Symmetric Electron Transfer Coordinates are Intrinsic to Bridged Systems: An ab Initio Treatment of the Creutz-Taube Ion.

A long-standing question in electron transfer research concerns the number and identity of collective nuclear motions that drive electron transfer or localisation. It is well established that these nuclear motions are commonly gathered into a so-called electron transfer coordinate. In this theoretical study, we demonstrate that both anti-symmetric and symmetric vibrational motions are intrinsic to bridged systems, and that both are required to explain the characteristic shape of their intervalence charge transfer bands. Using the properties of a two-state Marcus-Hush model, we identify and quantify these two coordinates as linear combinations of normal modes from ab initio calculations. This quantification gives access to the potential coupling, reorganization energy and curvature of the potential energy surfaces involved in electron transfer, independent of any prior assumptions about the system of interest. We showcase these claims with the Creutz-Taube ion, a prototypical Class III mixed valence complex. We find that the symmetric dimension is responsible for the asymmetric band shape, and trace this back to the offset of the ground and excited state potentials in this dimension. The significance of the symmetric dimension originates from geometry dependent coupling, which in turn is a natural consequence of the well-established superexchange mechanism. The conceptual connection between the symmetric and anti-symmetric motions and the superexchange mechanism appears as a general result for bridged systems.

Correlation between oral muscle pressure and malocclusion in mixed dentition: a cross-sectional study.

OBJECTIVE: To investigate the relationship between oral muscle pressure and malocclusion in the mixed dentition. MATERIALS AND METHODS: Maximum tongue, lip and cheek pressure was measured using the Iowa Oral Performance Instrument (IOPI) in 3 patient cohorts: patients with (1) posterior crossbite, (2) class II relationship and (3) a control group of patients without malocclusion. Linear models were used to compare the mean differences in muscle pressure between groups, with correction for age and gender. The imbalance between lips and tongue and between lips and cheeks was calculated by the Delta z-scores of each group. RESULTS: A total of 146 participants were included, 46 (mean age 8.71±0.85), 41 (mean age 11.74±1.17) and 35 (mean age 10.71±1.92) in groups 1, 2 and 3 respectively. Patients with malocclusion showed significantly higher lip and lower cheek pressure and imbalance favouring the lips over the tongue compared to controls. Class II,1 patients showed significantly higher tongue pressure than Class II,2. No differences were found in muscle pressure or imbalance between crossbite and Class II nor between crossbite types. CONCLUSION AND CLINICAL RELEVANCE: These findings suggest that oral muscle pressure may be associated with malocclusion. This highlights the importance of functional diagnosis and its implications on the prevention and treatment of malocclusion, as well as on orthodontic stability.

Multi-method characterization of groundwater nitrate and sulfate contamination by karst mines in southwest China.

Groundwater contamination by nitrate and sulfate in mining areas is a significant challenge. Consequently, the inputs sources of these contaminants and their evolution have received considerable attention, with the knowledge gained critical for improved management of water quality. This study integrated data on multiple stable isotopes and water chemistry data and a Bayesian isotope mixing model to investigate the relative contributions of inputs sources of sulfate and nitrate sources to bodies of water in a karst mining area in southwest China. The outcomes indicated that hydrochemical component in the water bodies of the study area is mainly derived from the dissolution of silicate rocks, carbonate rocks and sulfate minerals as well as the oxidation of sulfides. The human and agricultural wastewater, soil nitrogen, and fertilizers were the predominant inputs sources of nitrate to the mine water environment; the predominant inputs sources of sulfide were mineral oxidation, evaporite dissolution, atmospheric deposition, and sewage. Groundwater is mainly recharged from atmospheric precipitation, and surface water is closely hydraulically connected to groundwater. Nitrogen and oxygen isotope composition and water chemistry indicative of nitrification dominate the nitrogen cycle in the study area. The oxidation of pyrite and bacterial sulfate reduction (SRB) had no significant impact on the stable isotopes of groundwater. The results of this study demonstrate the inputs of different sources to nitrate and sulfate in karst mines and associated transformation processes. The results of this study can assist in the conservation of groundwater quality in mining areas and can act as a reference for future related studies.

Pollen foraging preferences in honey bees and the nutrient profiles of the pollen.

Honey bees are important insect pollinators that provide critical pollination services to fruit and nut crops in the US. They face challenges likely due to pressures associated with agricultural intensification related habitat loss. To better understand this, pollen preferences of foraging bees and the nutritional profile of pollen brought into hives by foraging bees in crop fields and nut orchards can provide valuable information. We trained bees to forage on bee-collected pollen from hives placed for pollination services in almond orchards, sunflower fields, or mixed species from inter-row plantings. Using bees trained to a certain kind of hive pollen, we applied a binary scoring system, to test preferences of these preconditioned foragers. We also performed metabolomic analyses of the hive pollen used for training and testing to elucidate their nutritional content. Irrespective of preconditioning, bees collected all the available choice pollen types, predominantly choosing hive-collected mixed species pollen (MSP), followed by almond orchard pollen. The hive-collected MSP was chemically diverse, richest in cholesterol, vitamins, and phytochemicals quercetin, kaempferol, coumarin, and quinine, but was not consistently high for essential amino acids and polyunsaturated fatty acids. Although diversity in chemical profiles may not directly relate to plant species diversity, our results suggest that foragers collect a variety of pollen types when available reiterating the importance of diverse floral resources.

Enhancing tunnel crack detection with linear seam using mixed stride convolution and attention mechanism.

Cracks in tunnel lining structures constitute a common and serious problem that jeopardizes the safety of traffic and the durability of the tunnel. The similarity between lining seams and cracks in terms of strength and morphological characteristics renders the detection of cracks in tunnel lining structures challenging. To address this issue, a new deep learning-based method for crack detection in tunnel lining structures is proposed. First, an improved attention mechanism is introduced for the morphological features of lining seams, which not only aggregates global spatial information but also features along two dimensions, height and width, to mine more long-distance feature information. Furthermore, a mixed strip convolution module leveraging four different directions of strip convolution is proposed. This module captures remote contextual information from various angles to avoid interference from background pixels. To evaluate the proposed approach, the two modules are integrated into a U-shaped network, and experiments are conducted on Tunnel200, a tunnel lining crack dataset, as well as the publicly available crack datasets Crack500 and DeepCrack. The results show that the approach outperforms existing methods and achieves superior performance on these datasets.

Media Use and Its Associations With Paranoia in Schizophrenia and Bipolar Disorder: Ecological Momentary Assessment.

Background: Paranoia is a spectrum of fear-related experiences that spans diagnostic categories and is influenced by social and cognitive factors. The extent to which social media and other types of media use are associated with paranoia remains unclear. Objective: We aimed to examine associations between media use and paranoia at the within- and between-person levels. Methods: Participants were 409 individuals diagnosed with schizophrenia spectrum or bipolar disorder. Measures included sociodemographic and clinical characteristics at baseline, followed by ecological momentary assessments (EMAs) collected 3 times daily over 30 days. EMA evaluated paranoia and 5 types of media use: social media, television, music, reading or writing, and other internet or computer use. Generalized linear mixed models were used to examine paranoia as a function of each type of media use and vice versa at the within- and between-person levels. Results: Of the 409 participants, the following subgroups reported at least 1 instance of media use: 261 (63.8%) for using social media, 385 (94.1%) for watching TV, 292 (71.4%) for listening to music, 191 (46.7%) for reading or writing, and 280 (68.5%) for other internet or computer use. Gender, ethnoracial groups, educational attainment, and diagnosis of schizophrenia versus bipolar disorder were differentially associated with the likelihood of media use. There was a within-person association between social media use and paranoia: using social media was associated with a subsequent decrease of 5.5% (fold-change 0.945, 95% CI 0.904-0.987) in paranoia. The reverse association, from paranoia to subsequent changes in social media use, was not statistically significant. Other types of media use were not significantly associated with paranoia. Conclusions: This study shows that social media use was associated with a modest decrease in paranoia, perhaps reflecting the clinical benefits of social connection. However, structural disadvantage and individual factors may hamper the accessibility of media activities, and the mental health correlates of media use may further vary as a function of contents and contexts of use.

Interplay between drought and plant viruses co-infecting melon plants.

Drought affects crops directly, and indirectly by affecting the activity of insect pests and the transmitted pathogens. Here, we established an experiment with well-watered or water-stressed melon plants, later single infected with either cucumber mosaic virus (CMV: non-persistent), or cucurbit aphid-borne yellow virus (CABYV: persistent), or both CMV and CABYV, and mock-inoculated control. We tested whether i) the relation between CMV and CABYV is additive, and ii) the relationship between water stress and virus infection is antagonistic, i.e., water stress primes plants for enhanced tolerance to virus infection. Water stress increased leaf greenness and temperature, and reduced leaf water potential, shoot biomass, stem dimensions, rate of flowering, CABYV symptom severity, and marketable fruit yield. Virus infection reduced leaf water potential transiently in single infected plants and persistently until harvest in double-infected plants. Double-virus infection caused the largest and synergistic reduction of marketable fruit yield. The relationship between water regime and virus treatment was additive in 12 out of 15 traits at harvest, with interactions for leaf water content, leaf:stem ratio, and fruit set. We conclude that both virus-virus relations in double infection and virus-drought relations cannot be generalized because they vary with virus, trait, and plant ontogeny.

Dilute acid-assisted microbubbles-mediated ozonolysis of Eucheuma denticulatum phycocolloid for biobased L-lactic acid production.

Biobased L-lactic acid (L-LA) appeals to industries; however, existing technologies are plagued by limited productivity and high energy consumption. This study established an integrated process for producing macroalgae-based L-LA from Eucheuma denticulatum phycocolloid (EDP). Dilute acid-assisted microbubbles-mediated ozonolysis (DAMMO) was selected for the ozonolysis of EDP to optimize D-galactose recovery. Through single-factor optimization of DAMMO treatment, a maximum D-galactose recovery efficiency (59.10 %) was achieved using 0.15 M H2SO4 at 80 °C for 75 min. Fermentation with 3 % (w/v) mixed microbial cells (Bacillus coagulans ATCC 7050 and Lactobacillus acidophilus-14) and fermented residues achieved a 97.67 % L-LA yield. Additionally, this culture approach was further evaluated in repeated-batch fermentation and showed an average L-LA yield of 93.30 %, providing a feasible concept for macroalgae-based L-LA production.

Monitoring of the disulfide scrambled species by mixed-mode SEC-HPLC during the purification of a bispecific antibody.

Size-exclusion chromatography-high performance liquid chromatography (SEC-HPLC) is an analytical method routinely used for assessing aggregation content in protein samples. As SEC-HPLC separates analytes based on their hydrodynamic radius, it generally lacks the capability of differentiating species that are similar in size. Recently while purifying a bispecific antibody (bsAb), we noticed that SEC-HPLC can provide certain degree of resolution between the target bsAb and a disulfide scrambled form, although these two species were identical in molecular weight. In seeing the unexpected potential of SEC-HPLC at resolving species with similar size, we further tested Zenix SEC-300, a mixed-mode SEC-HPLC column from Sepax, which was reported to be capable of separating protein analytes based on other factors besides size. The Zenix column indeed provided resolution much better than the regular SEC-HPLC column. Upon further optimization, the Zenix column allowed close to baseline separation of the correctly folded and the disulfide scrambled species. The current study, as a complement to the previous reports, further demonstrates that mix-mode SEC-HPLC is capable of separating protein analytes that are close in size but are different in conformation and/or surface characteristics.

Potency Assay Variability Estimation in Practice.

During the drug development process, testing potency plays an important role in the quality assessment required for the manufacturing and marketing of biologics. Due to multiple operational and biological factors, higher variability is usually observed in bioassays compared with physicochemical methods. In this paper, we discuss different sources of bioassay variability and how this variability can be statistically estimated. In addition, we propose an algorithm to estimate the variability of reportable results associated with different numbers of runs and their corresponding OOS rates under a given specification. Numerical experiments are conducted on multiple assay formats to elucidate the empirical distribution of bioassay variability.

Blood-Brain Barrier Permeability Is Associated With Cognitive Functioning in Normal Aging and Neurodegenerative Diseases.

BACKGROUND: The purpose of this study was to investigate the relationship between blood-brain barrier (BBB) permeability and cognitive functioning in healthy older adults and individuals with neurodegenerative diseases. METHODS AND RESULTS: A total of 124 participants with Alzheimer disease, cerebrovascular disease, or a mix Alzheimer's and cerebrovascular diseases and 55 controlparticipants underwent magnetic resonance imaging and neuropsychological testing. BBB permeability was measured with dynamic contrast-enhanced magnetic resonance imaging and white matter injury was measured using a quantitative diffusion-tensor imaging marker of white matter injury. Structural equation modeling was used to examine the relationships between BBB permeability, vascular risk burden, white matter injury, and cognitive functioning. Vascular risk burden predicted BBB permeability (r=0.24, P<0.05) and white matter injury (r=0.38, P<0.001). BBB permeability predicted increased white matter injury (r=0.34, P<0.001) and increased white matter injury predicted lower cognitive functioning (r=-0.51, P<0.001). CONCLUSIONS: The study provides empirical support for a vascular contribution to white matter injury and cognitive impairment, directly or indirectly via BBB permeability. This highlights the importance of targeting modifiable vascular risk factors to help mitigate future cognitive decline.

Barriers and facilitators to the implementation of rapid HIV testing in Canadian Emergency Departments: a mixed methods study.

OBJECTIVES: 1 in 7 Canadians with Human Immunodeficiency Virus (HIV) do not know their status. Patients at increased risk of HIV routinely access the emergency department (ED), yet few are tested, representing a missed opportunity for diagnosis and linkage-to-care. Rapid HIV testing provides reliable results within the same ED encounter but is not routinely implemented. The objective of this study was to identify barriers and facilitators to rapid HIV testing in Ontario EDs. METHODS: We employed a mixed-methods, convergent, parallel design study including online surveys and semi-structured interviews of physicians, nurses, and allied health across four hospitals in Toronto and Thunder Bay, Ontario. Data were analyzed in equal priority using descriptive statistics for quantitative data and thematic analysis for qualitative data guided by the Theoretical Domains framework and Capability, Opportunity, Motivation Behaviour change model. RESULTS: Among 187 survey respondents, 150 (80%) felt implementing rapid HIV testing would be helpful in the ED. Facilitators included availability of resources to link patients to care after testing (71%), testing early in patient encounters (41%), and having dedicated staff with lived experience support testing (34%). Motivation to offer testing included opportunities to support an underserved population (66%). Challenges to implementation included limited time during ED patient encounters (51%) and a lack of knowledge around HIV testing (42%) including stigma. Interview themes confirmed education, and integration of people with lived experience being essential to provide rapid HIV testing and linkage-to-care in the ED. CONCLUSIONS: Implementation of rapid HIV testing in the ED is perceived to be important irrespective of practice location or profession. Intrinsic motivations to support underserved populations and providing linkage-to-care are novel insights to facilitate testing in the ED. Streamlined implementation, including clear testing guidelines and improved access to follow-up care, is felt to be necessary for implementation.

ABSTRAIT: OBJECTIFS: 1 Canadien sur 7 atteint du virus de l'immunodéficience humaine (VIH) ne connaît pas son statut. Les patients présentant un risque accru de contracter le VIH ont régulièrement accès au service des urgences (SU), mais peu d'entre eux sont testés, ce qui représente une occasion manquée de diagnostic et de lien avec les soins. Le dépistage rapide du VIH fournit des résultats fiables dans la même situation d'urgence, mais n'est pas systématiquement mis en œuvre. L'objectif de cette étude était d'identifier les obstacles et les facilitateurs au dépistage rapide du VIH dans les urgences de l'Ontario. MéTHODES: Nous avons utilisé une étude de conception mixte, convergente et parallèle, y compris des sondages en ligne et des entrevues semi-structurées auprès de médecins, d'infirmières et d'auxiliaires de la santé dans quatre hôpitaux de Toronto et de Thunder Bay, en Ontario. Les données ont été analysées en priorité égale à l'aide de statistiques descriptives pour les données quantitatives et d'analyses thématiques pour les données qualitatives guidées par le cadre des domaines théoriques et le modèle de changement de capacité, d'opportunité et de motivation. RéSULTATS: Parmi 187 répondants au sondage, 150 (80 %) étaient d'avis que la mise en œuvre d'un dépistage rapide du VIH serait utile à l'urgence. Les facilitateurs comprenaient la disponibilité de ressources pour lier les patients aux soins après le test (71 %), le dépistage précoce lors des rencontres avec les patients (41 %) et la présence d'un personnel dévoué avec des tests de soutien de l'expérience vécue (34 %). La motivation à offrir des tests comprenait des occasions de soutenir une population mal desservie (66 %). Les difficultés de mise en œuvre comprenaient un temps limité pendant les rencontres avec les patients aux urgences (51 %) et un manque de connaissances sur le dépistage du VIH (42 %), y compris la stigmatisation. Les thèmes des entrevues ont confirmé que l'éducation et l'intégration des personnes ayant une expérience vécue sont essentielles pour fournir un dépistage rapide du VIH et un lien avec les soins aux urgences. CONCLUSIONS: La mise en œuvre du dépistage rapide du VIH aux urgences est perçue comme importante, quel que soit le lieu de pratique ou la profession. Les motivations intrinsèques à soutenir les populations mal desservies et à fournir un lien avec les soins sont de nouvelles idées pour faciliter les tests à l'urgence. Une mise en œuvre simplifiée, y compris des lignes directrices claires sur les tests et un meilleur accès aux soins de suivi, est jugée nécessaire pour la mise en œuvre.

Determinants of job continuity among older workers: a mixed-methods research in Japan.

This study aims to determine the factors that encourage older workers to continue working. This study had an exploratory sequential design using a mixed-methods approach, including interviews and questionnaire surveys. In the interview survey, we targeted 30 workers aged between 60-65 across three manufacturing companies. After using the results of the content analysis in the interviews, we conducted an online questionnaire survey with 1,500 workers aged between 60-89 across the country. We analyzed whether the 15 factors were related to intention to continue working using logistic regression analysis. We identified factors affecting job continuity from three perspectives: individual, company, and life. We determined several factors: health condition, job performance, self-esteem, conservatism, employment system, workload, medical insurance and welfare programs, monetary and non-monetary rewards, relationships, attachment to the organization, distance between living and work, social support, economic situation, and employment policy. In the questionnaire survey, some factors had no relationship with job continuity, including conservatism, employment systems, monetary rewards, and the distance between living and work. Employers and policymakers can use the findings to consider appropriate ways of supporting older workers.

Model selection of GLMMs in the analysis of count data in single-case studies: A Monte Carlo simulation.

Generalized linear mixed models (GLMMs) have great potential to deal with count data in single-case experimental designs (SCEDs). However, applied researchers have faced challenges in making various statistical decisions when using such advanced statistical techniques in their own research. This study focused on a critical issue by investigating the selection of an appropriate distribution to handle different types of count data in SCEDs due to overdispersion and/or zero-inflation. To achieve this, I proposed two model selection frameworks, one based on calculating information criteria (AIC and BIC) and another based on utilizing a multistage-model selection procedure. Four data scenarios were simulated including Poisson, negative binominal (NB), zero-inflated Poisson (ZIP), and zero-inflated negative binomial (ZINB). The same set of models (i.e., Poisson, NB, ZIP, and ZINB) were fitted for each scenario. In the simulation, I evaluated 10 model selection strategies within the two frameworks by assessing the model selection bias and its consequences on the accuracy of the treatment effect estimates and inferential statistics. Based on the simulation results and previous work, I provide recommendations regarding which model selection methods should be adopted in different scenarios. The implications, limitations, and future research directions are also discussed.

Understanding the capacity development of faculty development programs: a sequential explanatory mixed methods study.

BACKGROUND: Faculty development programs can bring about both individual and organizational capacity development by enhancing individuals' attitudes, values, and skillsto enable them to implement organizational change. Understanding how faculty development programs produce capacity development, and the influencing factors, requires further understanding. This study aimed to explore the perceptions of the participants of a faculty development program about the capacity development features of the program and the influencing factors. METHODS: A sequential explanatory mixed methods design was used. Faculty members were surveyed about their perspectives on capacity development of faculty development. Subsequently, 22 interviews were conducted with the respondents to deepem understanding of the survey results. Interview transcripts underwent conventional content analysis. RESULTS: A total of 203 completed the questionnaire. Most of the faculty highly agreed that the faculty development programs had produced capacity development. The combined data identified (a) "quality of faculty development programs", underscoring the significance of robust and comprehensive initiatives, (b) "development in instruction", emphasizing the importance of continuous improvement in pedagogical approaches (c) "development in professionalism", highlighting the necessity for cultivating a culture of professionalism among faculty members, (d) "development in attitude towards education", emphasizing the role of mindset in fostering effective teaching practices, and (e) "supporting faculty development programs", with fostering organizational growth and innovation. Important barriers and facilitators of the capacity development process included several organizational, interpersonal, and individual factors. CONCLUSION: The study identified specific features of the capacity development process in the context of a faculty development program and highlighted the importance of these programs in producing changes in both individuals and within the wider organizational system. Several factors that enabled and constrained the capacity development process were also identified. The findings of the study can inform future implementation of faculty development programs for capacity development.

Keloid of Pinna Revealed a Chondroid Syringoma in Disguise.

Cutaneous mixed tumor or chondroid syringoma is a rare benign, skin appendageal tumor prevalent in areas of the head and neck. It represents the cutaneous counterpart of the pleomorphic adenoma of salivary glands. Its clinical presentation often misguides the clinician to underdiagnose it as a reactive lesion. We report the case of a 94-year-old male admitted for excision of cutaneous carcinoma concurrently with a chondroid syringoma of the pinna provisionally misdiagnosed as a keloid.

eHealth Literacy and Web-Based Health Information-Seeking Behaviors on COVID-19 in Japan: Internet-Based Mixed Methods Study.

BACKGROUND: During the COVID-19 pandemic, much misinformation and disinformation emerged and spread rapidly via the internet, posing a severe public health challenge. While the need for eHealth literacy (eHL) has been emphasized, few studies have compared the difficulties involved in seeking and using COVID-19 information between adult internet users with low or high eHL. OBJECTIVE: This study examines the association between eHL and web-based health information-seeking behaviors among adult Japanese internet users. Moreover, this study qualitatively shed light on the difficulties encountered in seeking and using this information and examined its relationship with eHL. METHODS: This cross-sectional internet-based survey (October 2021) collected data from 6000 adult internet users who were equally divided into sample groups by gender, age, and income. We used the Japanese version of the eHL Scale (eHEALS). We also used a Digital Health Literacy Instrument (DHLI) adapted to the COVID-19 pandemic to assess eHL after we translated it to Japanese. Web-based health information-seeking behaviors were assessed by using a 10-item list of web sources and evaluating 10 topics participants searched for regarding COVID-19. Sociodemographic and other factors (eg, health-related behavior) were selected as covariates. Furthermore, we qualitatively explored the difficulties in information seeking and using. The descriptive contents of the responses regarding difficulties in seeking and using COVID-19 information were analyzed using an inductive qualitative content analysis approach. RESULTS: Participants with high eHEALS and DHLI scores on information searching, adding self-generated information, evaluating reliability, determining relevance, and operational skills were more likely to use all web sources of information about COVID-19 than those with low scores. However, there were negative associations between navigation skills and privacy protection scores when using several information sources, such as YouTube (Google LLC), to search for COVID-19 information. While half of the participants reported no difficulty seeking and using COVID-19 information, participants who reported any difficulties, including information discernment, incomprehensible information, information overload, and disinformation, had lower DHLI score. Participants expressed significant concerns regarding "information quality and credibility," "abundance and shortage of relevant information," "public trust and skepticism," and "credibility of COVID-19-related information." Additionally, they disclosed more specific concerns, including "privacy and security concerns," "information retrieval challenges," "anxieties and panic," and "movement restriction." CONCLUSIONS: Although Japanese internet users with higher eHEALS and total DHLI scores were more actively using various web sources for COVID-19 information, those with high navigation skills and privacy protection used web-based information about COVID-19 cautiously compared with those with lower proficiency. The study also highlighted an increased need for information discernment when using social networking sites in the "Health 2.0" era. The identified categories and themes from the qualitative content analysis, such as "information quality and credibility," suggest a framework for addressing the myriad challenges anticipated in future infodemics.

Experiences with implementing advance care planning (ACP-GP) in Belgian general practice in the context of a cluster RCT: a process evaluation using the RE-AIM framework.

BACKGROUND: General practice is often recommended as an ideal setting to initiate advance care planning (ACP), but uptake of ACP in this setting is low. ACP-GP is a complex intervention to facilitate ACP for patients with chronic, life-limiting illness in Belgian general practice. It aims to increase patient ACP engagement and general practitioner (GP) ACP self-efficacy. In a cluster-randomized controlled trial, the intervention was not superior to control in increasing these outcomes. A parallel process evaluation aimed to enhance understanding of how the intervention was implemented, and which factors might have influenced trial results. METHODS: We conducted a mixed-methods process evaluation following the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework. Data sources include recruitment and implementation monitoring, questionnaires for patients and GPs, and semi-structured (focus group) interviews with patients and GPs. Questionnaire data were analyzed descriptively. Qualitative data were first analyzed inductively; themes were then assigned deductively to RE-AIM dimensions. RESULTS: Thirty-five GPs and 95 patients were recruited to the trial; GP reach was low. Sixteen GPs and 46 patients provided questionnaire data at 3 months post-baseline; qualitative data were transcribed for 14 GPs and 11 patients. Adoption of intervention components was moderate to good, with the exception of the documentation template for GPs. Interviews revealed varying patient attitudes towards ACP, but patients nonetheless emphasized that conversations made them feel reassured. GPs especially valued a positive framing of ACP. When adopted, the intervention was well-implemented and participant satisfaction was high. However, intention for maintenance was moderate, with GPs raising questions of how to sustainably implement ACP conversations in the future. CONCLUSIONS: Implementing the complex ACP-GP intervention in general practice is feasible, and can be successful. However, the implementation process is challenging and the sustainability is suboptimal. Our findings will guide future research and recommendations for facilitating and implementing ACP in general practice. TRIAL REGISTRATION: ISRCTN12995230; prospectively registered on 19/06/2020.

Joint models reveal genetic architecture of pubertal stage transitions and their association with BMI in admixed Chilean population.

Early or late pubertal onset can lead to disease in adulthood, including cancer, obesity, type 2 diabetes, metabolic disorders, bone fractures, and psychopathologies. Thus, knowing the age at which puberty is attained is crucial as it can serve as a risk factor for future diseases. Pubertal development is divided into five stages of sexual maturation in boys and girls according to the standardized Tanner scale. We performed genome-wide association studies (GWAS) on the "Growth and Obesity Chilean Cohort Study" cohort composed of admixed children with mainly European and Native American ancestry. Using joint models that integrate time-to-event data with longitudinal trajectories of body mass index (BMI), we identified genetic variants associated with phenotypic transitions between pairs of Tanner stages. We identified $42$ novel significant associations, most of them in boys. The GWAS on Tanner $3\rightarrow 4$ transition in boys captured an association peak around the growth-related genes LARS2 and LIMD1 genes, the former of which causes ovarian dysfunction when mutated. The associated variants are expression and splicing Quantitative Trait Loci regulating gene expression and alternative splicing in multiple tissues. Further, higher individual Native American genetic ancestry proportions predicted a significantly earlier puberty onset in boys but not in girls. Finally, the joint models identified a longitudinal BMI parameter significantly associated with several Tanner stages' transitions, confirming the association of BMI with pubertal timing.

Advanced high pressure hyperbaric techniques in tunnelling.

Work in compressed air and diving are both occupational activities that have been around since the mid-19th century, and those undertaking their work under elevated pressure. Meeting the demand to go to "higher pressure for longer" in tunneling has lagged in diving, but both activities have found it necessary to adopt mixed gas breathing and saturation exposure techniques. This paper explains how work in hyperbaric conditions at high pressure is undertaken in tunneling and is illustrated by the hyperbaric activity likely to be involved in constructing a large-diameter road tunnel below a body of water such as an estuary. It also explores the practical differences between work in compressed air and diving.