for dietary competition in which gray squirrels have better feeding performance than reds and are thus able to extract nutrition from food more efficiently. In this scenario, we hypothesized that red squirrels would show higher stress, strain, and deformation across the skull than gray squirrels. To test our hypotheses, we created finite element models of the skull of a red and a gray squirrel and loaded them to simulate biting at the incisor, at two different gapes, and at the molar. The results showed similar distributions of strains and von Mises stresses in the two species, but higher stress and strain magnitudes in the red squirrel, especially during molar biting. Few differences were seen in stress and strain distributions or magnitudes between the two incisor gapes. A geometric morphometric analysis showed greater deformations in the red squirrel skull at all bites and gapes. These results are consistent with our hypothesis and indicate increased biomechanical performance of the skull in gray squirrels, allowing them to access and process food items more efficiently than red squirrels.

Using exploratory graph analysis (EGA) in validating the structure of the Perth alexithymia questionnaire in Iranians with chronic pain.

Background: Chronic pain's influence on emotional well-being can be significant. It may evoke feelings of despair, frustration, nervousness, and melancholy in individuals, which often manifest as reactions to enduring pain and disruptions in their daily lives. In this study, we seek to perform Bootstrap Exploratory Graph Analysis (EGA) on the Persian Version of the Perth Alexithymia Questionnaire (PAQ) in a cohort of people with chronic pain. Methods: The research concentrated on the population of individuals encountering chronic pain within Tehran province from 2022 to 2023. Ultimately, the analysis comprised information from 234 male participants (with a mean age of 30.59, SD = 6.84) and 307 female participants (with a mean age of 30.16, SD = 6.65). After data collection, statistical analysis was conducted using the EGAnet2.0.4 package in R.4.3.2 software. Results: The outcome of bootstrapped EGA unveiled a two-dimensional configuration of the PAQ comprising Factor 1 denoted as negative difficulty in describing and identifying feelings (N-DDIF) and Factor 2 characterized as general-externally orientated thinking (GEOT), representing robust structural integrity and item consistency (all items have stabilities > 0.70). Conclusion: These findings endorse the validity of the PAQ, as evidenced by its confirmation in a broader sample using a novel methodology consistent with existing literature on two-factor decentering models.

Ensemble of global climate simulations for temperature in historical, 1.5 °C and 2.0 °C scenarios from HadAM4.

Large ensembles of global temperature are provided for three climate scenarios: historical (2006-16), 1.5 °C and 2.0 °C above pre-industrial levels. Each scenario has 700 members (70 simulations per year for ten years) of 6-hourly mean temperatures at a resolution of 0.833° ´ 0.556° (longitude ´ latitude) over the land surface. The data was generated using the climateprediction.net (CPDN) climate simulation environment, to run HadAM4 Atmosphere-only General Circulation Model (AGCM) from the UK Met Office Hadley Centre. Biases in simulated temperature were identified and corrected using quantile mapping with reference temperature data from ERA5. The data is stored within the UK Natural and Environmental Research Council Centre for Environmental Data Analysis repository as NetCDF V4 files.

Effects of an 11-week vibro-tactile stimulation treatment on voice symptoms in laryngeal dystonia.

Background: Laryngeal dystonia is a task-specific focal dystonia of laryngeal muscles that impairs speech and voice production. At present, there is no cure for LD. The most common therapeutic option for patients with LD involves Botulinum neurotoxin injections. Objective: Provide empirical evidence that non-invasive vibro-tactile stimulation (VTS) of the skin over the voice box can provide symptom relief to those affected by LD. Methods: Single-group 11-week randomized controlled trial with a crossover between two dosages (20 min of VTS once or 3 times per week) self-administered in-home in two 4-week blocks. Acute effects of VTS on voice and speech were assessed in-lab at weeks 1, 6 and 11. Participants were randomized to receive either 40 Hz or 100 Hz VTS. Main outcome measures: Primary: smoothed cepstral peak prominence (CPPS) of the voice signal to quantify voice and speech abnormalities, and perceived speech effort (PSE) ranked by participants as a measure of voice effort (scale 1-10). Secondary: number of voice breaks during continuous speech, the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) inventory as a measure of overall disease severity and the Voice Handicap Index 30-item self report. Results: Thirty-nine people with a confirmed diagnosis of adductor-type LD (mean [SD] age, 60.3 [11.3] years; 18 women and 21 men) completed the study. A single application of VTS improved voice quality (median CPPS increase: 0.41 dB, 95% CI [0.20, 0.61]) and/or reduced voice effort (PSE) by at least 30% in up to 57% of participants across the three study visits. Effects lasted from less than 30 min to several days. There was no effect of dosage and no evidence that the acute therapeutic effects of VTS increased or decreased longitudinally over the 11-week study period. Both 100 and 40 Hz VTS induced measurable improvements in voice quality and speech effort. VTS induced an additional benefit to those receiving Botulinum toxin. Participants, not receiving Botulinum treatment also responded to VTS. Conclusion: This study provides the first systematic empirical evidence that the prolonged use of laryngeal VTS can induce repeatable acute improvements in voice quality and reductions of voice effort in LD. Clinical trial registration: ClinicalTrials.gov ID: NCT03746509.

Unraveling symptom interplay: a network analysis of procrastination in gifted students.

BACKGROUND: This study explores the intricate web of symptoms experienced by academically gifted high school students, focusing on procrastination, rumination, perfectionism, and cognitive flexibility. The well-being of these gifted adolescents remains a pivotal concern, and understanding the dynamics of these symptoms is vital. METHODS: A diverse sample of 207 academically gifted high school students from Mashhad, Iran, participated in this study. Using convenience sampling, participants from grades 10, 11, and 12 were included, with detailed assessments conducted through questionnaires measuring the mentioned symptoms. RESULTS: Our network analysis uncovers compelling insights into the interplay of these symptoms: Procrastination, though moderately central, exerts significant influence within the network, underscoring its relevance. Cognitive flexibility, while centrally positioned, curiously exhibits a negative influence, potentially serving as a protective factor. Negative perfectionism emerges as the keystone symptom, with both high centrality and a positive influence. Rumination displays substantial centrality and a positive influence, indicating its role in symptom exacerbation. Positive perfectionism, moderately central, lacks direct influence on other symptoms. CONCLUSION: This network analysis provides a nuanced understanding of the relationships among procrastination, rumination, perfectionism, and cognitive flexibility in academically gifted adolescents. Negative perfectionism and cognitive flexibility emerge as critical factors deserving attention in interventions aimed at enhancing the well-being of this unique group. Further research should explore causal relationships to refine targeted interventions.

Incorporating Equity, Diversity and Inclusion in a Canadian Biobank.

Equity, diversity, and inclusion (EDI) is an established concept and is an important issue in health research. It is now recognized that measures to address EDI in research can have a positive impact on the value of health research outputs and health outcomes based on this knowledge. EDI strategies, guidelines, and education and training are now embraced by national research funders and local research organizations. However, these initiatives are very broad and not specific to the field of biobanking. We have, therefore, set out to develop and implement a formal research biobank EDI action plan. This article describes the creation of an EDI action plan that provides an intentional approach to identifying and achieving EDI actions and priorities for our research biobank. The plan is framed by the definitions of EDI and an understanding of the topics, issues, and groups within the EDI field. The plan is founded on a set of guiding principles and delineates three pillars of work that align with team, participant, and researcher domains. The plan identifies a set of 31 actions that are categorized by implementation time frames, in order to positively address EDI issues across these pillars. The completion of these actions will help us to mitigate against bias and enrich our biobanking and research services. Ultimately, our goal is to realize more diverse participation in research supported by our biobank. This would support health research to explore and better understand differences in disease biology and the efficacy of medical treatments across all people.

Recognizing high-priority disinfection byproducts based on experimental and predicted endocrine disrupting data: Virtual screening and in vitro study.

So far, about 130 disinfection by-products (DBPs) and several DBPs-groups have had their potential endocrine-disrupting effects tested on some endocrine endpoints. However, it is still not clear which specific DBPs, DBPs-groups/subgroups may be the most toxic substances or groups/subgroups for any given endocrine endpoint. In this study, we attempt to address this issue. First, a list of relevant DBPs was updated, and 1187 DBPs belonging to 4 main-groups (aliphatic, aromatic, alicyclic, heterocyclic) and 84 subgroups were described. Then, the high-priority endocrine endpoints, DBPs-groups/subgroups, and specific DBPs were determined from 18 endpoints, 4 main-groups, 84 subgroups, and 1187 specific DBPs by a virtual-screening method. The results demonstrate that most of DBPs could not disturb the endocrine endpoints in question because the proportion of active compounds associated with the endocrine endpoints ranged from 0 (human thyroid receptor beta) to 32% (human transthyretin (hTTR)). All the endpoints with a proportion of active compounds greater than 10% belonged to the thyroid system, highlighting that the potential disrupting effects of DBPs on the thyroid system should be given more attention. The aromatic and alicyclic DBPs may have higher priority than that of aliphatic and heterocyclic DBPs by considering the activity rate and potential for disrupting effects. There were 2 (halophenols and estrogen DBPs), 12, and 24 subgroups that belonged to high, moderate, and low priority classes, respectively. For individual DBPs, there were 23 (2%), 193 (16%), and 971 (82%) DBPs belonging to the high, moderate, and low priority groups, respectively. Lastly, the hTTR binding affinity of 4 DBPs was determined by an in vitro assay and all the tested DBPs exhibited dose-dependent binding potency with hTTR, which was consistent with the predicted result. Thus, more efforts should be performed to reveal the potential endocrine disruption of those high research-priority main-groups, subgroups, and individual DBPs.

Infrared spectra and fragmentation dynamics of isotopologue-selective mixed-ligand complexes.

Isolated mixed-ligand complexes provide tractable model systems in which to study competitive and cooperative binding effects as well as controlled energy flow. Here, we report spectroscopic and isotopologue-selective infrared photofragmentation dynamics of mixed gas-phase Au(12/13CO)n(N2O)m+ complexes. The rich infrared action spectra, which are reproduced well using simulations of calculated lowest energy structures, clarify previous ambiguities in the assignment of vibrational bands, especially accidental coincidence of CO and N2O bands. The fragmentation dynamics exhibit the same unexpected behaviour as reported previously in which, once CO loss channels are energetically accessible, these dominate the fragmentation branching ratios, despite the much lower binding energy of N2O. We have investigated the dynamics computationally by considering anharmonic couplings between a relevant subset of normal modes involving both ligand stretch and intermolecular modes. Discrepancies between correlated and uncorrelated model fit to the ab initio potential energy curves are quantified using a Boltzmann sampled root mean squared deviation providing insight into efficiency of vibrational energy transfer between high frequency ligand stretches and the softer intermolecular modes which break during fragmentation.

Psychometric properties and item response theory analysis of the Persian version of the social pain questionnaire.

Introduction: Social pain is an emotional reaction which is triggered by social exclusion and has been extensively investigated in the literature. The Social Pain Questionnaire (SPQ) is a self-report instrument which is the only scale for measuring social pain as a dispositional factor. The current study aimed at examining the psychometric properties of the SPQ in an Iranian sample. Materials and methods: A sample of participants (N = 400) was recruited in a cross-sectional validation study. Exploratory Factor Analysis (EFA) as well as Confirmatory Factor Analysis (CFA) were conducted. The Item Response Theory (IRT) model parameters were evaluated and item response category curves were presented. Convergent and divergent validities as well as the reliability (by using Cronbach's alpha coefficient) were also assessed. Results: The SPQ's unidimensionality was affirmed (RMSEA = 0.078; CFI = 0.915; TLI = 0.99) and its internal consistency was robust (Cronbach's α = 0.94). The correlation between the SPQ and the following measures endorsed its divergent and convergent validity: Self-esteem (r = -0.424), Perceived Social Support (r = -0.161), and Interpersonal Sensitivity (r = 0.636). Finally, Item Response Theory Analysis emphasized the effectiveness of the SPQ items in discerning various levels of social pain. The theta level ranged between -1 and + 1.2 and the IRT-based marginal reliability was 0.92 for the total score. Discussion: The Persian SPQ stands as a reliable and valid measure for evaluating social pain. This scale has the potential to stimulate further research in the field for both clinical and non-clinical settings. Conclusion: By employing Item Response Theory (IRT) analysis, we have transcended the theoretical psychometric evaluation of the SPQ scale and demonstrated that SPQ is a unidimensional, valid and reliable measurement tool.

Thresholds in PROMIS Scores Anchored to Subsequent Unscheduled Health Service Use Among People Diagnosed With Cancer.

PURPOSE: To establish thresholds in the Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference, physical function, fatigue, and depression scores on the basis of their association with subsequent use of the emergency department (ED) or urgent care by people diagnosed with cancer. METHODS: Retrospective data from 952 people seen at Henry Ford Cancer and insured through the Health Alliance Plan were analyzed using generalized linear mixed-effects models. The log odds of ED or urgent care use during 14 or 30 days after each patient-reported outcome (PRO) assessment were related to PRO scores, while adjusting for comorbidity, sociodemographic, and tumor characteristics. RESULTS: Pain interference and physical function were associated with subsequent ED or urgent care visits, but fatigue and depression were not, and the results for 14- and 30-day visits were similar. Thresholds anchored in the likelihood of these visits differed according to cancer stage. For people with advanced cancer, a pain interference score of 60 or higher (odds ratio [OR] 3.75, [95% CI, 1.53 to 7.87]) and a physical function score lower than 40 (OR 2.94, [95% CI, 1.22 to 7.06]) produced the largest ORs with narrowest CIs for 30-day visits. For people with nonadvanced cancer, the thresholds of 65 for pain interference (OR 2.64, [95% CI, 1.40 to 5.01]) and 35 for physical function (OR 1.87, [95% CI, 1.01 to 3.45]) produced largest ORs with narrowest CIs for 30-day visits. CONCLUSION: These anchor-based thresholds in PROMIS scores can inform clinicians' actions with the goal of preventing ED or urgent care visits.

An Approach to Evaluate the Costs and Outputs of Academic Biobanks.

Academic biobanks commonly report sustainability challenges, which may be exacerbated by a lack of information on biobank value. To better understand the costs and supported outputs that contribute to biobank value, we developed a systematic, generalizable methodology to determine biobank inputs and publications arising from biobank-supported research. We then tested this in a small cohort (n = 12) of academic cancer biobanks in New South Wales, Australia. A proforma was developed to capture monetary and in-kind biobank costing data from biobank managers and publicly available sources. Participating biobanks were grouped and compared according to the following two classifications: open- versus restricted-access and high versus low total annual costs. Our methodology provides a feasible approach for capturing comprehensive costing data for a defined period. Characterization of biobanks using this approach showed that median total costs, as well as median staffing and in-kind costs, were comparable for open- and restricted-access biobanks, as were the quantity and journal impact metrics of supported publications. High- and low-cost biobanks supported similar median numbers of publications; however, high-cost biobanks supported publications with higher median journal impact factor and Altmetric scores. Overall, 9 of 10 biobanks had higher Field-Weighted Citation Impact scores than the global average for similar publications. This is the first tested, generalizable approach to analyze the costs and publications arising from biobank-supported research. By determining explicit cost and output data, academic biobanks, funders, and policymakers can engage in or support informed redirection of resourcing and/or benchmark setting with the aim of improving biobank support of research.

Work Engagement and Well-being Study (SWELL): a randomised controlled feasibility trial evaluating the effects of mindfulness versus light physical exercise at work.

BACKGROUND: Mindfulness-based programmes (MBPs) are increasingly offered at work, often in online self-guided format. However, the evidence on MBPs' effect on work performance (WP) is inconsistent. OBJECTIVE: This pragmatic randomised controlled feasibility trial assessed procedural uncertainties, intervention acceptability and preliminary effect sizes of an MBP on WP, relative to an alternative intervention. METHODS: 241 employees from eight employers were randomised (1:1) to complete a 4-week, self-guided, online MBP or a light physical exercise programme (LE)(active control). Feasibility and acceptability measures were of primary interest. WP at postintervention (PostInt) was the primary outcome for preliminary assessment of effect sizes. Secondary outcomes assessed mental health (MH) and cognitive processes hypothesised to be targeted by the MBP. Outcomes were collected at baseline, PostInt and 12-week follow-up (12wFUP). Prospective trial protocol: NCT04631302. FINDINGS: 87% of randomised participants started the course. Courses had high acceptability. Retention rates were typical for online trials (64% PostInt; 30% 12wFUP). MBP, compared with the LE control, offered negligible benefits for WP (PostInt (d=0.06, 95% CI -0.19 to 0.32); 12wFUP (d=0.02, 95% CI -0.30 to 0.26)). Both interventions improved MH outcomes (ds=-0.40 to 0.58, 95% CI -0.32 to 0.18); between-group differences were small (ds=-0.09 to 0.04, 95% CI -0.15 to 0.17). CONCLUSION: The trial is feasible; interventions are acceptable. Results provide little support for a later phase trial comparing an MBP to a light exercise control. To inform future trials, we summarise procedural challenges. CLINICAL IMPLICATIONS: Results suggest MBPs are unlikely to improve WP relative to light physical exercise. Although the MBP improved MH, other active interventions may be just as efficacious. TRIAL REGISTRATION NUMBER: NCT04631302.

Applying Findable, Accessible, Interoperable, and Reusable Principles to Biospecimens and Biobanks.

The importance of stimulating greater sharing of data for use and reuse in health research is widely recognized. To this end, the findable, accessible, interoperable, and reusable (FAIR) principles for data have been developed and widely accepted in the research community. Research biospecimens are a resource that leads to much of this health research data but are also a form of data. Therefore, the FAIR principles should apply to biospecimens. Nevertheless, there is a widespread problem of not sharing biospecimen resources that is clearly visible within the research arena. The impacts of this are likely to include diversion of precious research funds into compiling duplicate biospecimen cohorts, detraction from research productivity as researchers compete for and create duplicate resources, and deterrence of attempts to assess research reproducibility. This article explores some of the barriers that may limit availability of FAIR biospecimens. These barriers relate to the type of biospecimen collections and the characteristics of the custodians that influence their intention and interest in sharing. Barriers also relate to the ethical, legal, and social issues concerning collections, the research context of the collections, and cost and expertise involved in repurposing collections to enable sharing. Several solutions to increase sharing are identified. Some have recently been implemented, including enhancing biospecimen locators with tools to guide researchers and facilitating transfer of research collections to centralized biobank infrastructures at the conclusion of projects. New proposed solutions include improving search capabilities within publication databases, and introduction of evidence-based justifications for all new collections into peer-reviewed grant competition processes. It is recognized that there are both scientific factors and practical reasons that can impose limits to sharing biospecimens. However, funding availability, productivity, and progress in health research all stand to benefit from improved sharing of research biospecimen collections.