The cross-sectional and longitudinal interconnectedness of physical, psychological and role functioning following physical trauma: A network analysis.

OBJECTIVE: Surviving physical trauma can have a large impact on one's daily life. Patients are at increased risk for poor physical health, psychological complaints, and problems in role functioning - which is often experienced simultaneously. The present study explores the interconnectedness of physical, psychological, and role functioning during the first two years post-injury, both cross-sectionally and longitudinally from a network perspective. METHODS: 3785 trauma patients (Mage = 64.2 years, SDage = 18.9 years, 50.5% female) completed questionnaires on physical, psychological, and role functioning across six measurement occasions during the first two years post-injury. The Injury Severity Score (ISS) was retrieved from the local trauma registry. Mixed graphical network models and cross-lagged network models were estimated to examine which items of recovery played a central role and were mostly related to other items in cross-sectional and longitudinal networks respectively. RESULTS: The cross-sectional networks showed especially strong interconnections between impairments of physical and role functioning and also within post-traumatic stress symptoms. The longitudinal networks extended these results by showing that pain, impaired mobility, limitations in self-care, anxiety/depressive symptoms, and several post-traumatic stress symptoms were strong predictors for impairments in functioning at later stages of recovery. CONCLUSION: Our findings showed that impairments in physical, psychological, and role functioning experienced by trauma patients are largely intertwined across the two years following injury. Monitoring physical impairments and psychological complaints early in recovery might help to more promptly provide the best fitting aftercare for trauma patients, which can improve recovery on the long-term.

Gut microbiome diversity within Clostridia is negatively associated with human obesity.

Clostridia are abundant in the human gut and comprise families associated with host health such as Oscillospiraceae, which has been correlated with leanness. However, culturing bacteria within this family is challenging, leading to their detection primarily through 16S rRNA amplicon sequencing, which has a limited ability to unravel diversity at low taxonomic levels, or by shotgun metagenomics, which is hindered by its high costs and complexity. In this cross-sectional study involving 114 Colombian adults, we used an amplicon-based sequencing strategy with alternative markers-gyrase subunit B (gyrB) and DNA K chaperone heat protein 70 (dnaK)-that evolve faster than the 16S rRNA gene. Comparing the diversity and abundance observed with the three markers in our cohort, we found a reduction in the diversity of Clostridia, particularly within Lachnospiraceae and Oscillospiraceae among obese individuals [as measured by the body mass index (BMI)]. Within Lachnospiraceae, the diversity of Ruminococcus_A negatively correlated with BMI. Within Oscillospiraceae, the genera CAG-170 and Vescimonas also exhibited this negative correlation. In addition, the abundance of Vescimonas was negatively correlated with BMI. Leveraging shotgun metagenomic data, we conducted a phylogenetic and genomic characterization of 120 metagenome-assembled genomes from Vescimonas obtained from a larger sample of the same cohort. We identified 17 of the 72 reported species. The functional annotation of these genomes showed the presence of multiple carbohydrate-active enzymes, particularly glycosyl transferases and glycoside hydrolases, suggesting potential beneficial roles in fiber degradation, carbohydrate metabolism, and butyrate production. IMPORTANCE: The gut microbiota is diverse across various taxonomic levels. At the intra-species level, it comprises multiple strains, some of which may be host-specific. However, our understanding of fine-grained diversity has been hindered by the use of the conserved 16S rRNA gene. While shotgun metagenomics offers higher resolution, it remains costly, may fail to identify specific microbes in complex samples, and requires extensive computational resources and expertise. To address this, we employed a simple and cost-effective analysis of alternative genetic markers to explore diversity within Clostridia, a crucial group within the human gut microbiota whose diversity may be underestimated. We found high intra-species diversity for certain groups and associations with obesity. Notably, we identified Vescimonas, an understudied group. Making use of metagenomic data, we inferred functionality, uncovering potential beneficial roles in dietary fiber and carbohydrate degradation, as well as in short-chain fatty acid production.

Revealing the evolutionary history and contemporary population structure of Pacific salmon in the Fraser River through genome resequencing.

The Fraser River once supported massive salmon returns. However, over the last century, the largest returns have consistently been less than half of the recorded historical maximum. There is substantial interest from surrounding communities and governments to increase salmon returns for both human use and functional ecosystems. To generate resources for this endeavor, we resequenced genomes of Chinook (Oncorhynchus tshawytscha), coho (O. kisutch), and sockeye salmon (O. nerka) from the Fraser River at moderate coverage (∼16x). A total of 954 resequenced genomes were analyzed, with 681 collected specifically for this study from tissues sampled between 1997 and 2021. An additional 273 were collected from previous studies. At the species level, Chinook salmon appeared to have 1.6-2.1x more SNPs than coho or sockeye salmon, respectively. This difference may be attributable to large historical declines of coho and sockeye salmon. At the population level, three Fraser River genetic groups were identified for each species using principal component and admixture analyses, which is consistent with previous research and supports the continued use of these groups in conservation and management efforts. Environmental factors and a migration barrier were identified as major factors influencing the boundaries of these genetic groups. Additionally, 20 potentially adaptive loci were identified among the genetic groups. This information may be valuable in new management and conservation efforts. Furthermore, the resequenced genomes are an important resource for contemporary genomics research on Fraser River salmon and have been made publicly available.

Cannabinoid Content and Label Accuracy of Various Hemp-Derived Haircare, Cosmetic, and Edible Products Available at Retail Stores and Online in the United States.

Aim: To evaluate the label accuracy and content of various hemp-derived cannabidiol (CBD) products (cannabinoid products with ≤0.3% Δ9-tetrahydrocannabinol [THC]), as well as evaluate advertised claims on product labels. Methods: Hemp haircare, cosmetics, and food/drink products that were advertised to contain CBD were purchased from retail stores in the Baltimore, Maryland area (purchased in July 2020) and online (purchased in August 2020). Cannabinoid concentrations were measured using gas chromatography-mass spectrometry. Percent deviations between labeled and actual CBD concentrations were determined. Label information such as references to the Food and Drug Administration (FDA), external testing claims, and other claims (i.e., cosmetic or beauty, therapeutic, health halo effect, or "other") were quantified. Results: Ninety-seven products were purchased (35 in-store, 62 online). Of the 71 products with a specific total CBD amount on the label, 35 (49%) were underlabeled (>10% more CBD than advertised), 27 (38%) were overlabeled (>10% less CBD than advertised), and 9 (12.7%) were accurately labeled (within ±10% of labeled CBD). The median (range) percentage deviations were -53% (-100%-76%) for haircare products, +18% (-100%-1076%) for cosmetics, and -1% (-100%-4468%) for food/drinks. CBD label accuracy did not differ significantly between products with external testing claims versus those without (t40 = 0.23, p = 0.82). Overall, 24% of the 97 (total) products made a cosmetic or beauty claim (e.g., "skin looks more youthful"), 40% made a therapeutic claim (e.g., "pain relief"), and 86% made a health halo effect claim (e.g., "paraben-free," "dye-free," etc.). Most products (63%) did not include a disclaimer that claims had not been evaluated by the FDA. Conclusions: Most of the products included in this sample were inaccurately labeled for CBD content, including those claiming to have been tested by third party laboratories. A notable finding was that 10 products did not contain any CBD. Many products made therapeutic claims or used marketing tactics to seemingly convey they were safe/healthy, but only about one-third included disclaimers that these statements had not been evaluated by the FDA. These findings highlight the need for proper regulatory oversight of cannabinoid-containing products to ensure quality assurance and deter misleading or unfounded health claims in product marketing.

Home-monitoring for neovascular age-related macular degeneration in older adults within the UK: the MONARCH diagnostic accuracy study.

Background: Most neovascular age-related macular degeneration treatments involve long-term follow-up of disease activity. Home monitoring would reduce the burden on patients and those they depend on for transport, and release clinic appointments for other patients. The study aimed to evaluate three home-monitoring tests for patients to use to detect active neovascular age-related macular degeneration compared with diagnosing active neovascular age-related macular degeneration by hospital follow-up. Objectives: There were five objectives: Estimate the accuracy of three home-monitoring tests to detect active neovascular age-related macular degeneration. Determine the acceptability of home monitoring to patients and carers and adherence to home monitoring. Explore whether inequalities exist in recruitment, participants' ability to self-test and their adherence to weekly testing during follow-up. Provide pilot data about the accuracy of home monitoring to detect conversion to neovascular age-related macular degeneration in fellow eyes of patients with unilateral neovascular age-related macular degeneration. Describe challenges experienced when implementing home-monitoring tests. Design: Diagnostic test accuracy cohort study, stratified by time since starting treatment. Setting: Six United Kingdom Hospital Eye Service macular clinics (Belfast, Liverpool, Moorfields, James Paget, Southampton, Gloucester). Participants: Patients with at least one study eye being monitored by hospital follow-up. Reference standard: Detection of active neovascular age-related macular degeneration by an ophthalmologist at hospital follow-up. Index tests: KeepSight Journal: paper-based near-vision tests presented as word puzzles. MyVisionTrack®: electronic test, viewed on a tablet device. MultiBit: electronic test, viewed on a tablet device. Participants provided test scores weekly. Raw scores between hospital follow-ups were summarised as averages. Results: Two hundred and ninety-seven patients (mean age 74.9 years) took part. At least one hospital follow-up was available for 317 study eyes, including 9 second eyes that became eligible during follow-up, in 261 participants (1549 complete visits). Median testing frequency was three times/month. Estimated areas under receiver operating curves were < 0.6 for all index tests, and only KeepSight Journal summary score was significantly associated with the lesion activity (odds ratio = 3.48, 95% confidence interval 1.09 to 11.13, p = 0.036). Older age and worse deprivation for home address were associated with lower participation (χ2 = 50.5 and 24.3, respectively, p < 0.001) but not ability or adherence to self-testing. Areas under receiver operating curves appeared higher for conversion of fellow eyes to neovascular age-related macular degeneration (0.85 for KeepSight Journal) but were estimated with less precision. Almost half of participants called a study helpline, most often due to inability to test electronically. Limitations: Pre-specified sample size not met; participants' difficulties using the devices; electronic tests not always available. Conclusions: No index test provided adequate test accuracy to identify lesion diagnosed as active in follow-up clinics. If used to detect conversion, patients would still need to be monitored at hospital. Associations of older age and worse deprivation with study participation highlight the potential for inequities with such interventions. Provision of reliable electronic testing was challenging. Future work: Future studies evaluating similar technologies should consider: Independent monitoring with clear stopping rules based on test performance. Deployment of apps on patients' own devices since providing devices did not reduce inequalities in participation and complicated home testing. Alternative methods to summarise multiple scores over the period preceding a follow-up. Trial registration: This trial is registered as ISRCTN79058224. Funding: This award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/97/02) and is published in full in Health Technology Assessment; Vol. 28, No. 32. See the NIHR Funding and Awards website for further award information.

Treatment for neovascular age-related macular degeneration, the most common cause of sight loss in those over 50 years, involves regular eye injections and frequent follow-up appointments. This is inconvenient for patients and causes capacity issues in the hospital eye service. Finding tests that could be undertaken at home that could detect if a further injection and hospital appointment was required or not would increase capacity to see those at highest risk of sight loss and also reduce the burden on patients and their carers. We investigated three different visual function tests, one paper-based and two applications on an iPod Touch_TM tablet (Apple, Cupertino, CA, USA). We wanted to see if they could detect an increase in disease activity that would require treatment, compared to the decision by a retinal specialist at a traditional hospital eye outpatient visit based on clinical examination and retinal imaging. To encourage those without a smartphone or home internet to participate, we provided both an iPod Touch and Mobile Wireless-Fidelity device with a mobile contract. None of the tests performed well enough to safely monitor patients at home. Those who were willing to participate tended to be younger, had previous experience of using smartphones, sending e-mail and internet access and were more well-off than those who chose not to participate. Some participants also experienced difficulties with the devices provided and successfully uploading the data which were not related to the extent of previous information technology experience. There were also significant technical challenges for the research team. The study helpline was used heavily, considerably more than we anticipated. These tests are not ready to be used in this context. Future studies involving mobile health technology need to carefully consider how to reach those unlikely to participate and provide sufficient technical support to support long-term follow-up.

Accelerated degradation testing impacts the degradation processes in 3D printed amorphous PLLA.

Additive manufacturing and electrospinning are widely used to create degradable biomedical components. This work presents important new data showing that the temperature used in accelerated tests has a significant impact on the degradation process in amorphous 3D printed poly-l-lactic acid (PLLA) fibres. Samples (c. 100 µ m diameter) were degraded in a fluid environment at 37 ° C, 50 ° C and 80 ° C over a period of 6 months. Our findings suggest that across all three fluid temperatures, the fibres underwent bulk homogeneous degradation. A three-stage degradation process was identified by measuring changes in fluid pH, PLLA fibre mass, molecular weight and polydispersity index. At 37 ° C, the fibres remained amorphous but, at elevated temperatures, the PLLA crystallised. A short-term hydration study revealed a reduction in glass transition (Tg), allowing the fibres to crystallise, even at temperatures below the dry Tg. The findings suggest that degradation testing of amorphous PLLA fibres at elevated temperatures changes the degradation pathway which, in turn, affects the sample crystallinity and microstructure. The implication is that, although higher temperatures might be suitable for testing bulk material, predictive testing of the degradation of amorphous PLLA fibres (such as those produced via 3D printing or electrospinning) should be conducted at 37 ° C.

Island restoration to rebuild seabird populations and amplify coral reef functioning.

Mobile organisms like seabirds can provide important nutrient flows between ecosystems, but this connectivity has been interrupted by the degradation of island ecosystems. Island restoration (via invasive species eradications and the restoration of native vegetation) can reestablish seabird populations and their nutrient transfers between their foraging areas, breeding colonies, and adjacent nearshore habitats. Its diverse benefits are making island restoration increasingly common and scalable to larger islands and whole archipelagos. We identified the factors that influence breeding seabird abundances throughout the Chagos Archipelago in the Indian Ocean and conducted predictive modeling to estimate the abundances of seabirds that the archipelago could support under invasive predator eradication and native vegetation restoration scenarios. We explored whether the prey base exists to support restored seabird populations across the archipelago, calculated the nitrogen that restored populations of seabirds might produce via their guano, and modeled the cascading conservation gains that island restoration could provide. Restoration was predicted to increase breeding pairs of seabirds to over 280,000, and prey was predicted to be ample to support the revived seabird populations. Restored nutrient fluxes were predicted to result in increases in coral growth rates, reef fish biomasses, and parrotfish grazing and bioerosion rates. Given these potential cross-ecosystem benefits, our results support island restoration as a conservation priority that could enhance resilience to climatic change effects, such as sea-level rise and coral bleaching. We encourage the incorporation of our estimates of cross-ecosystem benefits in prioritization exercises for island restoration.

Restauración en islas para reconstruir las poblaciones de aves marinas y amplificar la funcionalidad de los arrecifes de coral Resumen Los organismos móviles como las aves marinas pueden proporcionar flujos importantes de nutrientes entre los ecosistemas, aunque esta conectividad ha sido interrumpida por la degradación de los ecosistemas isleñas. La restauración de islas (por medio de la erradicación de especies invasoras y la restauración de la vegetación nativa) puede reestablecer las poblaciones de aves marinas y su transferencia de nutrientes entre las áreas de forrajeo, las colonias reproductoras y los hábitats adyacentes a la costa. Los diferentes beneficios de la restauración de islas hacen que sea cada vez más común y escalable a islas más grandes y archipiélagos completos. Identificamos los factores que influyen sobre la abundancia de aves reproductoras en todo el archipiélago de Chagos en el Océano Índico y realizamos un modelo predictivo para estimar la abundancia de aves que podría soportar el archipiélago bajo escenarios de la erradicación de un depredador invasor y la restauración de la vegetación nativa. Exploramos si existe la base de presas para soportar las poblaciones restauradas de aves marinas en el archipiélago, calculamos el nitrógeno que las poblaciones restauradas podrían producir mediante el guano y modelamos la conservación en cascada que podría proporcionar la restauración de la isla. Se pronosticó que la restauración incrementaría las parejas reproductoras a más de 280,000 y que las presas serían las suficientes para soportar las poblaciones restauradas de aves marinas. También se pronosticó que los flujos restaurados de nutrientes resultarían en un incremento de la tasa de crecimiento de los corales, la biomasa de los peces del arrecife y las tasas de bio­erosión y de alimentación de los peces loro. Dados estos beneficios potenciales entre los ecosistemas, nuestros resultados respaldan a la restauración de islas como una prioridad de conservación que podría incrementar la resiliencia a los efectos del cambio climático, como el incremento en el nivel del mar y el blanqueamiento de los corales. Promovemos que se incorporen nuestras estimaciones de los beneficios transecosistémicos dentro de los ejercicios de priorización para la restauración de islas.

Depression disparities among sexual minority faculty of color in the United States.

This study aimed to examine potential differences in depression symptoms between sexual minority (SM) and heterosexual faculty of color (FOC). A United States (U.S.) national survey of early and mid-career faculty experiences was undertaken. A total of N = 676 participants were screened, with a total usable sample size of N = 596 (n = 80 surveys were missing sexual orientation information). Participants were U.S. born and self-identified as African American/Black, Mexican, Puerto Rican, Native American/American Indian, or other Hispanic, and held a tenure-track assistant or associate professor position at a research university. Participants were identified through network sampling techniques, such as use of academic listservs, personal contacts, respondent referrals, and university websites. The study aim was examined using multiple linear regression. In multivariable analysis, SM FOC were more likely to suffer from greater depression symptoms compared to heterosexual FOC (HFOC). Significant covariates included perceived career impact of inadequate mentoring, individual annual income, and home ownership. Study findings signify mental health threat among SM FOC compared to HFOC. There's an urgent public health need for future research to identify the underlying mechanisms driving mental health among SM FOC to inform the development of prevention programs that can mitigate these disparities, especially in higher education settings. Lastly, findings suggest a need for critical examination of mental health, socioeconomic, and mentoring resources for SM FOC in higher education institutions.

Evaluation of a Student Pharmacist-Driven Fall-Prevention Program for Older People.

There is limited research on the impact of fall prevention education for older community-living people led by student pharmacists, which includes a medication review to identify Fall Risk-Increasing Drugs (FRIDs). Study objectives were to first assess the knowledge and behavioral intentions of older people after attending a student pharmacist-led fall-prevention program (FPP) and secondly to quantify the number of FRIDs identified during a medication review. Between October 2022 and April 2023, four independent-living facilities and two senior centers served as programming locations. Events began with a fall prevention-focused presentation provided by student pharmacists. Attendees voluntarily filled out surveys to assess their knowledge and behavioral intentions regarding fall prevention. Optional medication reviews were offered. Additional survey questions were asked of medication review participants. If FRIDs were identified, the individual was provided documentation to share with their prescriber. Fall prevention bingo was offered at select events to review educational content and engage those waiting for a medication review. Eighty-six older people attended the presentations; 45 people completed medication reviews across six sites. Survey information was available for 65 presentation attendees and 29 medication review participants. After programming, 64 out of 65 participants stated they felt comfortable speaking to their pharmacist or provider about falls and their medications. Most survey respondents correctly selected which medications increase fall risk. Twenty-two of 29 medication review participants were taking at least one FRID. The FPP described showed positive results through a post-survey evaluation. Participants demonstrated knowledge of fall hazards including medications and a willingness to discuss falls and FRIDs with health professionals. These factors may lead to concrete interventions to avoid falls and their associated health consequences for older people.

Characterizing collagen scaffold compliance with native myocardial strains using an ex-vivo cardiac model: The physio-mechanical influence of scaffold architecture and attachment method.

Applied to the epicardium in-vivo, regenerative cardiac patches support the ventricular wall, reduce wall stresses, encourage ventricular wall thickening, and improve ventricular function. Scaffold engraftment, however, remains a challenge. After implantation, scaffolds are subject to the complex, time-varying, biomechanical environment of the myocardium. The mechanical capacity of engineered tissue to biomimetically deform and simultaneously support the damaged native tissue is crucial for its efficacy. To date, however, the biomechanical response of engineered tissue applied directly to live myocardium has not been characterized. In this paper, we utilize optical imaging of a Langendorff ex-vivo cardiac model to characterize the native deformation of the epicardium as well as that of attached engineered scaffolds. We utilize digital image correlation, linear strain, and 2D principal strain analysis to assess the mechanical compliance of acellular ice templated collagen scaffolds. Scaffolds had either aligned or isotropic porous architecture and were adhered directly to the live epicardial surface with either sutures or cyanoacrylate glue. We demonstrate that the biomechanical characteristics of native myocardial deformation on the epicardial surface can be reproduced by an ex-vivo cardiac model. Furthermore, we identified that scaffolds with unidirectionally aligned pores adhered with suture fixation most accurately recapitulated the deformation of the native epicardium. Our study contributes a translational characterization methodology to assess the physio-mechanical performance of engineered cardiac tissue and adds to the growing body of evidence showing that anisotropic scaffold architecture improves the functional biomimetic capacity of engineered cardiac tissue. STATEMENT OF SIGNIFICANCE: Engineered cardiac tissue offers potential for myocardial repair, but engraftment remains a challenge. In-vivo, engineered scaffolds are subject to complex biomechanical stresses and the mechanical capacity of scaffolds to biomimetically deform is critical. To date, the biomechanical response of engineered scaffolds applied to live myocardium has not been characterized. In this paper, we utilize optical imaging of an ex-vivo cardiac model to characterize the deformation of the native epicardium and scaffolds attached directly to the heart. Comparing scaffold architecture and fixation method, we demonstrate that sutured scaffolds with anisotropic pores aligned with the native alignment of the superficial myocardium best recapitulate native deformation. Our study contributes a physio-mechanical characterization methodology for cardiac tissue engineering scaffolds.

Phenotypic switching mechanisms determine the structure of cell migration into extracellular matrix under the 'go-or-grow' hypothesis.

A fundamental feature of collective cell migration is phenotypic heterogeneity which, for example, influences tumour progression and relapse. While current mathematical models often consider discrete phenotypic structuring of the cell population, in-line with the 'go-or-grow' hypothesis (Hatzikirou et al., 2012; Stepien et al., 2018), they regularly overlook the role that the environment may play in determining the cells' phenotype during migration. Comparing a previously studied volume-filling model for a homogeneous population of generalist cells that can proliferate, move and degrade extracellular matrix (ECM) (Crossley et al., 2023) to a novel model for a heterogeneous population comprising two distinct sub-populations of specialist cells that can either move and degrade ECM or proliferate, this study explores how different hypothetical phenotypic switching mechanisms affect the speed and structure of the invading cell populations. Through a continuum model derived from its individual-based counterpart, insights into the influence of the ECM and the impact of phenotypic switching on migrating cell populations emerge. Notably, specialist cell populations that cannot switch phenotype show reduced invasiveness compared to generalist cell populations, while implementing different forms of switching significantly alters the structure of migrating cell fronts. This key result suggests that the structure of an invading cell population could be used to infer the underlying mechanisms governing phenotypic switching.

Hit it hard: qualitative patient perspectives on the optimisation of immune checkpoint inhibition.

BACKGROUND: Immune checkpoint inhibitors have transformed the treatment landscape of many cancers, including melanoma and renal cell carcinoma (RCC). Randomised trials are evaluating outcomes from reduced ICI treatment schedules with the aim of improving quality of life, tolerability, and cost-effectiveness. This study aims to provide insight into patient and carer's perspectives of these trials. METHODS: Seven focus groups were conducted with 31 people with stage IV melanoma, RCC, or caregivers for people receiving ICI. Transcripts were analysed using reflexive thematic analysis. RESULTS: Three themes were generated: 1) "Treatment and clinic visits provide reassurance": reducing hospital visits may not improve quality of life. 2) "Assessment of personal risk versus benefit": the decision to participate in an ICI optimisation trial is influenced by treatment response, experience of toxicity and perceived logistical benefits based on the individual's circumstances. 3) "Pre-existing experience and beliefs about how treatment and trials work", including the belief that more treatment is better, influence views around ICI optimisation trials. CONCLUSION: This study provides insight into recruitment challenges and recommends strategies to enhance recruitment for ongoing ICI optimisation trials. These findings will influence the design of future ICI optimisation trials ensuring they are acceptable to patients.

Effectiveness of a symptom-clinic intervention delivered by general practitioners with an extended role for people with multiple and persistent physical symptoms in England: the Multiple Symptoms Study 3 pragmatic, multicentre, parallel-group, individually randomised controlled trial.

BACKGROUND: People with multiple and persistent physical symptoms have impaired quality of life and poor experiences of health care. We aimed to evaluate the effectiveness of a community-based symptom-clinic intervention in people with multiple and persistent physical symptoms, hypothesising that this symptoms clinic plus usual care would be superior to usual care only. METHODS: The Multiple Symptoms Study 3 was a pragmatic, multicentre, parallel-group, individually randomised controlled trial conducted in 108 general practices in the UK National Health Service in four regions of England between Dec 6, 2018, and June 30, 2023. Participants were individually randomised (1:1) to the symptom-clinic intervention plus usual care or to usual care only via a computer-generated, pseudo-random list stratified by trial centre. Allocation was done by the trial statistician and concealed with a centralised, web-based randomisation system; masking participants was not possible due to the nature of the intervention. The symptom-clinic intervention was a sequence of up to four medical consultations that aimed to elicit a detailed clinical history, fully hear and validate the participant, offer rational explanations for symptoms, and assist the participant to develop ways of managing their symptoms; it was delivered by general practitioners with an extended role. The primary outcome was Patient Health Questionnaire-15 (PHQ-15) score 52 weeks after randomisation, analysed by intention to treat. The trial is registered on the ISRCTN registry (ISRCTN57050216). FINDINGS: 354 participants were randomly assigned; 178 (50%) were assigned to receive the community-based symptoms clinic plus usual care and 176 (50%) were assigned to receive usual care only. At the primary-outcome point of 52 weeks, PHQ-15 scores were 14·1 (SD 3·7) in the group receiving usual care and 12·2 (4·5) in the group receiving the intervention. The adjusted between-group difference of -1·82 (95% CI -2·67 to -0·97) was statistically significantly in favour of the intervention group (p<0·0001). There were 39 adverse events in the group receiving usual care and 36 adverse events in the group receiving the intervention. There were no statistically significant between-group differences in the proportion of participants who had non-serious adverse events (-0·03, 95% CI -0·11 to 0·05) or serious adverse events (0·02, -0·02 to 0·07). No serious adverse event was deemed to be related to the trial intervention. INTERPRETATION: Our symptom-clinic intervention, which focused on explaining persistent symptoms to participants in order to support self-management, led to sustained improvement in multiple and persistent physical symptoms. FUNDING: UK National Institute for Health and Care Research.

Smoothing in linear multicompartment biological processes subject to stochastic input.

Many physical and biological systems rely on the progression of material through multiple independent stages. In viral replication, for example, virions enter a cell to undergo a complex process comprising several disparate stages before the eventual accumulation and release of replicated virions. While such systems may have some control over the internal dynamics that make up this progression, a challenge for many is to regulate behavior under what are often highly variable external environments acting as system inputs. In this work, we study a simple analog of this problem through a linear multicompartment model subject to a stochastic input in the form of a mean-reverting Ornstein-Uhlenbeck process, a type of Gaussian process. By expressing the system as a multidimensional Gaussian process, we derive several closed-form analytical results relating to the covariances and autocorrelations of the system, quantifying the smoothing effect discrete compartments afford multicompartment systems. Semianalytical results demonstrate that feedback and feedforward loops can enhance system robustness, and simulation results probe the intractable problem of the first passage time distribution, which has specific relevance to eventual cell lysis in the viral replication cycle. Finally, we demonstrate that the smoothing seen in the process is a consequence of the discreteness of the system, and does not manifest in systems with continuous transport. While we make progress through analysis of a simple linear problem, many of our insights are applicable more generally, and our work enables future analysis into multicompartment processes subject to stochastic inputs.

Birthdate-based commercial tobacco sales restrictions: will 'tobacco-free generation' policies advance or delay the endgame?

Endgame thinking means transitioning from merely trying to 'control' the tobacco epidemic to developing plans and measures to bring it to an end within a specific time, by changing the underlying dynamics that have created and perpetuated it for more than a century. Among the innovative policies characterised as 'endgame' policies are so-called 'tobacco-free generation' or 'smoke-free generation' policies, which prohibit sales of some or all tobacco products to individuals born on or after a particular date. Such birthdate-based sales restrictions (BSR) have intuitive appeal, largely because they do not appreciably disrupt the status quo of retail sales, which continue unchanged for all those born before the designated cut-off date. They also hold the potential for further denormalising tobacco use and sales by anticipating the long-term end of tobacco sales. In this Special Communication, we analyse BSR policies through an endgame lens and propose questions that should be discussed in jurisdictions considering them. We suggest that this policy has potential underexamined pitfalls, particularly related to equity, and that if enacted, it should include policy guardrails and be part of a package of endgame measures.

Strain tracking in complex microbiomes using synteny analysis reveals per-species modes of evolution.

Microbial species diversify into strains through single-nucleotide mutations and structural changes, such as recombination, insertions and deletions. Most strain-comparison methods quantify differences in single-nucleotide polymorphisms (SNPs) and are insensitive to structural changes. However, recombination is an important driver of phenotypic diversification in many species, including human pathogens. We introduce SynTracker, a tool that compares microbial strains using genome synteny-the order of sequence blocks in homologous genomic regions-in pairs of metagenomic assemblies or genomes. Genome synteny is a rich source of genomic information untapped by current strain-comparison tools. SynTracker has low sensitivity to SNPs, has no database requirement and is robust to sequencing errors. It outperforms existing tools when tracking strains in metagenomic data and is particularly suited for phages, plasmids and other low-data contexts. Applied to single-species datasets and human gut metagenomes, SynTracker, combined with an SNP-based tool, detects strains enriched in either point mutations or structural changes, providing insights into microbial evolution in situ.

Stability of Nano-Emulsified Cannabidiol in Acidic Foods and Beverages.

Introduction: Food and beverage products containing cannabidiol (CBD) is a growing industry, but some CBD products contain Δ9-tetrahydrocannabinol (Δ9-THC), despite being labeled as "THC-free". As CBD can convert to Δ9-THC under acidic conditions, a potential cause is the formation of Δ9-THC during storage of acidic CBD products. In this study, we investigated if acidic products (pH ≤ 4) fortified with CBD would facilitate conversion to THC over a 2-15-month time period. Materials and Methods: Six products, three beverages (lemonade, cola, and sports drink) and three condiments (ketchup, mustard, and hot sauce), were purchased from a local grocery store and fortified with a nano-emulsified CBD isolate (verified as THC-free by testing). The concentrations of CBD and Δ9-THC were measured by Gas Chromatography Flame Ionization Detector (GC-FID) and Liquid Chromatography with tandem mass spectrometry (LC-MS/MS), respectively, for up to 15 months at room temperature. Results: Coefficients of variation (CVs) of initial CBD concentrations by GC-FID were <10% for all products except ketchup (18%), showing homogeneity in the fortification. Formation of THC was variable, with the largest amount observed after 15 months in fortified lemonade #2 (3.09 mg Δ9-THC/serving) and sports drink #2 (1.18 mg Δ9-THC/serving). Both beverages contain citric acid, while cola containing phosphoric acid produced 0.10 mg Δ9-THC/serving after 4 months. The importance of the acid type was verified using acid solutions in water. No more than 0.01 mg Δ9-THC/serving was observed with the condiments after 4 months. Discussion: Conversion of CBD to THC can occur in some acidic food products when those products are stored at room temperature. Therefore, despite purchasing beverages manufactured with a THC-free nano-emulsified form of CBD, consumers might be at some risk of unknowingly ingesting small amounts of THC. The results indicate that up to 3 mg Δ9-THC from conversion can be present in a serving of CBD-lemonade. Based on the previous studies, 3 mg Δ9-THC might produce a positive urine sample (≥15 ng/mL THC carboxylic acid) in some individuals. Conclusion: Consumers must exert caution when consuming products with an acidic pH (≤4) that suggests that they are "THC-Free," because consumption might lead to positive drug tests or, in the case of multiple doses, intoxication.

PHA4GE quality control contextual data tags: standardized annotations for sharing public health sequence datasets with known quality issues to facilitate testing and training.

As public health laboratories expand their genomic sequencing and bioinformatics capacity for the surveillance of different pathogens, labs must carry out robust validation, training, and optimization of wet- and dry-lab procedures. Achieving these goals for algorithms, pipelines and instruments often requires that lower quality datasets be made available for analysis and comparison alongside those of higher quality. This range of data quality in reference sets can complicate the sharing of sub-optimal datasets that are vital for the community and for the reproducibility of assays. Sharing of useful, but sub-optimal datasets requires careful annotation and documentation of known issues to enable appropriate interpretation, avoid being mistaken for better quality information, and for these data (and their derivatives) to be easily identifiable in repositories. Unfortunately, there are currently no standardized attributes or mechanisms for tagging poor-quality datasets, or datasets generated for a specific purpose, to maximize their utility, searchability, accessibility and reuse. The Public Health Alliance for Genomic Epidemiology (PHA4GE) is an international community of scientists from public health, industry and academia focused on improving the reproducibility, interoperability, portability, and openness of public health bioinformatic software, skills, tools and data. To address the challenges of sharing lower quality datasets, PHA4GE has developed a set of standardized contextual data tags, namely fields and terms, that can be included in public repository submissions as a means of flagging pathogen sequence data with known quality issues, increasing their discoverability. The contextual data tags were developed through consultations with the community including input from the International Nucleotide Sequence Data Collaboration (INSDC), and have been standardized using ontologies - community-based resources for defining the tag properties and the relationships between them. The standardized tags are agnostic to the organism and the sequencing technique used and thus can be applied to data generated from any pathogen using an array of sequencing techniques. The tags can also be applied to synthetic (lab created) data. The list of standardized tags is maintained by PHA4GE and can be found at https://github.com/pha4ge/contextual_data_QC_tags. Definitions, ontology IDs, examples of use, as well as a JSON representation, are provided. The PHA4GE QC tags were tested, and are now implemented, by the FDA's GenomeTrakr laboratory network as part of its routine submission process for SARS-CoV-2 wastewater surveillance. We hope that these simple, standardized tags will help improve communication regarding quality control in public repositories, in addition to making datasets of variable quality more easily identifiable. Suggestions for additional tags can be submitted to PHA4GE via the New Term Request Form in the GitHub repository. By providing a mechanism for feedback and suggestions, we also expect that the tags will evolve with the needs of the community.

Needs and Challenges for Volunteering in Rural Areas: Lessons Learned From a Survey of a Service Organization in Rural Michigan.

BACKGROUND AND OBJECTIVES: Volunteers are the foundation of social service agencies in rural communities, yet limited research exists on their needs and challenges. Motivated by the multidimensional older voluntarism sustainability framework, this study aims to understand (1) the characteristics of volunteers, (2) the relationships between volunteers' sense of community and their own aging and volunteer retention, and (3) the unique challenges faced by volunteers and volunteer-based agencies. RESEARCH DESIGN AND METHODS: This study uses a mixed-methods design. Data were gathered via telephone interviews (n = 76) and in-person focus groups (n = 14) from the volunteer pool of a nonprofit organization in rural Michigan. Descriptive and regression analyses were conducted to understand the characteristics of the volunteers. Thematic analysis was conducted to identify unique challenges faced by rural agencies and volunteers. RESULTS: Findings show that most volunteers were over 70, women, married, volunteered weekly or more, and were affiliated with multiple agencies. Volunteers with a stronger attachment to the community and higher self-perceptions of aging were likelier to continue and increase volunteering commitments. Due to the low population density in rural areas, volunteers were concerned about the heavy burden of volunteering, the lack of social connections with fellow volunteers, and the lack of active involvement in shaping the organization. DISCUSSION AND IMPLICATIONS: Results from the study shed light on the urgent need for creative and engaging volunteer recruitment and retention strategies to sustain older adults, service agencies, and communities in rural areas.

Motivations for completing pulmonary rehabilitation - A qualitative analysis.

Background: Previous studies have focused on demographic factors that might predict non-completion of pulmonary rehabilitation (PR). We aimed to identify key modifiable factors that promote completion of PR. Methods: A mixed methods survey was offered to participants completing a discharge assessment following PR. Descriptive statistics and inductive thematic analysis were used to analyse the survey responses, with investigator triangulation. Results: 62 of 187 (33%) patients attending a PR discharge assessment between November 2022 and April 2023 returned the anonymised survey. Desire to improve health and wellbeing was the main reason for both initially committing to a course and for continuing with PR past transient thoughts of leaving. The positive impact of staff was the second most common reason. The enjoyment of the PR programme, being held accountable to attend classes, and the importance of other group members were other key themes identified. Conclusions: In conclusion, our findings suggest PR services need to implement strategies which ensure regular promotion and reinforcement of the health benefits of PR as well as implementation of PR modalities which best monopolise on the positive impact skilled staff have on motivating patients to complete PR.