Large floating abandoned, lost or discarded fishing gear (ALDFG) is frequent marine pollution in the Hawaiian Islands and Palmyra Atoll.

Abandoned, lost, or discarded fishing gear (ALDFG) is a major source of marine debris with significant ecological and economic consequences. We documented the frequency, types, sizes, and impacts of ALDFG recovered from Hawai'i and Palmyra Atoll in the Central North Pacific Ocean (CNPO) from 2009 to 2021. A total of 253 events weighing 15 metric tons were recovered, including 120 drifting fish aggregating device (dFAD) components, 61 conglomerates, fewer distinct nets, lines, buoys, and unique gear. The Hawaiian Islands were dominated by conglomerates and Palmyra Atoll by dFADs. DFADs were connected to the Eastern Pacific tropical tuna purse seine fishery. Windward O'ahu experienced up to seven events or 1800 kg of ALDFG per month. Across Hawai', ALDFG was present on 55 % of survey days, including hotspots with 100 % occurrence. Coral reef damage, entangled wildlife, navigational and removal costs are reported. The data highlight the large magnitude of ALDFG and associated impacts in the CNPO.

Direct differentiation of human pluripotent stem cells into vascular network along with supporting mural cells.

During embryonic development, endothelial cells (ECs) undergo vasculogenesis to form a primitive plexus and assemble into networks comprised of mural cell-stabilized vessels with molecularly distinct artery and vein signatures. This organized vasculature is established prior to the initiation of blood flow and depends on a sequence of complex signaling events elucidated primarily in animal models, but less studied and understood in humans. Here, we have developed a simple vascular differentiation protocol for human pluripotent stem cells that generates ECs, pericytes, and smooth muscle cells simultaneously. When this protocol is applied in a 3D hydrogel, we demonstrate that it recapitulates the dynamic processes of early human vessel formation, including acquisition of distinct arterial and venous fates, resulting in a vasculogenesis angiogenesis model plexus (VAMP). The VAMP captures the major stages of vasculogenesis, angiogenesis, and vascular network formation and is a simple, rapid, scalable model system for studying early human vascular development in vitro.

Improved Protocol for Reproducible Human Cortical Organoids Reveals Early Alterations in Metabolism with MAPT Mutations.

Cerebral cortical-enriched organoids derived from human pluripotent stem cells (hPSCs) are valuable models for studying neurodevelopment, disease mechanisms, and therapeutic development. However, recognized limitations include the high variability of organoids across hPSC donor lines and experimental replicates. We report a 96-slitwell method for efficient, scalable, reproducible cortical organoid production. When hPSCs were cultured with controlled-release FGF2 and an SB431542 concentration appropriate for their TGFBR1 / ALK5 expression level, organoid cortical patterning and reproducibility were significantly improved. Well-patterned organoids included 16 neuronal and glial subtypes by single cell RNA sequencing (scRNA-seq), frequent neural progenitor rosettes and robust BCL11B+ and TBR1+ deep layer cortical neurons at 2 months by immunohistochemistry. In contrast, poorly-patterned organoids contain mesendoderm-related cells, identifiable by negative QC markers including COL1A2 . Using this improved protocol, we demonstrate increased sensitivity to study the impact of different MAPT mutations from patients with frontotemporal dementia (FTD), revealing early changes in key metabolic pathways.

Engaging youth and parents in clinical pediatric research: A case-based example.

Background: Youth and parent engagement is a key component of clinical research. There are many ways to actively and meaningfully engage youth and parents as integral members of research teams, for example, through ad-hoc committees, advisory councils, or as co-leads on projects. When youth and parents are actively and meaningfully engaged in research projects, they share knowledge from their lived experiences to improve the quality and relevance of research. Methods: We describe a case-based example of engaging youth and parent research partners when co-designing a questionnaire to assess preferences for pediatric headache treatments, from both a researcher and youth/parent perspective. We also summarize best practices in patient and family engagement from the literature and pertinent guidelines to assist researchers with integrating patient and family engagement into their studies. Results: As researchers, we felt that the integration of a youth and parent engagement plan into our study significantly altered and strengthened questionnaire content validity. We encountered challenges throughout the process and detailed these experiences to help educate others about challenge mitigation and best practices in youth and parent engagement. As youth and parent partners, we felt that engaging in the process of questionnaire development was an exciting and empowering opportunity, and that our feedback was valued and integrated. Conclusions: By sharing our experience, we hope to catalyze thought and discussion around the importance of youth and parent engagement in pediatric research, with the goal of stimulating more appropriate, relevant, and high-quality pediatric research and clinical care in the future.

Revealing determinants of translation efficiency via whole-gene codon randomization and machine learning.

It has been known for decades that codon usage contributes to translation efficiency and hence to protein production levels. However, its role in protein synthesis is still only partly understood. This lack of understanding hampers the design of synthetic genes for efficient protein production. In this study, we generated a synonymous codon-randomized library of the complete coding sequence of red fluorescent protein. Protein production levels and the full coding sequences were determined for 1459 gene variants in Escherichia coli. Using different machine learning approaches, these data were used to reveal correlations between codon usage and protein production. Interestingly, protein production levels can be relatively accurately predicted (Pearson correlation of 0.762) by a Random Forest model that only relies on the sequence information of the first eight codons. In this region, close to the translation initiation site, mRNA secondary structure rather than Codon Adaptation Index (CAI) is the key determinant of protein production. This study clearly demonstrates the key role of codons at the start of the coding sequence. Furthermore, these results imply that commonly used CAI-based codon optimization of the full coding sequence is not a very effective strategy. One should rather focus on optimizing protein production via reducing mRNA secondary structure formation with the first few codons.

Vitruvian plot: a visualisation tool for multiple outcomes in network meta-analysis.

OBJECTIVE: A network meta-analysis (NMA) usually assesses multiple outcomes across several treatment comparisons. The Vitruvian plot aims to facilitate communication of multiple outcomes from NMAs to patients and clinicians. METHODS: We developed this tool following the recommendations on the communication of benefit-risk information from the available literature. We collected and implemented feedback from researchers, statisticians, methodologists, clinicians and people with lived experience of physical and mental health issues. RESULTS: We present the Vitruvian plot, which graphically presents absolute estimates and relative performance of competing interventions against a common comparator for several outcomes of interest. We use two alternative colour schemes to highlight either the strength of statistical evidence or the confidence in the evidence. Confidence in the evidence is evaluated across six domains (within-study bias, reporting bias, indirectness, imprecision, heterogeneity and incoherence) using the Confidence in Network Meta-Analysis (CINeMA) system. CONCLUSIONS: The Vitruvian plot allows reporting of multiple outcomes from NMAs, with colourings appropriate to inform credibility of the presented evidence.

Retro Diels-Alder Fragmentation of Fulvene-Maleimide Bioconjugates for Mass Spectrometric Detection of Biomolecules.

Diels-Alder chemistry is a well-explored avenue for the synthesis of bioactive materials; however, its potential applications have recently expanded following the development of reactions that can be performed in buffered aqueous environments at low temperatures, including fulvene-maleimide [4 + 2] cycloadditions. In this study, we synthesized two novel amine-reactive fulvene linkers to demonstrate the application of this chemistry for generating mass spectrometry-cleavable labels ("mass tags"), which can be used for the labeling and detection of proteins. Successful conjugation of these linkers to maleimide-labeled peptides was observed at low temperatures in phosphate-buffered saline, allowing the non-destructive modification of proteins with such mass tags. The labile nature of fulvene-maleimide adducts in the gas phase also makes them suitable for both matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) mass spectrometric analysis. Unlike previous examples of MALDI mass tags, we show that fulvene-maleimide cycloaddition adducts fragment predictably upon gas-phase activation without the need for bulky photocleavable groups. Further exploration of this chemistry could therefore lead to new approaches for mass spectrometry-based bioassays.

Feasibility, reliability and validity of the health-related quality of life instrument Child Health Utility 9D (CHU9D) among school-aged children and adolescents in Sweden.

BACKGROUND: This study was conducted in a general population of schoolchildren in Sweden, with the aim to assess the psychometric properties of a generic preference-based health related quality of life (HRQoL) instrument, the Swedish Child Health Utility 9D (CHU9D), among schoolchildren aged 7-15 years, and in subgroups aged 7-9, 10-12 and 13-15 years. METHODS: In total, 486 school aged children, aged 7-15 years, completed a questionnaire including the CHU9D, the Pediatric quality of life inventory 4.0 (PedsQL), KIDSCREEN-10, questions on general health, long-term illness, and sociodemographic characteristics. Psychometric testing was undertaken of feasibility, internal consistency reliability, test-retest reliability, construct validity, factorial validity, concurrent validity, convergent validity and divergent validity. RESULTS: The CHU9D evidenced very few missing values, minimal ceiling, and no floor effects. The instrument achieved satisfactory internal consistency (Cronbach's Alfa > 0.7) and strong test-retest reliability (r > 0.6). Confirmatory factor analyses supported the proposed one-factor structure of the CHU9D. For child algorithm, RMSEA = 0.05, CFI = 0.95, TLI = 0.94, and SRMR = 0.04. For adult algorithm RMSEA = 0.04, CFI = 0.96, TLI = 0.95, and SRMR = 0.04. The CHU9D utility value correlated moderately or strongly with KIDSCREEN-10 and PedsQL total scores (r > 0.5-0.7). The CHU9D discriminated as anticipated on health and on three of five sociodemographic characteristics (sex, age, and custody arrangement, but not socioeconomic status and ethnic origin). CONCLUSIONS: This study provides evidence that the Swedish CHU9D is a feasible, reliable and valid measure of preference-based HRQoL in children. The study furthermore suggests that the CHU9D is appropriate for use among children 7-15 years of age in the general population, as well as among subgroups aged 7- 9, 10-12 and 13-15 years.

Assessment of a regulatory measurement system for the determination of the non-volatile particulate matter emissions from commercial aircraft engines.

The SAE International has published Aerospace Information Report (AIR) 6241 which outlined the design and operation of a standardized measurement system for measuring non-volatile particulate matter (nvPM) mass and number emissions from commercial aircraft engines. Prior to this research, evaluation of this system by various investigators revealed differences in nvPM mass emissions measurement on the order of 15-30% both within a single sampling system and between two systems operating in parallel and measuring nvPM mass emissions from the same source. To investigate this issue, the U. S. Environmental Protection Agency in collaboration with the U. S. Air Force's Arnold Engineering Development Complex initiated the VAriable Response In Aircraft nvPM Testing (VARIAnT) research program to compare nvPM measurements within and between AIR-compliant sampling systems used for measuring combustion aerosols generated both by a 5201 Mini-CAST soot generator and a J85-GE-5 turbojet engine burning multiple fuels. The VARIAnT research program has conducted four test campaigns to date. The first campaign (VARIAnT 1) compared two essentially identical commercial versions of the sampling system while the second campaign (VARIAnT 2) compared a commercial system to the custom-designed Missouri University of Science and Technology's North American Reference System (NARS) built to the same specifications. Comparisons of nvPM particle mass (i.e., black carbon), number, and size were conducted in both campaigns. Additionally, the sensitivity to variation in system operational parameters was evaluated in VARIAnT 1. Results from both campaigns revealed agreement of about 12% between the two sampling systems, irrespective of manufacturer, in all aspects except for black carbon determination. The major source of measurement differences (20-70%) was due to low BC mass measurements made by the Artium Technologies LII-300 as compared to the AVL 483 Micro-Soot Sensor, the Aerodyne Cavity Attenuated Phase Shift (CAPS PMSSA) monitor, and the thermal-optical reference method for elemental carbon (EC) determination, which was used as the BC reference.

Conjugating immunoassays to mass spectrometry: Solutions to contemporary challenges in clinical diagnostics.

Developments in immunoassays and mass spectrometry have independently influenced diagnostic technology. However, both techniques possess unique strengths and limitations, which define their ability to meet evolving requirements for faster, more affordable and more accurate clinical tests. In response, hybrid techniques, which combine the accessibility and ease-of-use of immunoassays with the sensitivity, high throughput and multiplexing capabilities of mass spectrometry are continually being explored. Developments in antibody conjugation methodology have expanded the role of these biomolecules to applications outside of conventional colorimetric assays and histology. Furthermore, the range of different mass spectrometry ionisation and analysis technologies has enabled its successful adaptation as a detection method for numerous clinically relevant immunological assays. Several recent examples of combined mass spectrometry-immunoassay techniques demonstrate the potential of these methods as improved diagnostic tests for several important human diseases. The present challenges are to continue technological advancements in mass spectrometry instrumentation and develop improved bioconjugation methods, which can overcome their existing limitations and demonstrate the clinical significance of these hybrid approaches.

Brushing RemInder 4 Good oral HealTh (BRIGHT) trial: does an SMS behaviour change programme with a classroom-based session improve the oral health of young people living in deprived areas? A study protocol of a randomised controlled trial.

BACKGROUND: Almost one-half of 12-15 year olds living in deprived areas of the UK have dental caries (tooth decay) with few oral health promotion programmes aimed at children of this age. Mobile phone-based interventions such as short messaging service (SMS) interventions have been found effective at changing certain behaviours and improving health outcomes. This protocol describes the BRIGHT Trial, investigating the clinical and cost-effectiveness of a behaviour change intervention-classroom-based session (CBS) embedded in the curriculum and a series of SMS delivered to participants twice daily to remind them to brush their teeth, compared to usual curriculum and no SMS-to reduce the prevalence of dental caries in young people from deprived areas. OBJECTIVES: To investigate the clinical and cost-effectiveness of a complex intervention to improve the oral health of young people living in deprived areas. METHODS/DESIGN: This is a school-based, assessor-blinded, two-arm cluster-randomised controlled trial with an internal pilot trial. Overall, the trial will involve approximately 5040 11-13 year olds in 42 schools with a 3-year follow-up. The trial will take place in secondary schools in England, Scotland and Wales. The primary outcome is the presence of carious lesions in permanent teeth at 3 years. Secondary outcomes are: number of carious teeth, frequency of twice-daily toothbrushing, plaque levels, gingivitis, child health-related quality of life and oral health-related quality of life. A cost-utility analysis will be conducted. DISCUSSION: The findings of the trial have implications for embedding oral health interventions into school curricula guidance produced by national bodies, including departments for education and dental public health and guideline-development organisations. TRIAL REGISTRATION: ISRCTN registry, ISRCTN12139369 . Registered on 10 May 2017.

Scoring the Child Health Utility 9D instrument: estimation of a Chinese child and adolescent-specific tariff.

PURPOSE: To derive children and adolescents' preferences for health states defined by the Chinese version of Child Health Utility 9D (CHU9D-CHN) instrument in China that can be used to estimate quality-adjusted life years (QALYs) for economic evaluation. METHODS: A profile case best-worst scaling (BWS) and a time trade-off (TTO) method were combined to derive a Chinese-specific tariff for the CHU9D-CHN. The BWS survey recruited students from primary and high schools using a multi-stage random sampling method and was administered in a classroom setting, whilst the TTO survey adopted an interviewer-administrated conventional TTO task and was administered to a convenience sample of undergraduate students. A latent class modelling framework was adopted for analysing the BWS data. RESULTS: Two independent surveys were conducted in Nanjing, China, including a valid sample of 902 students (mean age 13 years) from the BWS survey and a valid sample of 38 students (mean age 18 years) from the TTO survey. The poolability of the best and the worst responses was rejected and the optimal result based on the best responses only. The optimal model suggests the existence of two latent classes. The BWS estimates were further re-anchored onto the QALY scale using the TTO generated health state values via a mapping approach. CONCLUSION: This study provides further insights into the use of the BWS method to generate health state values with young people and highlights the potential different decision rules that young people may employ for determining best vs. worst choices in this context.

Understanding the evolving phenotype of vascular complications in telomere biology disorders.

Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.

Estimating a Dutch Value Set for the Pediatric Preference-Based CHU9D Using a Discrete Choice Experiment with Duration.

OBJECTIVE: This article presents the development of the Dutch value set for the Child Health Utility 9D, a pediatric preference-based measure of quality of life that can be used to generate quality-adjusted life-years. METHODS: A large online survey was conducted using a discrete choice experiment including a duration attribute with adult members of the Netherlands general population (N = 1276) who were representative in terms of age, gender, marital status, employment, education, and region. Respondents were asked which of two health states they prefer, where each health state was described using the nine dimensions of the Child Health Utility 9D (worried, sad, pain, tired, annoyed, school work/homework, sleep, daily routine, able to join in activities) and duration. The data were modeled using conditional logit with robust standard errors to produce utility values for every health state described by the Child Health Utility 9D. RESULTS: The majority of the dimension level coefficients were monotonic, leading to a decrease in utility as severity increases. There was, however, evidence of some logical inconsistencies, particularly for the school work/homework dimension. The value set produced was based on the ordered model and ranges from -0.568 for the worst state to 1 for the best state. CONCLUSION: The valuation of the Child Health Utility 9D using online discrete choice experiment with duration with adult members of the Dutch general population was feasible and produced a valid model for use in cost utility analysis. Normative questions are raised around the valuation of pediatric preference-based measures, including the appropriate perspective for imagining hypothetical pediatric health states.

Canadian French translation and linguistic validation of the child health utility 9D (CHU9D).

BACKGROUND: Several preference based measures are validated for adults in cost utility analysis, but less are available for children and many researchers have criticized the quality of pediatric economic studies. The objective of this study was to perform a Canadian French translation and linguistic validation of the Child Health Utility 9D (CHU9D) that was conceptually equivalent to the original English version for use in Canada. METHODS: The translation and linguistic validation were realized by ICON Clinical Research (UK) Limited in association with the developer of the CHU9D and Canadian collaborators. This was done in accordance with industry standards and the guidance of the Food and Drug Administration (FDA) for patient-reported outcome (PRO) instruments. Five steps were considered: concept elaboration; forward translation; back translation; linguistic validation; proofreading and final verification. RESULTS: The CHU9D Canadian French translation and linguistic validation were realized without any major difficulties. Only 3 changes were made after the forward translation and 5 after the back translation. The result of back translation was very similar to the original English version. Six additional changes suggested by the developer team were accepted and the linguistic validation with five children led to 2 additional changes. Most changes were generally to change one word to better sounding Canadian French. CONCLUSION: We produced a Canadian French translation and cross-cultural adaptation of the Child Health Utility 9D (CHU9D). Before being used in clinical settings and research projects, the final Canadian French translation needs to be validated for metrological qualities of reliability and validity.

Estimating a Preference-Based Single Index Measuring the Quality-of-Life Impact of Self-Management for Diabetes.

OBJECTIVE: Self-management is becoming increasingly important in diabetes but is neglected in conventional preference-based measures. The objective of this paper was to generate health state utility values for a novel classification system measuring the quality-of-life impact of self-management for diabetes, which can be used to generate quality-adjusted life years (QALYs). METHODS: A large online survey was conducted using a discrete choice experiment (DCE), with duration as an additional attribute, on members of the UK general population ( n = 1,493) to elicit values for health (social limitations, mood, vitality, hypoglycaemia) and non-health (stress, hassle, control, support) aspects of self-management in diabetes. The data were modelled using a conditional fixed-effects logit model and utility estimates were anchored on the one to zero (full health to dead) scale. RESULTS: The model produced significant and consistent coefficients, with one logical inconsistency and 3 insignificant coefficients for the milder levels of some attributes. The anchored utilities ranged from 1 for the best state to -0.029 for the worst state (meaning worse than dead) defined by the classification system. CONCLUSION: The results presented here can potentially be used to generate utility values capturing the day to day impact of interventions in diabetes on both health and self-management. These utility values can potentially be used to generate QALYs for economic models of the cost-effectiveness of interventions in diabetes.

Using a Discrete-Choice Experiment Involving Cost to Value a Classification System Measuring the Quality-of-Life Impact of Self-Management for Diabetes.

OBJECTIVES: To describe the use of a novel approach in health valuation of a discrete-choice experiment (DCE) including a cost attribute to value a recently developed classification system for measuring the quality-of-life impact (both health and treatment experience) of self-management for diabetes. METHODS: A large online survey was conducted using DCE with cost on UK respondents from the general population (n = 1497) and individuals with diabetes (n = 405). The data were modeled using a conditional logit model with robust standard errors. The marginal rate of substitution was used to generate willingness-to-pay (WTP) estimates for every state defined by the classification system. Robustness of results was assessed by including interaction effects for household income. RESULTS: There were some logical inconsistencies and insignificant coefficients for the milder levels of some attributes. There were some differences in the rank ordering of different attributes for the general population and diabetic patients. The WTP to avoid the most severe state was £1118.53 per month for the general population and £2356.02 per month for the diabetic patient population. The results were largely robust. CONCLUSIONS: Health and self-management can be valued in a single classification system using DCE with cost. The marginal rate of substitution for key attributes can be used to inform cost-benefit analysis of self-management interventions in diabetes using results from clinical studies in which this new classification system has been applied. The method shows promise, but found large WTP estimates exceeding the cost levels used in the survey.

Estimating an exchange rate between the EQ-5D-3L and ASCOT.

BACKGROUND: The aim was to estimate an exchange rate between EQ-5D-3L and the Adult Social Care Outcome Tool (ASCOT) using preference-based mapping via common time trade-off (TTO) valuations. EQ-5D and ASCOT are useful for examining cost-effectiveness within the health and social care sectors, respectively, but there is a policy need to understand overall benefits and compare across sectors to assess relative value for money. Standard statistical mapping is unsuitable since it relies on conceptual overlap of the measures but EQ-5D and ASCOT have different conceptualisations of quality of life. METHODS: We use a preference-based mapping approach to estimate the exchange rate using common TTO valuations for both measures. A sample of health states from each measure was valued using TTO by 200 members of the UK adult general population. Regression analyses are used to generate separate equations between EQ-5D-3L and ASCOT values using their original value set and TTO values elicited here. These are solved as simultaneous equations to estimate the relationship between EQ-5D-3L and ASCOT. RESULTS: The relationship for moving from ASCOT to EQ-5D-3L is a linear transformation with an intercept of -0.0488 and gradient of 0.978. This enables QALY gains generated by ASCOT and EQ-5D to be compared across different interventions. CONCLUSIONS: This paper estimated an exchange rate between ASCOT and EQ-5D-3L using a preference-based mapping approach that does not compromise the descriptive systems of the two measures. This contributes to the development of preference-based mapping through the use of TTO as the common metric used to estimate the exchange rate between measures.