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We make two interventions in two evolving scholarly literatures. First, we show how fractal metaphors escape a recurring dichotomy in Christian pedagogical scholarship, the either/or of alienation from one's object of study versus union with it in "an act of love." Second, we try to replace recent interdisciplinary work's emphasis on "complexity" with "irreducibility." Fractals allow us to define these concepts and develop alternative "ways of knowing" with greater rigor. Both interventions bear directly on Christian formation, and so we derive five ways the Christian classroom can combat spiritual alienation and instead cultivate the "fractal imagination" of our students.

Telehealth can expand and enhance access to school-based health care, but its use has been relatively limited. Recognizing that school-based health care is still not reaching many students, the Health Resources and Services Administration (HRSA) funded the School Based Telehealth Network Grant Program to expand telehealth in rural school-based settings to help to increase the availability and use of these services. The 19 grantees delivered telehealth to over 200 schools across 17 states, choosing which services they would deliver and how. Looking across the services, these fell into three categories -- primary/urgent care, behavioral health, and other more specialized services. The majority of grantees offered multiple telehealth services with the combination of behavioral health and primary/urgent care the most common. The current study adds to the literature by elucidating that telehealth in schools can address multiple clinical conditions through separate services even though doing so involves using various combinations of clinicians providing different services.

Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

Abstract Objectives Serum protein abundance was assessed in adult and juvenile dermatomyositis (DM and JDM) patients to determine differentially regulated proteins, altered pathways, and candidate disease activity biomarkers. Methods Serum protein expression from 17 active adult DM and JDM patients each was compared to matched, healthy control subjects by a multiplex immunoassay. Pathway analysis and protein clustering of the differentially regulated proteins were examined to assess underlying mechanisms. Candidate disease activity biomarkers were identified by correlating protein expression with disease activity measures. Results Seventy-eight of 172 proteins were differentially expressed in the sera of DM and JDM patients compared to healthy controls. Forty-eight proteins were differentially expressed in DM, 32 proteins in JDM, and 14 proteins in both DM and JDM. Twelve additional differentially expressed proteins were identified after combining the DM and JDM cohorts. C-X-C motif chemokine ligand 10 (CXCL10) was the most strongly upregulated protein in both DM and JDM sera. Other highly upregulated proteins in DM included S100 calcium binding protein A12 (S100A12), CXCL9, and nicotinamide phosphoribosyltransferase (NAMPT), while highly upregulated proteins in JDM included matrix metallopeptidase 3 (MMP3), growth differentiation factor 15 (GDF15), and von Willebrand factor (vWF). Pathway analysis indicated that phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), and toll-like receptor 7 (TLR7) signaling were activated in DM and JDM. Additional pathways specific to DM or JDM were identified. A protein cluster associated with neutrophils and mononuclear leukocytes and a cluster of interferon-associated proteins were observed in both DM and JDM. Twenty-two proteins in DM and 24 proteins in JDM sera correlated with global, muscle, and/or skin disease activity. Seven proteins correlated with disease activity measures in both DM and JDM sera. IL-1 receptor like 1 (IL1RL1) emerged as a candidate global disease activity biomarker in DM and JDM. Conclusion Coordinate analysis of protein expression in DM and JDM patient sera by a multiplex immunoassay validated previous gene expression studies and identified novel dysregulated proteins, altered signaling pathways, and candidate disease activity biomarkers. These findings may further inform the assessment of DM and JDM patients and aid in the identification of potential therapeutic targets.

Abstract Mutations in SARS-CoV-2 variants of concern (VOCs) have expanded the viral host range beyond primates, and a few other mammals, to mice, affording the opportunity to exploit genetically diverse mouse panels to model the broad spectrum of responses to infection in patient populations. Here we surveyed responses to VOC infection in genetically diverse Collaborative Cross (CC) founder strains. Infection of wild-derived CC founder strains produced a broad range of viral burden, disease susceptibility and survival, whereas most other strains were resistant to disease despite measurable lung viral titers. In particular, CAST/EiJ, a wild-derived strain, developed high lung viral burdens, more severe lung pathology than seen in other CC strains, and a dysregulated cytokine profile resulting in morbidity and mortality. These inbred mouse strains may serve as a valuable platform to evaluate therapeutic countermeasures against severe COVID-19 and other coronavirus pandemics in the future.

This qualitative study is an examination of how 20 tenure-seeking Women of Color and White women academics at a public research-intensive university define collegiality and its perceived role in rank advancement. By engaging culture of hegemonic collegiality, we identified two salient themes: (a) collegiality is defined through weapon and survival metaphors; and (b) collegiality makes a gendered-race difference inconsistently in tenure decisions. Collegiality is and will likely remain relevant in tenure and promotion processes. We offer transformative collegiality, an equal power sharing of authority among colleagues that normalizes anti-oppressive norms, to possibly create and sustain dignity affirming faculty communities.

Introduction Treatment-emergent sexual dysfunction (TESD) is a commonly reported side effect of antidepressant medications in clinical trials. Limited literature exists exploring the role of routine use of the Arizona Sexual Experience Scale (ASEX) in identification of TESD in clinical practice. Therefore, we completed a retrospective study with the primary goal of capturing the rates of sexual dysfunction associated with antidepressant use among adult patients at an outpatient encounter with a psychiatric clinical pharmacist between June 2020 and March 2022. Methods Rates of identification of sexual dysfunction were compared pre-ASEX survey (June 2020 to June 2021) to post-ASEX survey (July 2021 to March 2022). Results There was a significant increase in the identification of sexual dysfunction following implementation of the ASEX scale (10% in the pre-ASEX group versus 59% meeting sexual dysfunction criteria with the ASEX scale). Approximately 70% of patients in the post-ASEX group shared they would not have reported symptoms unless directly asked. Discussion In conclusion, a validated survey (ASEX) in an ambulatory psychiatry clinic improves identification of sexual dysfunction associated with antidepressants. Use of interdisciplinary care teams in the setting of medication follow-up can assist with identifying tolerability concerns between visits with patients’ prescribing clinicians.

Abstract Background Chronic exposure to microorganisms inside homes can impact respiratory health. Few studies have used advanced sequencing methods to examine adult respiratory outcomes, especially continuous measures. We aimed to identify metagenomic profiles in house dust related to the quantitative traits of pulmonary function and airway inflammation in adults. Microbial communities, 1264 species (389 genera), in vacuumed bedroom dust from 779 homes in a US cohort were characterized by whole metagenome shotgun sequencing. We examined two overall microbial diversity measures: richness (the number of individual microbial species) and Shannon index (reflecting both richness and relative abundance). To identify specific differentially abundant genera, we applied the Lasso estimator with high-dimensional inference methods, a novel framework for analyzing microbiome data in relation to continuous traits after accounting for all taxa examined together. Results Pulmonary function measures (forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio) were not associated with overall dust microbial diversity. However, many individual microbial genera were differentially abundant (p-value < 0.05 controlling for all other microbial taxa examined) in relation to FEV1, FVC, or FEV1/FVC. Similarly, fractional exhaled nitric oxide (FeNO), a marker of airway inflammation, was unrelated to overall microbial diversity but associated with differential abundance for many individual genera. Several genera, including Limosilactobacillus, were associated with a pulmonary function measure and FeNO, while others, including Moraxella to FEV1/FVC and Stenotrophomonas to FeNO, were associated with a single trait. Conclusions Using state-of-the-art metagenomic sequencing, we identified specific microorganisms in indoor dust related to pulmonary function and airway inflammation. Some were previously associated with respiratory conditions; others were novel, suggesting specific environmental microbial components contribute to various respiratory outcomes. The methods used are applicable to studying microbiome in relation to other continuous outcomes. Video Abstract

ABSTRACT The gold standard for measuring insulin sensitivity (IS) is the hyperinsulinemic–euglycemic clamp, a time, costly, and labor‐intensive research tool. A low insulin sensitivity is associated with a complication‐risk in type 1 diabetes. Various formulae using clinical data have been developed and correlated with measured IS in type 1 diabetes. We consolidated multiple formulae into an online calculator (bit.ly/estimated‐GDR), enabling comparison of IS and its probability of IS 6.50 mg/kg/min (high), as measured in a validation set of clamps in 104 adults with type 1 diabetes. Insulin sensitivity calculations using different formulae varied significantly, with correlations (R2) ranging 0.005–0.87 with agreement in detecting low and high glucose disposal rates in the range 49–93% and 89–100%, respectively. We demonstrate that although the calculated IS varies between formulae, their interpretation remains consistent. Our free online calculator offers a user‐friendly tool for individual IS calculations and also offers efficient batch processing of data for research.

Over the last two decades, there have been numerous initiatives to improve undergraduate student outcomes in STEM. One model for scalable reform is the inclusive Research Education Community (iREC). In an iREC, STEM faculty from colleges and universities across the nation are supported to adopt and sustainably implement course-based research – a form of science pedagogy that enhances student learning and persistence in science. In this study, we used pathway modeling to develop a qualitative description that explicates the HHMI Science Education Alliance (SEA) iREC as a model for facilitating the successful adoption and continued advancement of new curricular content and pedagogy. In particular, outcomes that faculty realize through their participation in the SEA iREC were identified, organized by time, and functionally linked. The resulting pathway model was then revised and refined based on several rounds of feedback from over 100 faculty members in the SEA iREC who participated in the study. Our results show that in an iREC, STEM faculty organized as a long-standing community of practice leverage one another, outside expertise, and data to adopt, implement, and iteratively advance their pedagogy. The opportunity to collaborate in this manner and, additionally, to be recognized for pedagogical contributions sustainably engages STEM faculty in the advancement of their pedagogy. Here, we present a detailed pathway model of SEA that, together with underpinning features of an iREC identified in this study, offers a framework to facilitate transformations in undergraduate science education.

Synchronous neural oscillations are strongly associated with a variety of perceptual, cognitive, and behavioural processes. It has been proposed that the role of the synchronous oscillations in these processes is to facilitate information transmission between brain areas, the 'communication through coherence,' or CTC hypothesis. The details of how this mechanism would work, however, and its causal status, are still unclear. Here we investigate computationally a proposed mechanism for selective attention that directly implicates the CTC as causal. The mechanism involves alpha band (about 10 Hz) oscillations, originating in the pulvinar nucleus of the thalamus, being sent to communicating cortical areas, organizing gamma (about 40 Hz) oscillations there, and thus facilitating phase coherence and communication between them. This is proposed to happen contingent on control signals sent from higher-level cortical areas to the thalamic reticular nucleus, which controls the alpha oscillations sent to cortex by the pulvinar. We studied the scope of this mechanism in parameter space, and limitations implied by this scope, using a computational implementation of our conceptual model. Our results indicate that, although the CTC-based mechanism can account for some effects of top-down and bottom-up attentional selection, its limitations indicate that an alternative mechanism, in which oscillatory coherence is caused by communication between brain areas rather than being a causal factor for it, might operate in addition to, or even instead of, the CTC mechanism.

Abstract Introduction Past research shows that HIV self‐testing (HIVST) can increase testing and facilitate more HIV diagnoses relative to clinic testing. However, in the United States, the use of HIVSTs is limited due to concerns that those who use HIVST could be less likely to be linked to care. Methods From January 2019 to April 2022, we recruited 811 men who have sex with men (MSM) in the United States who tested infrequently using an online marketing campaign and randomized them 1:1:1 to receive one of the following every 3 months for a year: (1) text message reminders to get tested at a local clinic (control); (2) mailed HIVST kits with access to a free helpline (standard HIVST); and (3) mailed HIVST kits with counselling provided within 24 hours of opening a kit (eTest). Quarterly follow‐up surveys assessed HIV testing, sexually transmitted infection (STI) testing, pre‐exposure prophylaxis (PrEP) use and sexual risk behaviour. Findings Eight participants were diagnosed with HIV, and all but one were through HIVST. Participants in either HIVST condition, standard or eTest, had significantly higher odds of any testing (OR = 7.9, 95% CI = 4.9−12.9 and OR = 6.6, 95% CI = 4.2−10.5) and repeat testing (>1 test; OR = 8.5, 95% CI = 5.7−12.6; OR = 8.9, 95% CI = 6.1−13.4) over 12 months relative to the control group. Rates of STI testing and PrEP uptake did not differ across study condition, but those in the eTest condition reported 27% fewer sexual risk events across the study period relative to other groups. Conclusions HIVST vastly increased testing, encouraged more regular testing among MSM, and identified nearly all new cases, suggesting that HIVST could diagnose HIV acquisition earlier. Providing timely follow‐up counselling after HIVST did not increase rates of STI testing or PrEP use, but some evidence suggested that counselling may have reduced sexual risk behaviour. To encourage more optimal testing, programmes should incorporate HIVST and ship kits directly to recipients at regular intervals.

Global trends of ocean warming, deoxygenation, and acidification are not easily extrapolated to coastal environments. Local factors, including intricate hydrodynamics, high primary productivity, freshwater inputs, and pollution, can exacerbate or attenuate global trends and produce complex mosaics of physiologically stressful or favorable conditions for organisms. In the California Current System (CCS), coastal oceanographic monitoring programs document some of this complexity; however, data fragmentation and limited data availability constrain our understanding of when and where intersecting stressful temperatures, carbonate system conditions, and reduced oxygen availability manifest. Here, we undertake a large data synthesis to compile, format, and quality-control publicly available oceanographic data from the US West Coast to create an accessible database for coastal CCS climate risk mapping, available from the National Centers for Environmental Information (accession 0277984) at https://doi.org/10.25921/2vve-fh39 (Kennedy et al., 2023). With this synthesis, we combine publicly available observations and data contributed by the author team from synoptic oceanographic cruises, autonomous sensors, and shore samples with relevance to coastal ocean acidification and hypoxia (OAH) risk. This large-scale compilation includes 13.7 million observations from 66 sources and spans 1949 to 2020. Here, we discuss the quality and composition of the synthesized dataset, the spatial and temporal distribution of available data, and examples of potential analyses. This dataset will provide a valuable tool for scientists supporting policy- and management-relevant investigations including assessing regional and local climate risk, evaluating the efficacy and completeness of CCS monitoring efforts, and elucidating spatiotemporal scales of coastal oceanographic variability.

Cercospora leaf blight (CLB), caused by Cercospora cf. flagellaris, C. kikuchii, and C. cf. sigesbeckiae, is a significant soybean [Glycine max (L.) Merr.] disease in regions with hot and humid conditions causing yield loss in the United States and Canada. There is limited information regarding resistant soybean cultivars, and there have been marginal efforts to identify the genomic regions underlying resistance to CLB. A Genome-Wide Association Study was conducted using a diverse panel of 460 soybean accessions from maturity groups III to VII to identify the genomic regions associated to the CLB disease. These accessions were evaluated for CLB in different regions of the southeastern United States over 3 years. In total, the study identified 99 Single Nucleotide Polymorphism (SNPs) associated with the disease severity and 85 SNPs associated with disease incidence. Across multiple environments, 47 disease severity SNPs and 23 incidence SNPs were common. Candidate genes within 10 kb of these SNPs were involved in biotic and abiotic stress pathways. This information will contribute to the development of resistant soybean germplasm. Further research is warranted to study the effect of pyramiding desirable genomic regions and investigate the role of identified genes in soybean CLB resistance.

Abstract Sugar transport proteins (STPs) are high‐affinity H+‐coupled hexose symporters. Recently, the contribution of STP13 to bacterial and fungal pathogen resistance across multiple plant species has garnered significant interest. Quantitative PCR analysis of source leaves, developing embryos, and seed coats of Phaseolus vulgaris L. (common bean) revealed that PvSTP13.1 was expressed in source leaves and seed coats throughout seed development. In contrast, PvSTP13.1 transcripts were detected at exceedingly low levels in developing embryos. To characterize the transport mechanism, PvSTP13.1 was expressed in Xenopus laevis oocytes, and inward‐directed currents were analyzed using two‐electrode voltage clamping. PvSTP13.1 was shown to function as an H+‐coupled monosaccharide symporter exhibiting a unique high affinity for hexoses and aldopentoses at depolarized membrane potentials. Specifically, of the 31 assessed substrates, which included aldohexoses, deoxyhexoses, fructose, 3‐O‐methyl‐D‐glucose, aldopentoses, polyols, glycosides, disaccharides, trisaccharides, and glucuronic acid, PvSTP13.1 displayed the highest affinity (K0.5) for glucose (43 μM), mannose (92 μM), galactose (145 μM), fructose (224 μM), xylose (1.0 mM), and fucose (3.7 mM) at pH 5.6 at a depolarized membrane potential of −40 mV. The results presented here suggest PvSTP13.1 contributes to retrieval of hexoses from the apoplasmic space in source leaves and coats of developing seeds.

Abstract Background To determine the prevalence of sustained remission/low disease activity (LDA) in patients with rheumatoid arthritis (RA) after discontinuation of tumor necrosis factor inhibitors (TNFi), separately in induction treatment and maintenance treatment studies, and to identify predictors of successful discontinuation. Methods We performed a systematic literature review of studies published from 2005 to May 2022 that reported outcomes after TNFi discontinuation among patients in remission/LDA. We computed prevalences of successful discontinuation by induction or maintenance treatment, remission criterion, and follow-up time. We performed a scoping review of predictors of successful discontinuation. Results Twenty-two induction-withdrawal studies were identified. In pooled analyses, 58% (95% confidence interval (CI) 45, 70) had DAS28

Abstract Background Autonomic nerve stimulation is used as a treatment for a growing number of diseases. We have previously demonstrated that application of efferent vagus nerve stimulation (eVNS) has promising glucose lowering effects in a rat model of type 2 diabetes. This paradigm combines high frequency pulsatile stimulation to block nerve activation in the afferent direction with low frequency stimulation to activate the efferent nerve section. In this study we explored the effects of the parameters for nerve blocking on the ability to inhibit nerve activation in the afferent direction. The overarching aim is to establish a blocking stimulation strategy that could be applied using commercially available implantable pulse generators used in the clinic. Methods Male rats (n = 20) had the anterior abdominal vagus nerve implanted with a multi-electrode cuff. Evoked compound action potentials (ECAP) were recorded at the proximal end of the electrode cuff. The efficacy of high frequency stimulation to block the afferent ECAP was assessed by changes in the threshold and saturation level of the response. Blocking frequency and duty cycle of the blocking pulses were varied while maintaining a constant 4 mA current amplitude. Results During application of blocking at lower frequencies (≤ 4 kHz), the ECAP threshold increased (ANOVA, p 70%) led to an increase in evoked neural response threshold (p 70% duty cycle), the charge delivered per pulse had a significant influence on the magnitude of the block (ANOVA, p = 0.003), and was focal (

Abstract The specific activity of the $$\beta $$ β decay of $$^{39}$$ 39 Ar in atmospheric argon is measured using the DEAP-3600 detector. DEAP-3600, located 2 km underground at SNOLAB, uses a total of (3269 ± 24) kg of liquid argon distilled from the atmosphere to search for dark matter. This detector is well-suited to measure the decay of $$^{39}$$ 39 Ar owing to its very low background levels. This is achieved in two ways: it uses low background construction materials; and it uses pulse-shape discrimination to differentiate between nuclear recoils and electron recoils. With 167 live-days of data, the measured specific activity at the time of atmospheric extraction is (0.964 ± 0.001 $$_\textrm{stat}$$ stat ± 0.024 $$_\textrm{sys}$$ sys ) Bq/kg $$_\textrm{atmAr}$$ atmAr , which is consistent with results from other experiments. A cross-check analysis using different event selection criteria and a different statistical method confirms the result.

Abstract Practical-based laboratory instruction represents a substantial component of education in biological anthropology, a multidisciplinary field concerned with investigating human evolution, biology, and behaviour from an evolutionary perspective. The efficacy of online practical laboratory classes using 3D models as part of the mode of delivery, as compared to traditional face-to-face learning, is poorly understood in the field of biological anthropology despite an increased uptake of online learning and the potential benefits of embracing this delivery modality. We present the preliminary findings of an ongoing study exploring the effectiveness of online practical training using 3D resources in biological anthropology. Through a participant survey of undergraduate and postgraduate osteology and palaeoanthropology students (n = 27) from an Australian university, we assess (1) whether differences in teaching modality impact student comprehension of practical concepts and (2) whether student perceptions of learning vary between in-person and online teaching modalities. Our results show that there are no significant differences in test of knowledge scores between online and in-person in either biological anthropology sub-discipline. However, in-person students experienced an increased feeling of learning relative to the online students in our combined discipline and osteology-only cohorts. Feeling of learning scores were statistically significantly lower among the online osteology cohort relative to palaeoanthropology students. Our preliminary results suggest that online labs using 3D models may be an effective means of teaching practical skills in biological anthropology, although student perceptions of learning may be negatively impacted. Feelings of learning are also variable across sub-disciplines, suggesting a need for more nuanced investigations into the efficacy of online learning. Larger sample sizes are required to confirm these findings.

Cutaneous-skeletal hypophosphatemia syndrome (CSHS) is a rare bone disorder featuring fibroblast growth factor-23 (FGF23)-mediated hypophosphatemic rickets. We report a 2-year, 10-month-old girl with CSHS treated with burosumab, a novel human monoclonal antibody targeting FGF23. This approach was associated with rickets healing, improvement in growth and lower limb deformity, and clinically significant benefit to her functional mobility and motor development. This case report provides evidence for the effective use of FGF23-neutralizing antibody therapy beyond the classic FGF23-mediated disorders of X-linked hypophosphatemia and tumor-induced osteomalacia.

Abstract Understanding the adaptive potential of populations and species is pivotal for minimizing the loss of biodiversity in this era of rapid climate change. Adaptive potential has been estimated in various ways, including based on levels of standing genetic variation, presence of potentially beneficial alleles, and/or the severity of environmental change. Kokanee salmon, the non‐migratory ecotype of sockeye salmon (Oncorhynchus nerka), is culturally and economically important and has already been impacted by the effects of climate change. To assess its climate vulnerability moving forward, we integrated analyses of standing genetic variation, genotype‐environment associations, and climate modeling based on sequence and structural genomic variation from 224 whole genomes sampled from 22 lakes in British Columbia and Yukon (Canada). We found that variables for extreme temperatures, particularly warmer temperatures, had the most pervasive signature of selection in the genome and were the strongest predictors of levels of standing variation and of putatively adaptive genomic variation, both sequence and structural. Genomic offset estimates, a measure of climate vulnerability, were significantly correlated with higher increases in extreme warm temperatures, further highlighting the risk of summer heat waves that are predicted to increase in frequency in the future. Levels of standing genetic variation, an important metric for population viability and resilience, were not correlated with genomic offset. Nonetheless, our combined approach highlights the importance of integrating different sources of information and genomic data to formulate more comprehensive and accurate predictions on the vulnerability of populations and species to future climate change.

BackgroundNaloxone is critical for reversing opioid-related overdoses. However, there is a dearth of research examining how naloxone possession and carriage are impacted by time-varying individual and social determinants, and if this differed during the height of the COVID-related mitigation measures (e.g., shutdowns).MethodsWe utilized weekly ecological momentary assessments (EMA) to measure factors associated with naloxone possession and carriage among 40 people who use illicit opioids in New York City, for 24 months. Descriptive statistics were used to explore the frequency of weeks with consistent naloxone possession and carriage. Mixed effects binary and multivariable logistic regression was used to test for the impact of time-varying EMA- and baseline-level factors on each outcome.ResultsApproximately 70% of weekly EMAs were associated with consistent naloxone possession or carriage. In multivariable models, compared to during the height of the COVID-related shutdowns (March 12, 2020-May 19, 2021), the time before was associated with lower odds of consistent possession (Odds Ratio (OR) = 0.05, 95% Confidence Interval (CI) = 0.01-0.15) and consistent carriage (OR = 0.06, CI = 0.01-0.25). Additionally, being female (OR = 11.15, CI = 2.85-43.42), being White versus being Black or Hispanic/Latinx (OR = 8.05, CI = 1.96-33.06), and lifetime overdose (OR = 1.96, CI = 1.16-19.80) were associated with higher odds of consistent possession. Recent opioid injection (OR = 3.66, CI = 1.34-9.94), being female (OR = 7.91, CI = 3.91-8.23), and being White (OR = 5.77, CI = 1.35-24.55) were associated with higher odds of consistent carriage. Not wanting to be perceived as a drug user was reported in nearly one third (29.0%; 190/656) of EMAs where inconsistent possession was reported.ConclusionsOur findings paint a relatively positive picture of possession and carriage during COVID-related shutdowns, particularly among white and female participants, and highlight the importance of capturing time-varying factors to understand naloxone-related behavior. To curb growing disparities, outreach to equip Black and Hispanic/Latinx people with naloxone is needed as well as interventions to reduce stigma as a barrier to naloxone engagement.

Osteoporosis in childhood distinguishes itself from adulthood in four important ways: 1) challenges in distinguishing otherwise healthy children who have experienced fractures due to non-accidental injury or misfortunate during sports and play from those with an underlying bone fragility condition; 2) a preponderance of monogenic “early onset” osteoporotic conditions that unveil themselves during the pediatric years; 3) the unique potential, in those with residual growth and transient bone health threats, to reclaim bone density, structure, and strength without bone-targeted therapy; and 4) the need to benchmark bone health metrics to constantly evolving “normal targets”, given the changes in bone size, shape, and metabolism that take place from birth through late adolescence. On this background, the pediatric osteoporosis field has evolved considerably over the last few decades, giving rise to a deeper understanding of the discrete genes implicated in childhood-onset osteoporosis, the natural history of bone fragility in the chronic illness setting and associated risk factors, effective diagnostic and monitoring pathways in different disease contexts, the importance of timely identification of candidates for osteoporosis treatment, and the benefits of early (during growth) rather than late (post-epiphyseal fusion) treatment. While there has been considerable progress, a number of unmet needs remain, the most urgent of which is to move beyond the monotherapeutic anti-resorptive landscape to the study and application of anabolic agents that are anticipated to not only improve bone mineral density but also increase long bone cross-sectional diameter (periosteal circumference). The purpose of this review is to provide a practical guide to the diagnosis and management of osteoporosis in children presenting to the clinic with fragility fractures, one that serves as a step-by-step “how to” reference for clinicians in their routine clinical journey. The article also provides a sightline to the future, emphasizing the clinical scenarios with the most urgent need for an expanded toolbox of effective osteoporosis agents in childhood.

Abstract Introduction Mississippi has one of the highest rates of HIV in the United States but low PrEP uptake. Understanding patterns of PrEP use can improve PrEP initiation and persistence. Methods This is a mixed-method evaluation of a PrEP program in Jackson, Mississippi. Between November 2018-December 2019, clients at high risk for HIV attending a non-clinical testing site were referred to a pharmacist for same-day PrEP initiation. The pharmacist provided a 90-day PrEP prescription and scheduled a follow-up clinical appointment within three months. We linked client records from this visit to electronic health records from the two largest PrEP clinics in Jackson to determine linkage into ongoing clinical care. We identified four distinct PrEP use patterns, which we used for qualitative interview sampling: 1) filled a prescription and linked into care within three months; 2) filled a prescription and linked into care after three months; 3) filled a prescription and never linked into care; and 4) never filled a prescription. In 2021, we purposively sampled patients in these four groups for individual interviews to ascertain barriers and facilitators to PrEP initiation and persistence, using guides informed by the Theory of Planned Behavior. Results There were 121 clients evaluated for PrEP; all were given a prescription. One-third were less than 25 years old, 77% were Black, and 59% were cisgender men who have sex with men. One-quarter (26%) never filled their PrEP prescription, 44% picked up the prescription but never linked into clinical care, 12% linked into care at some point after three months (resulting in a gap in PrEP coverage), and 18% linked into care within 3 months. We interviewed 26 of 121 clients. Qualitative data revealed that cost, stigmas related to sexuality and HIV, misinformation about PrEP, and perceived side effects were barriers to uptake and persistence. Individuals’ desire to stay healthy and the support of PrEP clinic staff were facilitators. Conclusions The majority of individuals given a same-day PrEP prescription either never started PrEP or stopped PrEP within the first three months. Addressing noted barriers of stigma and misinformation and reducing structural barriers may increase PrEP initiation and persistence.

Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the Cannabis sativa plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated form. As minor cannabinoids become more popular due to their potential therapeutic properties, it becomes crucial to elucidate their metabolism in humans. Therefore, the goal of this was study to identify the major CBC phase I-oxidized metabolite generated in vitro following incubation with human liver microsomes. The novel metabolite structure was identified as 2′-hydroxycannabicitran using gas chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy. Following the identification, in silico molecular modeling experiments were conducted and predicted 2′-hydroxycannabicitran to fit in the orthosteric site of both the CB1 and CB2 receptors. When tested in vitro utilizing a competitive binding assay, the metabolite did not show significant binding to either the CB1 or CB2 receptors. Further work necessitates the determination of potential activity of CBC and the here-identified phase I metabolite in other non-cannabinoid receptors.

Course-based research pedagogy involves positioning students as contributors to authentic research projects as part of an engaging educational experience that promotes their learning and persistence in science. To develop a model for assessing and grading students engaged in this type of learning experience, the assessment aims and practices of a community of experienced course-based research instructors were collected and analyzed. This approach defines four aims of course-based research assessment—(1) Assessing Laboratory Work and Scientific Thinking; (2) Evaluating Mastery of Concepts, Quantitative Thinking and Skills; (3) Appraising Forms of Scientific Communication; and (4) Metacognition of Learning—along with a set of practices for each aim. These aims and practices of assessment were then integrated with previously developed models of course-based research instruction to reveal an assessment program in which instructors provide extensive feedback to support productive student engagement in research while grading those aspects of research that are necessary for the student to succeed. Assessment conducted in this way delicately balances the need to facilitate students’ ongoing research with the requirement of a final grade without undercutting the important aims of a CRE education.

Background Online advertisements on social media platforms are an important tool for engaging relevant populations in public health research. However, little is known about what platforms and ad characteristics are most effective in engaging high-priority HIV populations, including racial/ethnic and sexual minority individuals. Methods Data from this study were drawn from advertising campaigns conducted on popular websites and social media platforms that recruited for several nationwide randomized controlled trials of various HIV prevention and testing strategies among sexual minority men (SMM) from December 2019 until March 2022. Descriptive statistics and LASSO regression models were used to determine which platforms and ad characteristics were associated with significantly higher odds of engagement. Results Ads on Google search, Facebook, and Instagram yielded the most cost-effective engagement, while gay-oriented dating platforms and TrafficJunky yielded the highest percentage of users who appeared to meet basic eligibility criteria. The highest percentages of Black users were screened through ads on Jack’d, TrafficJunky, and Google search; for Hispanic/Latino users, Google search, Grindr, Facebook, and Instagram. Analyzing ad characteristics, we found ads that used suggestive content, animation, and included study or institution logos were associated with greater engagement. Ads that emphasized convenience of the research (e.g. mentioned participating “from home”) and that depicted people of similar races/ethnicities were also associated with greater engagement among Black and Hispanic/Latino sexual minority men. Conclusions We found that advertisements on mainstream social media sites are most cost effective. Although gay-oriented dating platforms were much more effective at reaching the target population, they were considerably more expensive. We also identified ad characteristics that were particularly effective in engaging users. These results could inform the design of online public health outreach campaigns for similar populations to improve their engagement and reach. Findings also demonstrated the value of conducting focused research on the effectiveness of various online marketing strategies.

Soft scale insects and mealybugs are phloem-feeding Hemipterans that are considered major pests in agriculture and horticulture throughout the world. However, correct taxonomic identification in the field can be difficult, making it hard for growers to implement control strategies. In viticulture, soft scale insects are a major issue due to their ability to secrete honeydew, which facilitates the development of sooty mould, and their propensity for being transmission vectors of several viral diseases of grapevine. To facilitate the rapid identification and quantification of vineyard-associated insects a metagenomic-based bioinformatic pipeline (MitoMonitor) was developed for generalised ecosystem monitoring, which automated the assembly and classification of insect mitochondrial genomes from shotgun sequencing data using the Barcode of Life Database API. The proof-of-concept application of MitoMonitor on metagenomic data obtained from eight samples from South Australian vineyards led to the identification of Parthenolecanium corni (European fruit scale)—which was thought to be absent in Australian vineyards—as the dominant coccoid species across the samples, with less frequent, and also lower abundance of Pseudococcus viburni (obscure mealybug) and Pseudo. longispinus (long-tailed mealybug). In addition, parisitoidism by Coccophagus scutellaris (Aphelinidae) wasps was also detected. The discovery of Parth. corni as a member of scale communities in these samples has significant implications for the development of effective control strategies for this important group of pests in affected areas.

IntroductionThere is no universally appropriate basis for delimiting species in protists, including parasites. Many molecular markers used for species delimitation are part of the ribosomal RNA (rRNA) array, with different regions of the array being used for different parasitic protist taxa. However, little is known about sequence variability across the rRNA in most organisms, and there is no standard threshold at which divergence in the sequence of a particular gene can be used as a basis for species delimitation. MethodsHere we demonstrate a method to generate the full rRNA array of parasitic protists by amplification of the array in two long, overlapping fragments followed by Illumina and Nanopore sequencing to produce high quality assemblies, to determine variations in sequence variability across the array. We apply this approach to two pairs of closely related ascetosporean parasites of crustaceans and molluscs [respectively Paramarteilia canceri/P. orchestiae and Marteilia cochillia/M. cocosarum (Rhizaria; Endomyxa; Ascetosporea)] and Bonamia ostreae and demonstrate how full-length rRNA sequences can be used to determine regions of the rRNA array that are most discriminatory, and robustly differentiate between species in combination with other lines of evidence. ResultsPhylogenetic analyses of the transcribed regions of the rRNA array demonstrate maximal support for, and separation of, all four parasite species. Sliding window global alignment analysis determined the regions of the rRNA array that had the most consistent nucleotide differences between the closely related parasites in a 1 kb region of the array. For Paramarteilia, this region was a combined internal transcribed spacer 1-5.8S-internal transcribed spacer 2 alignment, and for Marteilia, it was the external transcribed spacer. Phylogenetic analysis of these regions were able to recover the respective species, demonstrating that these regions could be used for improved diagnostic PCR assays.DiscussionOur method could be adapted to quickly generate sequence data and determine regions more suitable for diagnostic assays for a wide diversity of parasite groups. It also allows the generation of sequence data for regions of the rRNA not commonly studied (e.g. regions of the intergenic spacer), thus enabling research into their suitability as marker regions.

Abstract Indigo is an economically important dye, especially for the textile industry and the dyeing of denim fabrics for jeans and garments. Around 80,000 tonnes of indigo are chemically produced each year with the use of non-renewable petrochemicals and the use and generation of toxic compounds. As many microorganisms and their enzymes are able to synthesise indigo after the expression of specific oxygenases and hydroxylases, microbial fermentation could offer a more sustainable and environmentally friendly manufacturing platform. Although multiple small-scale studies have been performed, several existing research gaps still hinder the effective translation of these biochemical approaches. No article has evaluated the feasibility and relevance of the current understanding and development of indigo biocatalysis for real-life industrial applications. There is no record of either established or practically tested large-scale bioprocess for the biosynthesis of indigo. To address this, upstream and downstream processing considerations were carried out for indigo biosynthesis. 5 classes of potential biocatalysts were identified, and 2 possible bioprocess flowsheets were designed that facilitate generating either a pre-reduced dye solution or a dry powder product. Furthermore, considering the publicly available data on the development of relevant technology and common bioprocess facilities, possible platform and process values were estimated, including titre, DSP yield, potential plant capacities, fermenter size and batch schedule. This allowed us to project the realistic annual output of a potential indigo biosynthesis platform as 540 tonnes. This was interpreted as an industrially relevant quantity, sufficient to provide an annual dye supply to a single industrial-size denim dyeing plant. The conducted sensitivity analysis showed that this anticipated output is most sensitive to changes in the reaction titer, which can bring a 27.8% increase or a 94.4% drop. Thus, although such a biological platform would require careful consideration, fine-tuning and optimization before real-life implementation, the recombinant indigo biosynthesis was found as already attractive for business exploitation for both, luxury segment customers and mass-producers of denim garments. Graphical Abstract

Abstract Background Black and Latino sexual minority men in the Southern United States have the highest HIV infection rates in the country. Increased HIV testing can help decrease onward HIV transmission through detecting previously undiagnosed infections. HIV self-testing is an evidence-based strategy to increase HIV testing among sexual minority men, but the implementation of this intervention in the Southern United States is limited. One implementation barrier is the lack of knowledge of Black and Latino sexual minority men’s preferences for various HIV self-testing program characteristics and their willingness to pay for these preferences. In addition, little is known about facilitators and barriers to initiating HIV self-testing programs from the perspectives of HIV prevention implementation decision-makers in this region. Methods We will conduct an online discrete choice experiment among Black and Latino sexual minority men in the Southern United States (n = 300) to estimate this population’s preferences for the following HIV self-testing program characteristics: delivery strategy (home delivery, peer delivery, clinic pickup); delivery speed (same day, next day, 3 days, and 5 days); support (instructions only, during test, and 1 week after delivery); and price ($0, $20, $40, $50, $60). We will also use this choice data to generate willingness-to-pay estimates for each program characteristic. Guided by the Consolidated Framework for Implementation Research, we will then conduct semi-structured interviews (n = 30) with HIV prevention program decision-makers at various health organizations serving Black and Latino sexual minority men in the region to further understand facilitators and barriers to implementation of the most preferred HIV self-testing program design. Discussion By gaining perspectives on HIV self-testing implementation from patients and providers, this project will build a roadmap for the initiation of HIV self-testing programs to decrease HIV incidence among one of the most disproportionately impacted populations in the USA.

Abstract Individuals infected by SARS-CoV-2 are at risk of developing neurological-related post-acute disorders. Disputed epidemiological data indicated nicotine may reduce the severity of infection. Here we find exposure to nicotine in drinking water does not alter the moribundity of hACE2 mice. However, pre-exposure to nicotine decreased the likelihood of SARS-CoV-2 RNA expression and pathology in the brain. These results suggest mechanisms involving targets of nicotine could be leveraged to prevent the neurovirulence of SARS-CoV-2.

Driving evaluations aim to ensure adequate skills; however, feedback beyond pass/fail is needed for improvement. Therefore, the goal of this study was to inform driving feedback report design to ensure ease of use and understandability while motivating improvements. Participants ages 18–25 years (n = 521) were recruited from CloudResearch Prime Panels to rate one of nine report design conditions with various combinations of five key features: performance summary presence, action plan (AP) length, AP order, AP grading system, and peer comparison presence; they then completed questionnaires. Participants were more motivated to improve when a summary was present (p = 0.02); they rated reports easier to use if they had a long AP (p = 0.01), a short AP paired with a summary (p = 0.007), or an AP with a number grade (p = 0.016); and they rated reports easier to understand if they had a short AP (p = 0.002) or an AP ordered by worst-to-best performance (p = 0.05). These results suggest that feedback reports designed with a performance summary and short, targeted action plan starting with the biggest area for improvement are likely to motivate action to improve driving skills while being easy to use and understand. Future research should evaluate the effect of such a redesigned report on driving outcomes among young drivers.

BackgroundThe COVID-19 pandemic triggered widespread adjustments across the US health care system. Telehealth use showed a substantial increase in mental health conditions and services due to acute public health emergency (PHE) behavioral health needs on top of long-standing gaps in access to behavioral health services. How health systems that were already providing behavioral telehealth services adjusted services and staffing during this period has not been well documented, particularly in rural areas with chronic shortages of behavioral health providers and services. ObjectiveThis study investigates patient and treatment characteristic changes from before the COVID-19 PHE to during the PHE within both telehealth and in-person behavioral health services provided in 95 rural communities across the United States. MethodsWe used a nonrandomized, prospective, multisite research design involving 2 active treatment groups. The telehealth cohort included all patients who initiated telehealth treatment regimens during the data collection period. A comparison group included a cohort of patients who initiated in-person treatment regimen. Patient enrollment occurred on a rolling basis, and data collection was extended for 3 months after treatment initiation for each patient. Chi-square tests compared changes from pre-PHE to PHE time periods within telehealth and in-person treatment cohorts. The dependent measures included patient diagnosis, clinicians providing treatment services, and type of treatment services provided at each encounter. The 4780 patients in the telehealth cohort and the 6457 patients in the in-person cohort had an average of 3.5 encounters during the 3-month follow-up period. ResultsThe encounters involving anxiety, dissociative, and stress-related disorders in the telehealth cohort increased from 30% (698/2352) in the pre-PHE period to 35% (4632/12,853) in the PHE period (P

Background: Outpatient parenteral antimicrobial therapy (OPAT), when required, is beneficial to patients and healthcare systems by reducing hospital length-of-stay, providing cost savings, and improving patient satisfaction. Objectives: The purpose of this study is to determine readmission rates and associated risk factors in patients receiving OPAT at home. Methods: This retrospective study included hospitalized patients 15 years and older who were discharged on intravenous antimicrobial therapy via OPAT at home between January 2018 and December 2019. Patients receiving antimicrobials at a skilled nursing facility, long-term acute care, or dialysis center, and those who began OPAT at home directly from the outpatient setting were excluded. The primary outcome of this study was all-cause 30-day readmission rate. Secondary outcomes included 90-day readmission rate, rates of complications related to OPAT, emergency department visits during OPAT, and predictors of all-cause 30-day readmission through a logistic regression analysis. Results: Two hundred individual patients were included in the analysis; 60% were male and the mean age was 49 years. The most common indications for OPAT at home were bone and joint infection (52%) and bacteremia (26%). Forty patients (20%) experienced an unplanned, all-cause 30-day readmission, with a total of 48 readmission events. Of the 40 patients who were readmitted within 30 days, 20 (50%) were due to non-OPAT related reasons. Sixty patients (30%) experienced an OPAT-related complication, and chronic kidney disease was found to be an independent predictor of readmission (OR: 2.8, 95% CI: 1.0–7.6). Conclusions: Patients receiving OPAT at home are at increased risk for early hospital readmission, but it is often due to reasons not associated with OPAT. Patients with chronic kidney disease beginning OPAT at home should be closely monitored after discharge.

Objectives To enhance the confidence of children and adolescents with medical conditions and disabilities to engage in healthy, active lifestyles. Children with medical conditions and disabilities often exhibit more sedentary lifestyles relative to peers and are at increased risk of poor health outcomes. Clinical experience suggests physical activity confidence is an important factor influencing physical activity participation. Methods This randomized controlled trial evaluates an evidence-based intervention targeting physical activity confidence among children and adolescents with medical conditions and disabilities. Potential participants, 8 to 18 years of age diagnosed with a medical condition or disability, will be screened for adequate physical activity motivation but a lack confidence. Consenting participants (n=128) will be randomized 1:1 to a 12-week in-person or virtual physical activity intervention (24 hours/week total) led by a Registered Kinesiologist or control (assessments only). The intervention will combine physical activity participation with education about physical activity knowledge, goal setting, motivation and self-management. Primary outcomes are self-reported physical activity confidence and motivation at baseline, post-intervention and three months following intervention completion. A secondary outcome will be daily physical activity minutes assessed by accelerometry. A repeated measures mixed model will be used to compare outcomes between the in-person intervention, virtual intervention, and control groups (alpha=0.05). Conclusions This trial aims to assess the impact of a novel application of behaviour change theory on physical activity confidence among children and adolescents living with medical conditions or disabilities. Increased physical activity confidence, knowledge and skills could enable these youth to lead a more active lifestyle.

X-linked hypophosphatemia (XLH) is a rare, progressive, genetic disease with multisystem impact that typically begins to manifest in early childhood. Two treatment options exist: oral phosphate in combination with active vitamin D (“conventional therapy”) and a fully human monoclonal anti-FGF23 antibody, burosumab. The clinical benefit of conventional therapy in adults is limited, and poor tolerance and complications are common. Burosumab was first approved as a treatment for XLH in 2018 and its disease-modifying benefits in clinical trials in children suggest burosumab treatment could also alter the disease course in adults. Without long-term clinical data on multiple XLH-related sequelae available, the results of an elicitation exercise are reported, in which eight global experts in XLH posited how long-term treatment with burosumab is anticipated to impact the life course of clinical sequelae in adults with XLH. Based on their clinical experiences, the available evidence and their disease understanding, the experts agreed that some long-term benefits of using burosumab are likely in adults with XLH even if they have a misaligned skeleton from childhood. Burosumab treatment is anticipated to reduce the incidence of fractures and halt the progression of clinical sequelae associated with conventional therapy. While the trajectories for established dental abscesses are not expected to improve with burosumab treatment, dental abscess development may be prevented. Starting treatment with burosumab in childhood to increase the likelihood of an aligned skeleton and continuation into and throughout adulthood to maintain euphosphatemia may optimize patient outcomes, although future real-world investigation is required to support this hypothesis.

By using an ultradeep JWST/MIRI image at 5.6 μ m in the Hubble eXtreme Deep Field, we constrain the role of strong H α emitters (HAEs) during “cosmic reionization” at z ≃ 7–8. Our sample of HAEs is comprised of young (

Osteochondritis dissecans (OCD) is a disease of the joints characterized by idiopathic focal subchondral lesions. Aggrecan, a proteoglycan encoded by the ACAN gene, is important for cartilage structure and function. We describe the clinical evolution of a patient with short stature, multi-focal OCD, and subchondral osteopenia that appeared linked to a novel pathogenic ACAN variant. A multi-disciplinary approach including medical (bisphosphonate) therapy, surgical intervention and rehabilitation were successful in restoring wellness and physical function.

BackgroundNumerous reports contend opioids can augment or inhibit malignancy. At present, there is no consensus on the risk or benefit posed by opioids on malignancy or chemotherapeutic activity. Distinguishing the consequences of opioid use from pain and its management is challenging. Additionally, opioid concentration data is often lacking in clinical studies. A scoping review approach inclusive of preclinical and clinical data will improve our understanding of the risk-benefit relationship concerning commonly prescribed opioids and cancer and cancer treatment. ObjectiveThe aim of the study is to map diverse studies spanning from preclinical to clinical regarding opioids with malignancy and its treatment. MethodsThis scoping review will use the Arksey six stages framework to (1) identify the research question; (2) identify relevant studies; (3) select studies meeting criteria; (4) extract and chart data; (5) collate, summarize, and report results; and (6) conduct expert consultation. An initial pilot study was undertaken to (1) parameterize the extent and scale of existing data for an evidence review, (2) identify key factors to be extracted in systematic charting efforts, and (3) assess opioid concentration as a variable for its relevance to the central hypothesis. Six databases will be searched with no filters: MEDLINE, Embase, CINAHL Complete, Cochrane Library, Biological Sciences Collection, and International Pharmaceutical Abstracts. Trial registries will include ClinicalTrials.gov, Cochrane CENTRAL, International Standard Randomised Controlled Trial Number Registry, European Union Clinical Trials Register, and World Health Organization International Clinical Trials Registry. Eligibility criteria will include preclinical and clinical study data on opioids effects on tumor growth or survival, or alteration on the antineoplastic activity of chemotherapeutics. We will chart data on (1) opioid concentration from human subjects with cancer, yielding a “physiologic range” to better interpret available preclinical data; (2) patterns of opioid exposure with disease and treatment-related patient outcomes; and (3) the influence of opioids on cancer cell survival, as well as opioid-related changes to cancer cell susceptibility for chemotherapeutics. ResultsThis scoping review will present results in narrative forms as well as with the use of tables and diagrams. Initiated in February 2021 at the University of Utah, this protocol is anticipated to generate a scoping review by August 2023. The results of the scoping review will be disseminated through scientific conference proceedings and presentations, stakeholder meetings, and by publication in a peer-reviewed journal. ConclusionsThe findings of this scoping review will provide a comprehensive description of the consequences of prescription opioids on malignancy and its treatment. By incorporating preclinical and clinical data, this scoping review will invite novel comparisons across study types that could inform new basic, translational, and clinical studies regarding risks and benefits of opioid use among patients with cancer. International Registered Report Identifier (IRRID)PRR1-10.2196/38167

Abstract Increased gut permeability is implicated in the initiation and extent of the cytokine inflammatory response associated with exertional heat stroke (EHS). The primary objective of this study was to determine if a five amino acid oral rehydration solution (5AAS), specifically designed for the protection of the gastrointestinal lining, would prolong time to EHS, maintain gut function and dampen the systemic inflammatory response (SIR) measured during EHS recovery. Male C57/BL6J mice instrumented with radiotelemetry were gavaged with 150 μL of 5AAS or H2O, and ≈12 h later were either exposed to an EHS protocol where mice exercised in a 37.5°C environmental chamber to a self‐limiting maximum core temperature (Tc,max) or performed the exercise control (EXC) protocol (25°C). 5AAS pretreatment attenuated hypothermia depth and length (p

IntroductionThe emergence of extensively drug-resistant strains of Mycobacterium tuberculosis threatens decades of progress in the treatment of a disease which remains one of the leading infectious causes of death worldwide. The development of novel antimycobacterial compounds is therefore essential to reinforce the existing antitubercular drug discovery pipeline. There is also interest in new compounds which can synergize with existing antitubercular drugs and can be deployed as part of a combination therapy. This strategy could serve to delay the emergence of resistance to first-line anti-tuberculosis drugs and increase their efficacy against resistant strains of tuberculosis. Previous research has established that several C-1 substituted tetrahydroisoquinolines have antimycobacterial activity. Here we sought to expand our understanding of their antimycobacterial structure activity relationships and their potential to act as adjunct therapies alongside existing antitubercular drugs.MethodsThree chemical series were synthesised and assayed for their antimycobacterial potency, mammalian cell toxicity, inhibition of whole-cell efflux and synergism with isoniazid, rifampicin, and ethambutol.ResultsSeveral compounds were found to inhibit the growth of mycobacteria. Potent inhibitors of whole-cell efflux were also identified, as well as compounds which exhibited synergism with rifampicin and ethambutol.ConclusionsStructure-activity relationships were identified for antimycobacterial potency, improved selectivity, whole cell efflux inhibition and synergism. Potent whole-cell efflux inhibitors and synergistic compounds were identified, suggesting potential development as adjuncts to existing anti-tuberculosis chemotherapy.

Psychosis spectrum disorders (PSDs), as well as other severe mental illnesses where psychotic features may be present, like bipolar disorder, are associated with intrinsic metabolic abnormalities. Antipsychotics (APs), the cornerstone of treatment for PSDs, incur additional metabolic adversities including weight gain. Currently, major gaps exist in understanding psychosis illness biomarkers, as well as risk factors and mechanisms for AP-induced weight gain. Metabolomic profiles may identify biomarkers and provide insight into the mechanistic underpinnings of PSDs and antipsychotic-induced weight gain. In this 12-week prospective naturalistic study, we compared serum metabolomic profiles of 25 cases within approximately 1 week of starting an AP to 6 healthy controls at baseline to examine biomarkers of intrinsic metabolic dysfunction in PSDs. In 17 of the case participants with baseline and week 12 samples, we then examined changes in metabolomic profiles over 12 weeks of AP treatment to identify metabolites that may associate with AP-induced weight gain. In the cohort with pre-post data (n = 17), we also compared baseline metabolomes of participants who gained ≥5% baseline body weight to those who gained