User Experience of a Large-Scale Smartphone-Based Observational Study in Multiple Sclerosis: Global, Open-Access, Digital-Only Study.

BACKGROUND: The Floodlight Open app is a digital health technology tool (DHTT) that comprises remote, smartphone sensor-based tests (daily activities) for assessing symptoms of multiple sclerosis (MS). User acquisition, engagement, and retention remain a barrier to successfully deploying such tools. OBJECTIVE: This study aims to quantitatively and qualitatively investigate key user experience (UX) factors associated with the Floodlight Open app. METHODS: Floodlight Open is a global, open-access, digital-only study designed to understand the drivers and barriers in deploying a DHTT in a naturalistic setting without supervision and onboarding by a clinician. Daily activities included tests assessing cognition (Information Processing Speed and Information Processing Speed Digit-Digit), hand-motor function (Pinching Test and Draw a Shape Test), and postural stability and gait (Static Balance Test, U-Turn Test, and Two-Minute Walk Test [2MWT]). All daily activities except the 2MWT were taken in a fixed sequence. Qualitative UX was studied through semistructured interviews in a substudy of US participants with MS. The quantitative UX analysis investigated the impact of new UX design features on user engagement and retention in US participants for 3 separate test series: all daily activities included in the fixed sequence (DA), all daily activities included in the fixed sequence except the Static Balance Test and U-Turn Test (DAx), and the 2MWT. RESULTS: The qualitative UX substudy (N=22) revealed the need for 2 new UX design features: a more seamless user journey during the activation process that eliminates the requirement of switching back and forth between the app and the email that the participants received upon registration, and configurable reminders and push notifications to help plan and remind the participants to complete their daily activities. Both UX design features were assessed in the quantitative UX analysis. Introducing the more seamless user journey (original user journey: n=608; more seamless user journey: n=481) improved the conversion rate of participants who enrolled in the study and proceeded to successfully activate the app from 53.9% (328/608) to 74.6% (359/481). Introducing reminders and push notifications (with reminders and notifications: n=350; without reminders and notifications: n=172) improved continuous usage time (proportion of participants with ≥3 consecutive days of usage: DA and DAx: ~30% vs ~12%; 2MWT: ~30% vs ~20%); test completion rates (maximum number of test series completed: DA: 279 vs 64; DAx: 283 vs 126; 2MWT: 302 vs 76); and user retention rates (at day 30: DA: 53/172, 30.8% vs 34/350, 9.7%; DAx: 53/172, 30.8% vs 60/350, 17.1%; 2MWT: 39/172, 22.6% vs 22/350, 6.2%). Inactivity times remained comparable. CONCLUSIONS: The remote assessment of MS with DHTTs is a relatively nascent but growing field of research. The continued assessment and improvement of UX design features can play a crucial role in the successful long-term adoption of new DHTTs.

Loneliness and low life satisfaction associated with older adults' poor oral health.

Objective: To examine the association of older adults' loneliness, life satisfaction, and other psychological stressors and resources with oral health status. Methods: This study merged 2018 data from the Health and Retirement Study (HRS) CORE survey with the HRS-Dental Module, and Psychosocial and Lifestyle Questionnaire-Panel A "Leave Behind" surveys (HRS-LB)(N = 418). Dental Module outcomes of interest were self-rated oral health status (SROH), and oral health-related quality of life (OHQOL). Older adults reported on loneliness, life satisfaction, perceived age, social status, control, mastery, and chronic stressors. Three distinct profiles based on the distribution of loneliness and life satisfaction were previously identified in the combined HRS and HRS-LB study population (N = 4,703) using latent class analysis (LCA). Class A:"Not Lonely/Satisfied" adults had the fewest psychosocial risk factors and most resources; Class C:"Lonely/Unsatisfied" adults exhibited the opposite profile (most risk factors, fewest resources); Class B:"Lonely/Satisfied" adults exhibited loneliness with favorable life satisfaction. Regression models examined associations between LCA classes and fair/poor SROH and the OHQOL scale score and individual items, after adjusting for socio-demographics. Results: About 13% of older adults experienced loneliness, and about 16% reported low life satisfaction. About one-quarter (28%) of older adults reported fair/poor SROH, and they experienced more psychosocial risk factors than their counterparts with better oral health status. Nearly half the older adults were categorized in Class A:"Not Lonely/Satisfied" (n = 201), and about one-quarter each in Class B:"Lonely/Satisfied" (n = 103) and Class C:"Lonely/Unsatisfied" (n = 112). In fully adjusted models, Class B older adults had 1.81 (1.11-2.96) times greater odds of fair/poor SROH, and Class C had 4.64 (2.78-7.73) times greater odds of fair/poor SROH than Class A. Fully adjusted linear regression model results indicated a gradient by LCA class. OHQOL varied; Class A older adults had the best (lowest) OHQOL score (mean = 8.22, 4.37-12.10), Class B scored in the middle (mean = 12.00, 7.61-16.50), while Class C had the worst (highest) OHQOL score (mean = 16.20, 11.80-20.60). Conclusion: Loneliness, as a defining characteristic distinguishing three latent classes of older adults, was associated with more risk factors and poorer oral health outcomes. Loneliness, life satisfaction, perceived age, social status, control, mastery, and chronic stressors vary widely for older adults and matter for oral health and OHQOL.

Project Sandman: A Quasi-Experimental Evaluation of a Group-Based Brief Sleep Intervention in Air Force Technical Training.

OBJECTIVES: Approximately 70% of the military personnel experience chronic sleep insufficiency, which negatively impacts military readiness and health. Military sleep health does not appear to be improving despite targeted programs to optimize sleep. The present quasi-experimental study aims to evaluate a single-session sleep intervention in United States Air Force (USAF) Technical Training. METHOD: A group-based Brief Sleep Intervention (BSI) was developed for the target population. Participants included 321 technical school students (Mean age = 21; 82% male; 67% White) who were assigned to the BSI (n = 203) or a control group (n = 118). Propensity-score-weighted multivariable logistic regression was employed to compare outcomes. RESULTS: At the 2-week follow-up, students in the BSI were significantly more likely to report sleeping 6 or more hours on weekdays (OR = 1.49, p < .001) and "Good/Very Good" sleep quality (OR = 1.50, p = .032) than those in the control group. In addition, 69.2% of the students in BSI reported having engaged in the self-selected "Action Step" chosen during the intervention. CONCLUSIONS: To our knowledge, this is the first study to test a preventative sleep intervention in USAF Technical Training. Results suggest that a single-session group intervention can promote behavioral changes and improve sleep health.

Microplastic pollution and nutrient enrichment shift the diet of freshwater macroinvertebrates.

Microplastic pollution poses a global threat to freshwater ecosystems, with laboratory experiments indicating potential toxic impacts through chemical toxicity, physical abrasion, and false satiation. Bioplastics have emerged as a potential greener alternative to traditional oil-based plastics. Yet, their environmental effects remain unclear, particularly at scales relevant to the natural environment. Additionally, the interactive impacts of microplastics with other environmental stressors, such as nutrient enrichment, are poorly understood and rarely studied. Under natural conditions organisms might be able to mitigate the toxic effects of microplastics by shifting their diet, but this ability may be compromised by other stressors. This study combines an outdoor mesocosm experiment and stable isotope analysis to determine changes in the trophic niches of three freshwater invertebrate species exposed to conventional (HDPE) and bio-based biodegradable (PLA) microplastics at two concentrations, both independently and combined with nutrient enrichment. Exposure to microplastics altered the isotopic niches of two of the invertebrate species, with nutrient enrichment mediating this effect. Moreover, the effects of microplastics were consistent regardless of their type or concentration. Under enriched conditions, two of the species exposed to microplastics shifted to a specialised diet compared with controls, whereas little difference was observed between the isotopic niches of those exposed to microplastic and controls under ambient nutrient conditions. Additionally, PLA was estimated to support 24 % of the diet of one species, highlighting the potential assimilation of bioplastics by biota and possible implications. Overall, these findings suggest that the toxic effects of microplastics suggested from laboratory studies might not manifest under real-world conditions. However, this study does demonstrate that subtle sublethal effects occur even at environmentally realistic microplastic concentrations. The crucial role of nutrient enrichment in mediating microplastic effects underscores the importance of considering microplastic pollution in the context of other environmental stressors.

Time series of freshwater macroinvertebrate abundances and site characteristics of European streams and rivers.

Freshwater macroinvertebrates are a diverse group and play key ecological roles, including accelerating nutrient cycling, filtering water, controlling primary producers, and providing food for predators. Their differences in tolerances and short generation times manifest in rapid community responses to change. Macroinvertebrate community composition is an indicator of water quality. In Europe, efforts to improve water quality following environmental legislation, primarily starting in the 1980s, may have driven a recovery of macroinvertebrate communities. Towards understanding temporal and spatial variation of these organisms, we compiled the TREAM dataset (Time seRies of European freshwAter Macroinvertebrates), consisting of macroinvertebrate community time series from 1,816 river and stream sites (mean length of 19.2 years and 14.9 sampling years) of 22 European countries sampled between 1968 and 2020. In total, the data include >93 million sampled individuals of 2,648 taxa from 959 genera and 212 families. These data can be used to test questions ranging from identifying drivers of the population dynamics of specific taxa to assessing the success of legislative and management restoration efforts.

Evaluation of TrpM and PsiD substrate promiscuity reveals new biocatalytic capabilities.

N-methylated tryptamines, such as the hallucinogenic natural products, psilocybin and N,N-dimethyltryptamine (DMT), are gaining interest from the medical community due to their potential as next generation treatments for mental health disorders. The clinical relevance of these compounds has driven scientists to develop biosynthetic production routes to a number of tryptamine drug candidates, and efforts are ongoing to expand and further develop these biosynthetic capabilities. To that end, we have further characterized the substrate preferences of two enzymes involved in tryptamine biosynthesis: TrpM, a tryptophan N-methyltransferase from Psilocybe serbica, and PsiD, the gateway decarboxylase of the psilocybin biosynthesis pathway. Here, we show that TrpM can N-methylate the non-native amino acid substrate, 4-hydroxytryptophan, a key intermediate in the Escherichia coli-based recombinant psilocybin biosynthesis pathway. However, the ability to incorporate TrpM into a functional psilocybin biosynthesis pathway was thwarted by PsiD's inability to use N,N-dimethyl-4-hydroxytryptophan as substrate, under the culturing conditions tested, despite demonstrating activity on N-methylated and 4-hydroxylated tryptophan derivatives individually. Taken together, this work expands upon the known substrates for TrpM and PsiD, further increasing the diversity of tryptamine biosynthetic products.

Effect of oral tryptamines on the gut microbiome of rats-a preliminary study.

Background: Psilocybin and related tryptamines have come into the spotlight in recent years as potential therapeutics for depression. Research on the mechanisms of these effects has historically focused on the direct effects of these drugs on neural processes. However, in addition to such neural effects, alterations in peripheral physiology may also contribute to their therapeutic effects. In particular, substantial support exists for a gut microbiome-mediated pathway for the antidepressant efficacy of other drug classes, but no prior studies have determined the effects of tryptamines on microbiota. Methods: To address this gap, in this preliminary study, male Long Evans rats were treated with varying dosages of oral psilocybin (0.2 or 2 mg/kg), norbaeocystin (0.25 or 2.52 mg/kg), or vehicle and their fecal samples were collected 1 week and 3 weeks after exposure for microbiome analysis using integrated 16S ribosomal DNA sequencing to determine gut microbiome composition. Results: We found that although treatment with neither psilocybin nor norbaeocystin significantly affected overall microbiome diversity, it did cause significant dose- and time-dependent changes in bacterial abundance at the phylum level, including increases in Verrucomicrobia and Actinobacteria, and decreases in Proteobacteria. Conclusion and Implications: These preliminary findings support the idea that psilocybin and other tryptamines may act on the gut microbiome in a dose- and time-dependent manner, potentially identifying a novel peripheral mechanism for their antidepressant activity. The results from this preliminary study also suggest that norbaeocystin may warrant further investigation as a potential antidepressant, given the similarity of its effects to psilocybin.

Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms.

BACKGROUND AND PURPOSE: Demand for new antidepressants has resulted in a re-evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin-containing "magic" mushrooms share chemical similarities with psilocybin. Early work suggests they may share biological targets. However, few studies have explored their pharmacological and behavioural effects. EXPERIMENTAL APPROACH: We compared baeocystin, norbaeocystin and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, similarly penetrate the blood-brain barrier, serve as ligands for similar receptors and modulate behaviour in rodents similarly. We also assessed the stability and optimal storage and handling conditions for each compound. KEY RESULTS: In vitro enzyme kinetics assays found that all compounds had nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin crossed a blood-brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. The dephosphorylated form of norbaeocystin was found to activate the 5-HT2A receptor with similar efficacy to psilocin and norpsilocin in in vitro cell imaging assays. Behaviourally, only psilocybin induced head twitch responses in rats, a marker of 5-HT2A-mediated psychedelic effects and hallucinogenic potential. However, like psilocybin, norbaeocystin improved outcomes in the forced swim test. All compounds caused minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles. CONCLUSIONS AND IMPLICATIONS: Collectively, this work suggests that other naturally occurring tryptamines, especially norbaeocystin, may share overlapping therapeutic potential with psilocybin, but without causing hallucinations.

Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (25), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 (25) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.

Water for agriculture: more crop per drop.

Global crop production in agriculture depends on water availability. Future scenarios predict increasing occurrence of flash floods and rapidly developing droughts accompanied by heatwaves in humid regions that rely on rain-fed agriculture. It is challenging to maintain high crop yields, even in arid and drought-prone regions that depend on irrigation. The average water demand of crops varies significantly, depending on plant species, development stage, and climate. Most crops, such as maize and wheat, require relatively more water during the vegetative phase compared to the ripening phase. In this review, we explain WUE and options to improve water use and thus crop yield. Nutrient management might represent another possibility to manipulate water uptake and use by plants. An emerging topic involves agroforest co-cultivation, where trees in the system facilitate water transfer through hydraulic lift, benefiting neighbouring crops. Other options to enhance crop yield per water use are discussed.

Exploring the potential of biofiltration for mitigating harmful gaseous emissions from small or old landfills: a review.

Landfills are widely employed as the primary means of solid waste disposal. However, this practice generates landfill gas (LFG) which contains methane (CH4), a potent greenhouse gas, as well as various volatile organic compounds and volatile inorganic compounds. These emissions from landfills contribute to approximately 25% of the total atmospheric CH4, indicating the imperative need to valorize or treat LFG prior to its release into the atmosphere. This review first aims to outline landfills, waste disposal and valorization, conventional gas treatment techniques commonly employed for LFG treatment, such as flares and thermal oxidation. Furthermore, it explores biotechnological approaches as more technically and economically feasible alternatives for mitigating LFG emissions, especially in the case of small and aged landfills where CH4 concentrations are often below 3% v/v. Finally, this review highlights biofilters as the most suitable biotechnological solution for LFG treatment and discusses several advantages and challenges associated with their implementation in the landfill environment.

Inconclusive decisions and error rates in forensic science.

In recent years, there has been discussion and controversy relating to the treatment of inconclusive decisions in forensic feature comparison disciplines when considering the reliability of examination methods and results. In this article, we offer a brief review of the various viewpoints and suggestions that have been recently put forth, followed by a solution that we believe addresses the treatment of inconclusive decisions. We consider the issues in the context of method conformance and method performance as two distinct concepts, both of which are necessary for the determination of reliability. Method conformance relates to an assessment of whether the outcome of a method is the result of the analyst's adherence to the procedures that define the method. Method performance reflects the capacity of a method to discriminate between different propositions of interest (e.g., mated and non-mated comparisons). We then discuss implications of these issues for the forensic science community.

A single-cell atlas enables mapping of homeostatic cellular shifts in the adult human breast.

Here we use single-cell RNA sequencing to compile a human breast cell atlas assembled from 55 donors that had undergone reduction mammoplasties or risk reduction mastectomies. From more than 800,000 cells we identified 41 cell subclusters across the epithelial, immune and stromal compartments. The contribution of these different clusters varied according to the natural history of the tissue. Age, parity and germline mutations, known to modulate the risk of developing breast cancer, affected the homeostatic cellular state of the breast in different ways. We found that immune cells from BRCA1 or BRCA2 carriers had a distinct gene expression signature indicative of potential immune exhaustion, which was validated by immunohistochemistry. This suggests that immune-escape mechanisms could manifest in non-cancerous tissues very early during tumor initiation. This atlas is a rich resource that can be used to inform novel approaches for early detection and prevention of breast cancer.

Versican Associates with Tumor Immune Phenotype and Limits T-cell Trafficking via Chondroitin Sulfate.

Immunotherapies for cancers of epithelial origin have limited efficacy, and a growing body of evidence links the composition of extracellular matrix (ECM) with the likelihood of a favorable response to treatment. The ECM may be considered an immunologic barrier, restricting the localization of cytotoxic immune cells to stromal areas and inhibiting their contact with tumor cells. Identifying ECM components of this immunologic barrier could provide targets that whether degraded in situ may support antitumor immunity and improve immunotherapy response. Using a library of primary triple-negative breast cancer tissues, we correlated CD8+ T-cell tumor contact with ECM composition and identified a proteoglycan, versican (VCAN), as a putative member of the immunologic barrier. Our analysis reveals that CD8+ T-cell contact with tumor associates with the location of VCAN expression, the specific glycovariant of VCAN [defined through the pattern of posttranslational attachments of glycosaminoglycans (GAG)], and the cell types that produce the variant. In functional studies, the isomers of chondroitin sulfate presented on VCAN have opposing roles being either supportive or inhibiting of T-cell trafficking, and removal of the GAGs ameliorates these effects on T-cell trafficking. Overall, we conclude that VCAN can either support or inhibit T-cell trafficking within the tumor microenvironment depending on the pattern of GAGs present, and that VCAN is a major component of the ECM immunologic barrier that defines the type of response to immunotherapy. SIGNIFICANCE: The response to immunotherapy has been poor toward solid tumors despite immune cells infiltrating into the tumor. The ECM has been associated with impacting T-cell infiltration toward the tumor and in this article we have identified VCAN and its structural modification, chondroitin sulfate as having a key role in T-cell invasion.