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Abstract Feedlot cattle may be subjected to digestive disorders, including ruminal acidosis, due to high concentration of grain in their diet. Therefore, novel feeding strategies are required to maximize animal performance and mitigate economic losses in the operation. This study employed a two-period crossover design to assess the effect of direct ruminal administration of native rumen microorganisms (NRM) inoculation on cattle that underwent a high-grain challenge. The NRM inoculation consisted of six microorganisms (1.70 M CFU /day/animal) isolated from the rumen of healthy feedlot cattle: Succinivibrio dextrinosolvens ASCUSBF53, Prevotella albensis ASCUSBF41, Chordicoccus furentiruminis ASCUSBF65, Bacteroides xylanisolvens ASCUSBF52, Clostridium beijerinckii ASCUSBF26, and Syntrophococcus sp. ASCUSBF60. The trial consisted of 16 Angus heifers receiving NRM (n = 8) or a CON (CON = Carrier Buffer; n = 8) inoculation daily for 14-days as pre-challenge while on a high-grain diet and continued daily for a 21-day treatment period. The combined 35 days of microbial supplementation resulted in an improved average daily gain (ADG) of 29% (P = 0.037) and a tendency toward a 19% decrease in the feed efficiency metric, gain to feed ratio (G: F) (P = 0.055). Additionally, administration of NRM to animals on a high-grain diet, improved ruminal microbiome stability (P

Digital storytelling has been applied in research in varied contexts and with varied purposes. Implicit in the process of digital storytelling is the potential to develop and/or enhance a range of individual skills (e.g., multimedia, literacy, communication, etc.). However, further research is needed to gain a deeper understanding of the potential impact of digital storytelling on skill enhancement for disabled youth. This paper provides an overview of Phase 1 of the study “My life. My story: The Youth Digital Storytelling Project” that utilized elements of a community-based participatory action research approach to host a peer-facilitated digital storytelling workshop for young adults with developmental disabilities aimed at capturing and sharing their lived experiences with, knowledge of, and perspectives on significant life-stage transitions in the areas of education, employment, or living. The results from the pre- and post-workshop questionnaires suggest that the participants improved skills in media literacy, communication, and leadership. Additionally, the participants highlighted the importance of considering the delivery format, fostering connections, and enhancing self-confidence in the development of the workshop’s design and delivery. This research adds to the extant literature demonstrating the potential of digital storytelling as a pedagogical tool, offering implications for the design and implementation of online workshops for disabled youth.

Abstract Background Youth engagement refers to the collaboration between researchers and youth to produce research. Youth engagement in health research has been shown to inform effective interventions aimed at improving health outcomes. However, limited evidence has identified promising practices to meaningfully engage youth. This synthesis aims to describe youth engagement approaches, frameworks, and barriers, as well as provide both evidence-based and youth-generated recommendations for meaningful engagement. Main body This review occurred in two stages: 1) a narrative review of existing literature on youth engagement and 2) a Youth Advisory Council (YAC) to review and supplement findings with their perspectives, experiences, and recommendations. The terms ‘youth engagement’ and ‘health research’ were searched in Google Scholar, PubMed, Web of Science, Scopus, and PsycINFO. Articles and non-peer reviewed research works related to youth engagement in health research were included, reviewed, and summarized. The YAC met with research team members and in separate youth-only forums to complement the narrative review with their perspectives. Types of youth engagement include participation as research participants, advisors, partners, and co-investigators. Barriers to youth engagement were organized into youth- (e.g., time commitments), researcher- (e.g., attitudes towards youth engagement), organizational- (e.g., inadequate infrastructure to support youth engagement), and system-level (e.g., systemic discrimination and exclusion from research). To enhance youth engagement, recommendations focus on preparing and supporting youth by offering flexible communication approaches, mentorship opportunities, diverse and inclusive recruitment, and ensuring youth understand the commitment and benefits involved. Conclusions To harness the potential of youth engagement, researchers need to establish an inclusive and enabling environment that fosters collaboration, trust, and valuable contributions from youth. Future research endeavors should prioritize investigating the dynamics of power-sharing between researchers and youth, assessing the impact of youth engagement on young participants, and youth-specific evaluation frameworks.

BACKGROUND: Postpartum contraception is typically provided during postpartum visits. When desired and accessible, the immediate postpartum period provides an additional opportunity to increase the use of more effective contraceptive methods to potentially reduce subsequent unintended pregnancies and improve pregnancy outcomes. In New York State, recent policy changes expanded Medicaid coverage to include immediate postplacental intrauterine device insertion. OBJECTIVE: This study aimed to investigate clinically documented intrauterine device expulsion within 12 months of placement in patients who depend on state-funded health insurance. STUDY DESIGN: This retrospective cohort study included Medicaid patients with an immediate postplacental intrauterine device placed after third-trimester delivery, who delivered between March 2, 2017 and September 2, 2019. Current Procedural Terminology code billing data were used to identify 238 patients who underwent intrauterine device placement during their delivery admission. Electronic medical record data were analyzed using chi-squared tests, t tests, and multivariable logistic regression. RESULTS: There were 17.6% (42/238) documented intrauterine device expulsions within the first year after placement. Among patients with vaginal deliveries, 22.1% (29/131) of intrauterine devices placed had a documented expulsion, whereas the expulsion rate was 12.2% (13/107) among patients who had cesarean deliveries (P=.04). After controlling for body mass index, parity, intrauterine device type, and gestational age, patients who delivered vaginally were more likely to experience intrauterine device expulsion within 1 year compared with those who had cesarean delivery (adjusted odds ratio, 2.71; 95% confidence interval, 1.27–5.80). Patients with a documented intrauterine device expulsion within 1 year were more likely to have a subsequent pregnancy before October 2020 (35.7% [15/42] vs 15.3% [30/196] in the no-expulsion group; P=.002). CONCLUSION: The overall percentage of documented intrauterine device expulsion within 1 year following immediate postplacental placement was 17.6%, with a greater percentage of expulsion in patients who underwent vaginal delivery. Patients with a documented intrauterine device expulsion within 1 year of placement were significantly more likely to experience a subsequent pregnancy.

Nonsuicidal self-injury disorder (NSSI-D) is presently a condition for further study in the Diagnostic & Statistical Manual of Mental Disorders (DSM-5-TR) (American Psychiatric Association, 2022). While previous studies focused on NSSI-D through the lens of experts, there is a shortage of research that explores the potential impact of NSSI-D from the perspective of those most directly affected - individuals with NSSI lived experience. The present study aimed to expand this limited literature and provide a more enhanced and nuanced understanding of the potential implications and consequences of NSSI-D from lived experience viewpoints. Adults with lifetime NSSI history (N = 38) completed a semi-structured interview that surveyed perspectives on NSSID, including the meaning of officially recognizing NSSI-D, potential impacts of receiving an NSSI-D diagnosis, and the impact of NSSI-D on one’s decision to speak with a clinician. Results from our thematic analysis of the interview data suggested opinions about NSSI-D and its potential impact were generally positive (e.g., increased awareness, understanding, and validation, increased comfort with disclosing NSSI behavior, positive impacts on treatment, and improved functioning). Participants also highlighted potential concerns about the potential consequences of NSSI-D (e.g., negative self-perception, increased stigma, and concerns about the necessity and utility of NSSI-D), and some expressed neutral/indifferent opinions about NSSI-D. Overall, results provide valuable insights regarding potential implications and consequences of official recognition and diagnosis of NSSID and have relevant implications for client-clinician interactions. Results also highlight the importance and value of amplifying lived experience perspectives.

Background/ObjectivesPatients with ovarian cancer commonly experience metastases and recurrences, which contribute to high mortality. Our objective was to better understand ovarian cancer metastasis and identify candidate biomarkers and drug targets for predicting and preventing ovarian cancer recurrence.MethodsTranscripts of 770 cancer-associated genes were compared in cells collected from ascitic fluid versus resected tumors of an ES-2 orthotopic ovarian cancer mouse model. Associated cell types and pathways were explored with bioinformatics. FGF7 protein was measured using capillary-based immunoassays or ELISA in mouse and clinical specimens. Significances of differential gene expression and patient prognosis were determined by volcano plot and log-rank test, respectively.ResultsTumor transcriptomes exhibited higher endothelial cells, oxygenation, proteasome activity, and metabolism in comparison to ascites, but similar percentages of cancer-associated fibroblasts and immune cells. FGF7 mRNA was significantly higher in mouse tumors compared to ascites. FGF7 protein was significantly higher in tumors than in ascites in independent mouse models and clinical specimens. Serum FGF7 protein levels above the median of 25 patients with ovarian cancer were associated with worse progression-free and overall survival (p = 0.005 and 0.019, respectively) independent of patient and tumor characteristics.ConclusionsIn comparison to ascites, tumors exhibit different transcriptomic profiles that identify candidate biomarkers and drug targets for predicting and preventing recurrence. Among these, elevated tumoral FGF7 validated at the protein level and elevated serum FGF7 were significantly associated with worse patient survival. These results support further development of FGF7 receptor-targeted drugs and serum FGF7 to prevent and predict recurrence, respectively.

Introduction: The transition from pediatric to adult care poses challenges for adolescents and young adults (AYA) with chronic conditions and their caregivers. A patient navigator (PN) intervention may mitigate transition-related barriers. Methods: A qualitative study was conducted within a pragmatic randomized controlled trial. A purposive sample was recruited of AYA with diverse diagnostic and demographic characteristics who worked with the PN and/or their caregivers. Seventeen participants completed semi-structured interviews at baseline and post-intervention and optional journal entries. Thematic analysis was used inductively. Results: Analysis yielded two themes from baseline interviews: 1) uncertainty and hesitation with leaving a place of support, 2) navigator assistance with post-secondary education, and three themes from post-intervention interviews: 1) emotional support, 2) informational and task-focused support, 3) navigator guidance to become more independent. Discussion: Our findings describe the needs of AYA and the experience of PN support; our findings may guide future implementation of PNs in transition care.

Two trials were conducted to determine interactive effects between lipid source (palm oil, PO versus soybean oil, SO) and emulsifier addition (none versus glycerol monolaurate-GML) on apparent total tract digestibility (ATTD) of gross energy (GE) in broilers and growth performance in poults. In trial 1, 0.05 % GML addition had no impact on the ATTD of GE of SO but improved the ATTD of PO from 77.11 % to 88.21 % (interaction, P=0.03). Without GML addition, PO had a lower ATTD of GE (77.11 %) compared to SO (96.48 %) resulting in an AME of 7,259 versus 9,092 kcal/kg for PO and SO, respectively. In trial 2, the addition of 0.10 % GML reduced ADFI in poults fed diets containing 5 % PO compared to poults fed 0 or 0.05 % GML, while the addition of either 0.05 or 0.10 % GML reduced ADFI in poults fed diets containing 5 % SO compared to poults fed no GML (P=0.01). There was a similar response with ADG (P=0.01) where the addition of either 0.05 or 0.10 % GML reduced ADG in poults fed diets containing SO compared to poults fed no GML, while the addition of GML was largely without effect in poults fed diets containing PO. There was no interaction between lipid source and emulsifier addition on feed efficiency (P>0.10). Poults fed diets containing PO had a poorer feed efficiency compared to birds fed diets containing SO (P=0.01). The main effect of emulsifier was inconsistent in that poults fed the diets containing 0.10 % GML had the greatest feed efficiency compared to poults fed the diets containing 0.05 % GML, with poults fed diets containing no emulsifier being intermediate (P=0.10). In conclusion, addition of GML improved the ATTD of GE for PO but had no effect on the ATTD of GE for SO. This improvement in energy digestibility, did not however, translate to an improvement in poult performance. Broilers and poults fed diets containing SO had a greater feed efficiency compared to birds fed diets containing PO.

Abstract Familial chylomicronemia syndrome (FCS) is a rare disorder of triglyceride (TG) metabolism caused by loss of function variants in one of five known canonical genes involved in chylomicron lipolysis and clearance—LPL, APOC2, APOA5, LMF1, and GPIHBP1. Pathogenic variants in LPL, which encodes the hydrolytic enzyme lipoprotein lipase, account for over 80%–90% of cases. FCS may present in infancy with hypertriglyceridemia‐induced acute pancreatitis and is challenging to manage both acutely and in the long‐term. Here, we report our experience managing two unrelated infants consecutively diagnosed with hypertriglyceridemia‐induced acute pancreatitis caused by LPL deficiency. Both had elevated TGs at presentation (205 and 30 mmol/L, respectively) and molecular genetic testing confirmed each infant carried a different homozygous pathogenic variant in the LPL gene, specifically, c.987C>A (p.Tyr329Ter) and c.632C>A (p.Thr211Lys). The more severely affected infant had cutaneous xanthomata, lipemia retinalis and lipemic plasma at presentation, and required management in an intensive care setting. Acute stabilisation was achieved using insulin and heparin infusions together with the iterative implementation of a fat‐restricted diet, low in long chain triglycerides (LCT) and supplemented with medium chain triglycerides (MCT). In both cases, provision of adequate caloric intake (~110–120 kcal/kg/day) was also found to be important for a sustained TG reduction during the acute phase of management. In summary, a high index of suspicion is required to diagnose FCS in infants with hypertriglyceridemia‐induced acute pancreatitis, management of which can be challenging, highlighting the need for more evidence‐based recommendations.

Background and aims: Severe hypertriglyceridemia (HTG), defined as plasma triglyceride (TG) concentration > 10 mmol/L, is relatively uncommon, and its implications for atherosclerotic cardiovascular disease (ASCVD) risk remain somewhat unclear. We evaluated the association between severe HTG and carotid intima-media thickness (IMT), a marker for ASCVD. Methods: We studied three clinical cohorts: 88 patients with severe HTG (mean TG level 20.6 mmol/L), 271 patients with familial hypercholesterolemia (FH) as a contrast group, and 70 normolipidemic controls. Carotid IMT was measured using standardized ultrasound imaging. Statistical analysis was conducted using one-way analysis of variance (ANOVA) to compare mean IMT values, analysis of covariance (ANCOVA) to adjust for confounding variables, specifically age and sex, as well as Spearman pairwise correlation analysis between variables. Results: Unadjusted mean carotid IMT was greater in severe HTG and FH groups compared to controls, however, this was no longer significant for severe HTG after adjustment for age and sex. In contrast, adjusted carotid IMT remained significantly different between the FH and control groups. Conclusions: Our findings suggest that extreme TG elevations in severe HTG patients are not significantly associated with carotid IMT, in contrast to the increased IMT seen in FH patients. These findings add perspective to the complex relationship between severe HTG and ASCVD risk.

Species persist through resistance and recovery traits induced by natural stressors. Whether human activities exacerbate or moderate the effects of natural stressors is an open question. Because eelgrass (Zostera marina) creates coastal habitat, its response to natural stressors and human activities is of particular management importance. In this study, traits of intertidal eelgrass were examined across cumulative stressors of emersion and oyster culture, including two culture types: oysters grown directly on sediment (ground culture) or supported by gear above the sediment (off-bottom culture). Summer eelgrass was larger above- and below-ground and branched less than in spring, while density and cover were similar seasonally but declined at higher elevation and in ground culture. Eelgrass traits were divided into those related to resistance (larger above-ground size and below-ground storage) and recovery (increased flowering, branching, and rhizome extension). Resistance traits responded additively to intertidal elevation and oyster culture, with above- and below-ground size reduced in all conditions except that rhizome mass was maintained in ground culture. Smaller above-ground size may confer resistance to emersion stress, as a departure from expectations for other stressors. For resilience traits, flowering increased and internode length declined at higher elevation, whereas these traits did not change in ground culture, and off-bottom culture was associated with shorter internodes (additive cumulative stressor) and tended to moderate the enhanced flowering at higher elevations (non-additive, P=0.058). Transitory disturbance in ground culture may reduce eelgrass density with few effects on resilience, whereas off-bottom culture involves longer-term gear placement and trait responses by eelgrass.

With an expected increase in population by 2050, the demand for high-quality protein for human consumption will increase. To improve the sustainability of US cattle production, producers and researchers have historically focused on improving the feed efficiency of steers through improvements in genetics, nutrition, and microbiome management, producing a more marketable beef product. However, without a successful pregnancy, there would be no marketable animal to feed. The objective of this study was to examine the impact of pregnancy on the rumen environment, microbial communities, and the correlation to feed efficiency status in Angus heifers. Utilizing 17 cannulated Angus heifers, feed efficiency status was determined using the GrowSafe 8000 feed intake monitoring system to monitor feed intake for a 70d trial period to calculate residual feed intake. Following the trial, heifers were bred and 40mL rumen fluid and content samples were collected every two weeks during gestation. Metagenomic DNA was extracted from the rumen samples, sequencing libraries were prepared targeting the bacterial V4 region of the 16S rRNA gene, and resultant libraries were sequenced on an Illumina MiSeq. All microbial analyses were conducted in the R environment v2.6.2 where alpha diversity, beta diversity, and differential abundances were determined. Metabolites were identified using ultra high-performance liquid chromatography high resolution mass spectrometry, and Metabolomic Analysis and Visualization Engine was used to select metabolite peaks. Differential abundance analyses using “ANCOMBC” indicated 10 amplicon sequence variants (ASVs), assigned to seven Prevotella and three Succiniclasticum, significantly varied among weeks of gestation (P

Human islets can be transplanted into the portal vein for T1 diabetes, and a similar procedure is being used in a clinical trial for stem cell–derived beta-like cells. Efforts have been underway to find an alternative transplant site that will foster better islet cell survival and function. Although conceptually attractive, the subcutaneous (SC) site has yielded disappointing results, in spite of some improvements resulting from more attention paid to vascularization and differentiation factors, including collagen. We developed a method to transplant rat islets in a disk of type 1 collagen gel and found improved efficacy of these transplants. Survival of islets following transplantation (tx) was determined by comparing insulin content of the graft to that of the pre-transplant islets from the same isolation. At 14 days after transplantation, grafts of the disks had more than double the recovered insulin than islets transplanted in ungelled collagen. SC grafts of disks had similar insulin content to grafts in a kidney site and in epididymal fat pads. In vivo disks underwent contraction to 10% of initial volume within 24 h but the islets remained healthy and well distributed. Whole mount imaging showed that residual donor vascular cells within the islets expanded and connected to ingrowing host blood vessels. Islets (400 rat islet equivalents (IEQ)) in the collagen disks transplanted into an SC site of NOD scid IL2R gammanull (NSG) mice reversed streptozotocin (STZ)-induced diabetes within 10 days as effectively as transplants in the kidney site. Thus, a simple change of placing islets into a gel of collagen 1 prior to transplantation allowed a prompt reversal of STZ-induced diabetes using SC site.

Continuous monitoring of high-risk neonates is essential for the timely management of medical conditions. However, the current reliance on wearable or contact sensor technologies for vital sign monitoring often leads to complications including discomfort, skin damage, and infections which can impede medical management, nursing care, and parental bonding. Moreover, the dependence on multiple devices is problematic since they are not interconnected or time-synchronized, use a variety of different wires and probes/sensors, and are designed based on adult specifications. Therefore, there is an urgent unmet need to enable development of wireless, non- or minimal-contact, and non-adhesive technologies capable of integrating multiple signals into a single platform, specifically designed for neonates. This paper summarizes the limitations of existing wearable devices for neonates, discusses advancements in non-contact sensor technologies, and proposes directions for future research and development.

Abstract DNA replication through a challenging genomic landscape is coordinated by the replisome, which must adjust to local conditions to provide appropriate replication speed and respond to lesions that hinder its progression. We have previously shown that proteasome shuttle proteins, DNA Damage Inducible 1 and 2 (DDI1/2), regulate Replication Termination Factor 2 (RTF2) levels at stalled replisomes, allowing fork stabilization and restart. Here, we show that during unperturbed replication, RTF2 regulates replisome localization of RNase H2, a heterotrimeric enzyme that removes RNA from RNA-DNA heteroduplexes. RTF2, like RNase H2, is essential for mammalian development and maintains normal replication speed. However, persistent RTF2 and RNase H2 at stalled replication forks prevent efficient replication restart, which is dependent on PRIM1, the primase component of DNA polymerase α-primase. Our data show a fundamental need for RTF2-dependent regulation of replication-coupled ribonucleotide removal and reveal the existence of PRIM1-mediated direct replication restart in mammalian cells.

Background: The American Heart Association’s Life’s Essential 8 (LE8) Presidential Advisory deemed psychological health foundational for cardiovascular health (CVH) but did not include it as a CVH metric. Objectives: The purpose of this study was to evaluate associations of a CVH construct enhanced with a ninth metric for psychological health based on readily administered depression screening with mortality risk in U.S. adults. Methods: Participants were 21,183 adults (mean age: 48y, 51% female, 11% Black, 15% Hispanic, 65% White) from the 2011 to 2018 National Health and Nutrition Examination Survey. The LE8 algorithm was used to assess CVH. Two enhanced CVH constructs that include a ninth psychological health metric based on depression screening using the Patient Health Questionnaires (PHQ-2 and PHQ-9) were computed. Multivariable Cox proportional hazards models compared all-cause and cause-specific mortality risk across CVH score tertiles and a priori defined categories (high: 80-100, moderate: 50-79, low: 0-49) in the overall sample and by sex and race and ethnicity. Results: There were 1,397 deaths (414 cardiovascular and 329 cancer deaths). High vs low CVH scores, enhanced with PHQ-2 and PHQ-9, were associated with 69% and 70% lower mortality risk, while a high vs low LE8 score was associated with 65% lower risk (p-trend

Burkholderia pseudomallei (Bp) causes the tropical disease melioidosis that afflicts an estimated 165,000 people each year. Bp is a facultative intracellular pathogen that transits through distinct intracellular stages including attachment to host cells, invasion through the endocytic pathway, escape from the endosome, replication in the cytoplasm, generation of protrusions towards neighboring cells, and host cell fusion allowing Bp infection to spread without exiting the intracellular environment. We have identified a TetR-like transcriptional regulator, BP1026B_II1561, that is up-regulated during the late stages of infection as Bp protrudes toward neighboring cells. We have characterized BP1026B_II1561 and determined that it has a role in pathogenesis. A deletional mutant of BP1026B_II1561 is attenuated in RAW264.7 macrophage and BALB/c mouse models of infection. Using RNA-seq, we found that BP1026B_II1561 controls secondary metabolite biosynthesis, fatty acid degradation, and propanoate metabolism. In addition, we identified that BP1026B_II1561 directly controls expression of an outer membrane porin and genes in the shikimate biosynthetic pathway using ChIP-seq. Transposon mutants of genes within the BP1026B_II1561 regulon show defects during intracellular replication in RAW264.7 cells confirming the role of this transcriptional regulator and the pathways it controls in pathogenesis. BP1026B_II1561 also up-regulates the majority of the enzymes in shikimate and tryptophan biosynthetic pathways, suggesting their importance for Bp physiology. To investigate this, we tested fluorinated analogs of anthranilate and tryptophan, intermediates and products of the shikimate and tryptophan biosynthetic pathways, respectively, and showed inhibition of Bp growth at nanomolar concentrations. The expression of these pathways by BP1026b_II1561 and during intracellular infection combined with the inhibition of Bp growth by fluorotryptophan/anthranilate highlights these pathways as potential targets for therapeutic intervention against melioidosis. In the present study, we have identified BP1026B_II1561 as a critical transcriptional regulator for Bp pathogenesis and partially characterized its role during host cell infection.

Background Black patients meeting indications for implantable cardioverter‐defibrillators (ICDs) have lower rates of implantation compared with White patients. There is little understanding of how mental health impacts the decision‐making process among Black patients considering ICDs. Our objective was to assess the association between depressive symptoms and ICD implantation among Black patients with heart failure. Methods and Results This is a secondary analysis of the VIVID (Videos to Address Racial Disparities in ICD Therapy via Innovative Designs) randomized trial, which enrolled self‐identified Black individuals with chronic systolic heart failure. Depressive symptoms were assessed by the Patient Health Questionnaire‐2 and the Mental Component Summary of the 12‐Item Short‐Form Health Survey. Decisional conflict was measured by an adapted Decisional Conflict Scale (DCS). ANCOVA was used to assess differences in Decisional Conflict Scale scores. Multivariable logistic regression was used to examine the association between depressive symptoms and ICD implantation. Among 306 participants, 60 (19.6%) reported depressed mood, and 142 (46.4%) reported anhedonia. Participants with the lowest Mental Component Summary of the 12‐Item Short‐Form Health Survey scores (poorer mental health and higher likelihood of depression) had greater decisional conflict regarding ICD implantation compared with those with the highest Mental Component Summary of the 12‐Item Short‐Form Health Survey scores (adjusted mean difference in Decisional Conflict Scale score, 3.2 [95% CI, 0.5–5.9]). By 90‐day follow‐up, 202 (66.0%) participants underwent ICD implantation. There was no association between either the Patient Health Questionnaire‐2 score or the Mental Component Summary of the 12‐Item Short‐Form Health Survey score and ICD implantation. Conclusions Depressed mood and anhedonia were prevalent among ambulatory Black patients with chronic systolic heart failure considering ICD implantation. The presence of depressive symptoms did not impact the likelihood of ICD implantation in this population.

Summary: Background: Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can ‘open’ chromatin and encourage gene expression. Preclinical studies have shown that the ketogenic diet rescues hippocampal memory neurogenesis in mice with KS via the epigenetic effects of ketones. Methods: Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n = 4) versus controls (n = 4). Findings: Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR

Abstract Gut microbiota, or the collection of diverse microorganisms in a specific ecological niche, are known to significantly impact human health. Decreased gut microbiota production of short-chain fatty acids (SCFAs) has been implicated in type 2 diabetes mellitus (T2DM) disease progression. Most microbiome studies focus on ethnic majorities. This study aims to understand how the microbiome differs between an ethnic majority (the Dutch) and minority (the South-Asian Surinamese (SAS)) group with a lower and higher prevalence of T2DM, respectively. Microbiome data from the Healthy Life in an Urban Setting (HELIUS) cohort were used. Two age- and gender-matched groups were compared: the Dutch (n = 41) and SAS (n = 43). Microbial community compositions were generated via DADA2. Metrics of microbial diversity and similarity between groups were computed. Biomarker analyses were performed to determine discriminating taxa. Bacterial co-occurrence networks were constructed to examine ecological patterns. A tight microbiota cluster was observed in the Dutch women, which overlapped with some of the SAS microbiota. The Dutch gut contained a more interconnected microbial ecology, whereas the SAS network was dispersed, i.e., contained fewer inter-taxonomic correlational relationships. Bacteroides caccae, Butyricicoccus, Alistipes putredinis, Coprococcus comes, Odoribacter splanchnicus, and Lachnospira were enriched in the Dutch gut. Haemophilus, Bifidobacterium, and Anaerostipes hadrus discriminated the SAS gut. All but Lachnospira and certain strains of Haemophilus are known to produce SCFAs. The Dutch gut microbiome was distinguished from the SAS by diverse, differentially abundant SCFA-producing taxa with significant cooperation. The dynamic ecology observed in the Dutch was not detected in the SAS. Among several potential gut microbial biomarkers, Haemophilus parainfluenzae likely best characterizes the ethnic minority group, which is more predisposed to T2DM. The higher prevalence of T2DM in the SAS may be associated with the gut dysbiosis observed.

Abstract Background A large proportion of youth with chronic conditions have mental health comorbidities. However, the effect of these comorbidities on paediatric–adult transition readiness, and the relevance of widely used tools for measuring transition readiness, are unknown. Objective The objectives of this study were to describe and explore the transition readiness of youth with co‐occurring chronic health and mental health conditions using a combination of quantitative data obtained from participants completing the Transition Readiness Assessment Questionnaire (TRAQ) and qualitative data. Design and Participants A three‐phase sequential explanatory mixed methods design was employed, with the qualitative strand taking priority. First, the TRAQ scores (range 1–5) of youth with co‐occurring conditions (n = 61) enroled in a multisite randomized controlled trial were measured, followed by qualitative interviews with a sample of youth (n = 9) to explain the quantitative results. Results from both strands were then integrated, yielding comprehensive insights. Results Median TRAQ scores ranged from 2.86 on the appointment keeping subscale to 5.00 on the talking with providers subscale. The qualitative results uncovered the complexities faced by this group concerning the impact of a mental health comorbidity on transition readiness and self‐management skills across TRAQ domains. The integrated findings identified a diverse and highly individualized set of strengths and challenges amongst this group that did not align with overarching patterns as measured by the TRAQ. Conclusions This mixed methods study generated novel understandings about how youth with co‐occurring conditions develop competencies related to self‐care, self‐advocacy and self‐management in preparation for paediatric–adult service transitions. Results demonstrated the assessment of transition readiness using a generic scale does not address the nuanced and complex needs of youth with co‐occurring chronic health and mental health conditions. Our findings suggest tailoring transition readiness practices for this group based on youths' own goals, symptoms, coping mechanisms and resources. Patient or Public Involvement This study was conducted in collaboration with five young adult research partners (YARP) with lived experience transitioning from paediatric to adult health/mental health services. The YARP's contributions across study phases ensured the perspectives of young people were centred throughout data collection, analysis, interpretation and presentation of findings. All five YARP co‐authored this manuscript.

Abstract Background The involvement of adolescents and young adults (AYAs) with lived experience of health and mental health conditions as partners in research is increasing given the prominence of participatory approaches to research, including patient-oriented research (POR). Much of the relevant research is conducted by graduate students. While guiding AYA engagement frameworks and models exist, the processes of partnering with AYAs in patient-oriented graduate-level research projects have not been well established. Co-developed tools and practices are required to support strengths-based, developmentally appropriate AYA-graduate student partnerships. Objectives The objectives of this commentary are: (1) to share the processes of partnership between a graduate student and five Young Adult Research Partners (YARP), (2) to describe the co-design and implementation of the Strengths, Skills, and Goals Matrix (SSGM), a tool for facilitating strengths-based AYA engagement in research, and (3) to outline considerations for applying this tool across a variety of research contexts with patient partners. Main body Within the YARP-graduate student partnership, the SSGM offered extensive benefits, including tangible skill development, peer mentorship, and rapport building among all members. This tool offers strategies for strengths-based engagement practices which emphasize AYAs’ preferences and goals throughout POR projects. Practical recommendations and considerations for applying the SSGM within graduate-level research and beyond are described, including the importance of connecting AYAs’ current (and desired) skills to specific tasks within the research project and resulting outputs. Conclusions The SSGM has possible relevance in a variety of settings given its broadly applicable structure. Future research could explore the adaptation, application, and evaluation of the SSGM across research contexts to determine its feasibility and ease of implementation. Patient or public contribution This article was conceived of and co-authored by five young adult research partners. The YARP co-designed the SSGM presented in this article, the figures, and substantially contributed to the preparation of the article.

Abstract Sleep restriction is associated with increased cardiovascular risk, which is more pronounced in female than male persons. We reported recently first causal evidence that mild, prolonged sleep restriction mimicking “real-life” conditions impairs endothelial function, a key step in the development and progression of cardiovascular disease, in healthy female persons. However, the underlying mechanisms are unclear. In model organisms, sleep restriction increases oxidative stress and upregulates antioxidant response via induction of the antioxidant regulator nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Here, we assessed directly endothelial cell oxidative stress and antioxidant responses in healthy female persons (n = 35) after 6 weeks of mild sleep restriction (1.5 h less than habitual sleep) using randomized crossover design. Sleep restriction markedly increased endothelial oxidative stress without upregulating antioxidant response. Using RNA-seq and a predicted protein–protein interaction database, we identified reduced expression of endothelial Defective in Cullin Neddylation-1 Domain Containing 3 (DCUN1D3), a protein that licenses Nrf2 antioxidant responses, as a mediator of impaired endothelial antioxidant response in sleep restriction. Thus, sleep restriction impairs clearance of endothelial oxidative stress that over time increases cardiovascular risk. Trial Registration: NCT02835261

Abstract Background Mobility is an important risk determinant for HIV given the potential for intermittent access to HIV services. Mobility may be particularly relevant among female sex workers, (FSW) who have been shown to be at high risk for HIV in settings around the world. Data regarding the role mobility plays in exacerbating HIV risks among FSW across Sub-Saharan Africa remains limited, and data on FSW in Guinea-Bissau is sparse. Methods FSW in four regions of Guinea-Bissau were recruited with a respondent-driven sampling (RDS) method and participated in an integrated bio-behavioral survey between September 27, 2017 and January 26, 2018. Associations between reported general mobility, mobility to or residence in Bissau, and social and HIV vulnerabilities among FSW in Guinea-Bissau were assessed using multivariable logistic regression models. Population proportions were weighted for RDS sampling, while logistic regression models were not. Results Survey respondents included 323 individuals in Bissau, 45 in Bissorã, 140 in Bafatá, and 59 in Gabu. Statistical analyses demonstrated that mobility to more than one destination was significantly associated with recent sex without a condom (ie, sex without a condom within the last three sex acts) with both clients (aOR: 2.47 (95% CI: 1.08, 5.64)) and non-paying partners (aOR: 5.39 (95% CI: 2.61, 11.15)) compared to non-mobility. However, mobility to one or more locations was also associated with higher odds of receiving HIV prevention information, and mobility to more than one location was associated with participating in programming with HIV-related organizations. Conclusions These results suggest that while some prevention services including HIV prevention information reach mobile FSW in Guinea-Bissau more than their non-mobile counterparts, the higher rates of condomless sex among mobile FSW suggest that HIV prevention needs may remain unmet for mobile FSW in Guinea-Bissau. Additionally, the results suggest a nuanced relationship between mobility, place of residence, and HIV and social vulnerabilities and prevention indicators.

IntroductionCoxiella burnetii is a gram-negative obligate intracellular bacterium and a zoonotic pathogen that causes human Q fever. The lack of effective antibiotics and a licensed vaccine for Coxiella in the U.S. warrants further research into Coxiella pathogenesis. Within the host cells, Coxiella replicates in an acidic phagolysosome-like vacuole termed Coxiella-containing vacuole (CCV). Previously, we have shown that the CCV pH is critical for Coxiella survival and that the Coxiella Type 4B secretion system regulates CCV pH by inhibiting the host endosomal maturation pathway. However, the trafficking pattern of the ‘immature’ endosomes in Coxiella- infected cells remained unclear.MethodsWe transfected HeLa cells with GFP-tagged Rab proteins and subsequently infected them with mCherry-Coxiella to visualize Rab protein localization. Infected cells were immunostained with anti-Rab antibodies to confirm the Rab localization to the CCV, to quantitate Rab11a and Rab35- positive CCVs, and to quantitate total recycling endosome content of infected cells. A dual-hit siRNA mediated knockdown combined with either immunofluorescent assay or an agarose-based colony-forming unit assay were used to measure the effects of Rab11a and Rab35 knockdown on CCV area and Coxiella intracellular growth.ResultsThe CCV localization screen with host Rab proteins revealed that recycling endosome-associated proteins Rab11a and Rab35 localize to the CCV during infection, suggesting that CCV interacts with host recycling endosomes during maturation. Interestingly, only a subset of CCVs were Rab11a or Rab35-positive at any given time point. Quantitation of Rab11a/Rab35-positive CCVs revealed that while Rab11a interacts with the CCV more at 3 dpi, Rab35 is significantly more prevalent at CCVs at 6 dpi, suggesting that the CCV preferentially interacts with Rab11a and Rab35 depending on the stage of infection. Furthermore, we observed a significant increase in Rab11a and Rab35 fluorescent intensity in Coxiella-infected cells compared to mock, suggesting that Coxiella increases the recycling endosome content in infected cells. Finally, siRNA-mediated knockdown of Rab11a and Rab35 resulted in significantly smaller CCVs and reduced Coxiella intracellular growth, suggesting that recycling endosomal Rab proteins are essential for CCV expansion and bacterial multiplication.DiscussionOur data, for the first time, show that the CCV dynamically interacts with host recycling endosomes for Coxiella intracellular survival and potentially uncovers novel host cell factors essential for Coxiella pathogenesis.

The placenta plays a critical role in nutrient-waste exchange between the maternal and fetal circulation, and thus impacts fetal growth and development. We have previously shown that nano-titanium dioxide (nano-TiO2) inhalation exposure during gestation decreased fetal female pup and placenta mass [1], which persists in the following generation [2]. In utero exposed females, once mated, their offspring's placentas had increased capacity for H2O2 production. Generation of oxidants such as hydrogen peroxide (H2O2), have been shown to impact cyclooxygenase activity, specifically metabolites such as prostacyclin (PGI2) or thromboxane (TXA2). Therefore, we hypothesized that maternal nano-TiO2 inhalation exposure during gestation results in alterations in placental production of prostacyclin and thromboxane mediated by enhanced H2O2 production in a sexually dimorphic manner. Pregnant Sprague-Dawley rats were exposed to nano-TiO2 aerosols or filtered air (sham-control) from gestational day (GD) 10–19. Dams were euthanized on GD 20, and fetal serum and placental tissue were collected based on fetal sex. Fetal placental zones (junctional zone (JZ) and labyrinth zone (LZ)) were assessed for xanthine oxidoreductase (XOR) activity, H2O2, and catalase activity, as well as 6-keto-PGF1α and TXB2 levels. Nano-TiO2 exposed fetal female LZ demonstrated significantly greater XOR activity compared to exposed males. Exposed fetal female LZ also demonstrated significantly diminished catalase activity compared to sham-control females. Exposed fetal female LZ had significantly increased abundance of 6-keto-PGF1α compared to sham-control females and increased TXB2 compared to exposed males. In the aggregate these data indicate that maternal nano-TiO2 inhalation exposure has a greater impact on redox homeostasis and PGI2/TXA2 balance in the fetal female LZ. Future studies need to address if treatment with an XO inhibitor during gestation can prevent diminished fetal female growth during maternal nano-TiO2 inhalation exposure.

BackgroundDigital phenotyping has seen a broad increase in application across clinical research; however, little research has implemented passive assessment approaches for suicide risk detection. There is a significant potential for a novel form of digital phenotyping, termed screenomics, which captures smartphone activity via screenshots. ObjectiveThis paper focuses on a comprehensive case review of 2 participants who reported past 1-month active suicidal ideation, detailing their passive (ie, obtained via screenomics screenshot capture) and active (ie, obtained via ecological momentary assessment [EMA]) risk profiles that culminated in suicidal crises and subsequent psychiatric hospitalizations. Through this analysis, we shed light on the timescale of risk processes as they unfold before hospitalization, as well as introduce the novel application of screenomics within the field of suicide research. MethodsTo underscore the potential benefits of screenomics in comprehending suicide risk, the analysis concentrates on a specific type of data gleaned from screenshots—text—captured prior to hospitalization, alongside self-reported EMA responses. Following a comprehensive baseline assessment, participants completed an intensive time sampling period. During this period, screenshots were collected every 5 seconds while one’s phone was in use for 35 days, and EMA data were collected 6 times a day for 28 days. In our analysis, we focus on the following: suicide-related content (obtained via screenshots and EMA), risk factors theoretically and empirically relevant to suicide risk (obtained via screenshots and EMA), and social content (obtained via screenshots). ResultsOur analysis revealed several key findings. First, there was a notable decrease in EMA compliance during suicidal crises, with both participants completing fewer EMAs in the days prior to hospitalization. This contrasted with an overall increase in phone usage leading up to hospitalization, which was particularly marked by heightened social use. Screenomics also captured prominent precipitating factors in each instance of suicidal crisis that were not well detected via self-report, specifically physical pain and loneliness. ConclusionsOur preliminary findings underscore the potential of passively collected data in understanding and predicting suicidal crises. The vast number of screenshots from each participant offers a granular look into their daily digital interactions, shedding light on novel risks not captured via self-report alone. When combined with EMA assessments, screenomics provides a more comprehensive view of an individual’s psychological processes in the time leading up to a suicidal crisis.

Abstract Blood chemistry may provide indicators to greater feed efficient cattle. As a side objective to previous research, 17 Angus heifers approximately two years old underwent a feed efficiency trial to determine residual feed intake (RFI) and identify variation in blood chemistry in beef cattle divergent in feed efficiency. Heifers were categorized as high- or low-RFI based ± 0.25 standard deviations around mean RFI. Blood samples were analyzed using an i-STAT handheld blood analyzer to measure sodium, potassium, glucose, blood urea nitrogen (BUN), creatinine, hematocrit, and hemoglobin. BUN was greater in high-RFI heifers (µ = 8.7 mg/dL) contrasted to low-RFI heifers (µ = 6.5 mg/dL; P = 0.01), whereas glucose was greater in low-RFI heifers (µ = 78.1 mg/dL) contrasted to high-RFI heifers (µ = 82.0 mg/dL; P = 0.05). No other blood chemistry parameters differed by RFI. The greater abundance of BUN in high-RFI heifers may indicate inefficient utilization of protein or mobilization of tissue protein for non-protein use. Greater blood glucose concentrations in low-RFI heifers may indicate greater utilization of energy precursors, such as volatile fatty acids, or metabolites. These data suggest there are readily measurable indicators of physiological variation in nutrient utilization; however, this warrants additional studies to explore.

Saponin surfactants extracted from plants have significant potential applications in many industries. The interfacial properties of extracts of Alphitonia excelsa, a native Australian plant rich in saponins, have been characterised to assess their suitability as dual-purpose foaming and antibacterial additives. Two sources of the plant (Adelaide Botanic Gardens and homelands of Chuulangun Aboriginal Corporation) were investigated to look for alteration of properties as a result of differences in cultivation and geographic location. Two methods of saponin extraction (water and water/ethanol mixtures) were investigated to determine differences in extraction efficiency and performance. Distinct differences were observed between the traditional analytical analysis (for saponin content) of the extracts based on source and extraction method; however, these differences were not as stark when considering the effect of the extracts on air–water interfacial tension and dilatational rheology, with extraction method proving to be the single biggest factor in extract efficacy. The data obtained point toward the presence of an altered array of surface-active species (different relative amounts of particular saponins in the water/ethanol extracted material) as a function of the extraction method. All extracts presented some antibacterial effect, albeit modest. This work highlights that the extraction method needs to be carefully considered and tailored for a given application.

Bottle conditioning of beer is an additional fermentation step where yeast and fermentable extract are added to the beer for carbonation. During this process, yeast must overcome environmental stresses to ensure sufficient fermentation in the bottle. Additionally, the yeast must be able to survive for a prolonged time, as a decline in viability will lead to alterations in the product. Here, we investigated the effects of bottle conditioning on beer using six different yeast strains from the brewing, wine making, and distilling industries over 120 days. The ale and lager strains resulted in a beer possessing typical characteristics of a pale ale-style beer, whereas sparkling wine and distilling yeast strains resulted in aromas that were uncharacteristic, which was expected. In addition, we observed that the various strains had different propensities to survive during bottle conditioning. Proteomic analysis was performed to ascertain protein abundance changes and reveal biological processes that potentially enabled specific yeast strains to survive longer during secondary fermentation. Our results showed that proteins associated with oxidoreductase activity and mitochondrial ribosomes were increased in the yeast strain with superior survival and were able to respond to cellular stress more effectively, whereas proteins associated with cell wall modulation were increased in the strain with poor survival characteristics. Overall, we demonstrated the impact of yeast selection on bottle conditioning and the biological processes involved in yeast physiology under these conditions.

Serine protease inhibitors are a superfamily of proteins that regulate various physiological processes including fibrinolysis, inflammation and immune responses. In parasite systems, serpins are believed to play important roles in parasite colonization, inhibition of host immune serine proteases and penetration of defensive barriers. However, serpins are less well characterized in schistosomes. In this study, a Schistosoma mansoni serpin (Smserpin-p46) containing a 1360 base pair open reading frame, was cloned, expressed and functionally characterized. Bioinformatics analysis revealed that Smserpin-p46 contains the key residues, structural domains and motifs characteristic of inhibitory serpins. Gene expression profiling demonstrated stage-specific expression of Smserpin-p46 with the highest expression in adult male worms. Recombinant Smserpin-p46 (rSmserpin-p46) inhibited both human neutrophil cathepsin G and elastase, key serine proteases involved in NETosis, a program for the formation of neutrophil extracellular traps. Using specific rabbit antiserum, Smserpin-p46 was detected in soluble worm antigen preparation and was localized to the adult worm tegument. Cumulatively, the expression of Smserpin-p46 on the parasite tegument and its ability to inhibit proteases involved in NETosis highlights the importance of this serpin in parasite-host interactions and encourages its further investigation as a candidate vaccine antigen for the control of schistosomiasis.

Long-and middle-wavelength cone photoreceptors, which are responsible for our visual acuity and color vision, comprise ~95% of our total cone population and are concentrated in the fovea of our retina. Previously, we characterized the disease mechanisms of the L/M-cone opsin missense mutations N94K, W177R, P307L, R330Q and G338E, all of which are associated with congenital blue cone monochromacy (BCM) or color-vision deficiency. Here, we used a similar viral vector-based gene delivery approach in M-opsin knockout mice to investigate the pathogenic consequences of the BCM or color-vision deficient associated L-cone opsin (OPN1LW) mutants K82E, P187S, and M273K. We investigated their subcellular localization, the pathogenic effects on cone structure, function, and cone viability. K82E mutants were detected predominately in cone outer segments, and its expression partially restored expression and correct localization of cone PDE6α’ and cone transducin γ. As a result, K82E also demonstrated the ability to mediate cone light responses. In contrast, expression of P187S was minimally detected by either western blot or by immunohistochemistry, probably due to efficient degradation of the mutant protein. M273K cone opsin appeared to be misfolded as it was primarily localized to the cone inner segment and endoplasmic reticulum. Additionally, M273K did not restore the expression of cone PDE6α’ and cone transducin γ in dorsal cone OS, presumably by its inability to bind 11-cis retinal. Consistent with the observed expression pattern, P187S and M273K cone opsin mutants were unable to mediate light responses. Moreover, expression of K82E, P187S, and M273K mutants reduced cone viability. Due to the distinct expression patterns and phenotypic differences of these mutants observed in vivo, we suggest that the pathobiological mechanisms of these mutants are distinct.

Background Patients with ischemic stroke and concomitant COVID‐19 infection have worse outcomes than those without this infection, but the impact of COVID‐19 on hemorrhagic stroke remains unclear. We aimed to assess if COVID‐19 worsens outcomes in intracerebral hemorrhage (ICH). Methods and Results We conducted an observational study of ICH outcomes using Get With The Guidelines Stroke data. We compared patients with ICH who were COVID‐19 positive and negative during the pandemic (March 2020–February 2021) and prepandemic (March 2019–February 2020). Main outcomes were poor functional outcome (defined as a modified Rankin scale score of 4 to 6 at discharge), mortality, and discharge to a skilled nursing facility or hospice. The first stage included 60 091 patients with ICH who were COVID‐19 negative and 1326 COVID‐19 positive. In multivariable analyses, patients with ICH with versus without COVID‐19 infection had 68% higher odds of poor outcome (odds ratio [OR], 1.68 [95% CI, 1.41–2.01]), 51% higher odds of mortality (OR, 1.51 [95% CI, 1.33–1.71]), and 66% higher odds of being discharged to a skilled nursing facility/hospice (OR, 1.66 [95% CI, 1.43–1.93]). The second stage included 62 743 prepandemic and 64 681 intrapandemic cases with ICH. In multivariable analyses, patients with ICH admitted during versus before the COVID‐19 pandemic had 10% higher odds of poor outcomes (OR, 1.10 [95% CI, 1.07–1.14]), 5% higher mortality (OR, 1.05 [95% CI, 1.02–1.08]), and no significant difference in the risk of being discharged to a skilled nursing facility/hospice (OR, 0.93 [95% CI, 0.90–0.95]). Conclusions The pathophysiology of the COVID‐19 infection and changes in health care delivery during the pandemic played a role in worsening outcomes in the patient population with ICH.

Abstract Human disturbance including rapid urbanization and increased temperatures can have profound effects on the ecology of local populations. Eusocial insects, such as ants, have adapted to stressors of increasing temperature and urbanization; however, these evolutionary responses are not consistent among populations across geographic space. Here we asked how urbanization and incubation temperature influence critical thermal maximum (CTmax) and various ecologically relevant behaviors in three ant species in urban and rural locations in Worcester, MA, USA. We did this by incubating colonies of three species of cavity dwelling ant (Aphaenogaster picea, Tapinoma sessile, and Temnothorax longispinosus) from 2 habitat types (Rural and Urban), for 60‐days at multiple temperatures. We found that incubation temperature, urbanization, and species of ant all significantly affected overall colony critical thermal maximum. We also found that recruitment time, colonization time, and defense response were significantly affected by incubation temperature and varied between species of ant, while recruitment and colonization time were additionally affected by urbanization. These variable changes in performance and competitive traits across species suggest that responses to urbanization and shifting temperatures are not universal across species. Changes in behavioral responses caused by urbanization may disrupt biodiversity, creating unusual competitive environments as a consequence of natural adaptations and cause both direct and indirect mechanisms for which human disturbance can lead to local species extinction.

Background: The transition from pediatric to adult care is a period associated with adverse health outcomes (e.g., health care dropout, health deterioration and poor adherence to management) for adolescents and young adults (AYA) with chronic conditions and their caregivers. AYA and caregivers often struggle to adapt to adult care settings resulting from a lack of preparedness and difficulties accessing services to manage their health conditions. To adequately design transition interventions and supports, it is critical to explore what skills AYA think would increase their confidence and ability to successfully move into adult health care. Methods: The Transition Navigator Trial is a randomized controlled trial being conducted in Alberta, Canada, recruiting from three major tertiary care pediatric centers, in which half of participants receive a patient navigator, whose goal is to assist with this transition. Twenty-seven youth were interviewed at baseline, with a planned follow-up interview at the end of the trial. Participants were asked about their perspectives on the upcoming transition and how working with the navigator may assist with the transfer to adult-oriented services. Using an inductive approach to thematic analysis, baseline interviews were analyzed to explore AYA perspectives on their wants and needs for an upcoming transition to adult health care. The overarching guiding question is: what skills do AYA desire to assist with the transition to adult health care services? Results: Two broad themes were generated based on participant baseline interviews: 1) ownership of care; and 2) system navigation. Participants identified that self-management and self-advocacy skills are essential for taking ownership of their own healthcare. Participants identified that even when they have acquired the necessary skills to take ownership of their care, there is a further step of system navigation that they might require external help with. Conclusions: It has been highlighted in the literature that health-related knowledge, self-advocacy, and self-management skills promote a more successful transition, however, a gap exists in what youth prioritize as important skills. These findings exemplify that AYA want to gain skills that will allow for independence and success in the transition to adult health care. By involving youth in the development of future transition interventions, we can better understand the needs and priorities of AYA to assist in the success of transition to adult health care.

Background: Adolescents and emerging adults (AEA) with chronic health conditions may face numerous challenges when undergoing the transition from pediatric to adult health care. Despite the need for engagement with AEA in health research, little is known about how researchers operationalize this engagement. In an effort to enhance transparency in the practices of patient engagement, this commentary details the process of developing a pediatric-adult transition-specific youth advisory council in Alberta: the Transition Research Advisory Council (TRAC). Objectives: We provide an overview of AEA engagement in health research and detail TRAC’s recruitment and onboarding strategies. Moreover, TRAC members provided reflections on their motivations and experiences during the onboarding process. Key recommendations: This commentary provides key recommendations for AEA council development, emphasizing equity, diversity, and inclusion principles, optimizing compensation plans, adopting an iterative engagement approach, fostering capacity-building and mentorship, and promoting empowerment in decision-making.

Sexual conflict theory has been successfully applied to predict how in non-human animal populations, sex ratios can lead to conflicting reproductive interests of females and males and affect their bargaining positions in resolving such conflicts of interests. Recently this theory has been extended to understand the resolution of sexual conflict in humans, but with mixed success. We argue that an underappreciation of the complex relationship between gender norms and sex ratios has hampered a successful understanding of sexual conflict in humans. In this paper, we review and expand upon existing theory to increase its applicability to humans, where gender norms regulate sex ratio effects on sexual conflict. Gender norms constrain who is on the marriage market and how they are valued, and may affect reproductive decision-making power. Gender norms can also directly affect sex ratios, and we hypothesize that they structure how individuals respond to market value gained or lost through biased sex ratios. Importantly, gender norms are in part a product of women's and men's sometimes conflicting reproductive interests, but these norms are also subject to other evolutionary processes. An integration of sexual conflict theory and cultural evolutionary theory is required to allow for a full understanding of sexual conflict in humans.

Objectives Intersectionality conceptualises how different parts of our identity compound, creating unique and multifaceted experiences of oppression. Our objective was to explore and compare several quantitative analytical approaches to measure interactions among four sociodemographic variables and interpret the relative impact of axes of marginalisation on self-reported health, to visualise the potential elevated impact of intersectionality on health outcomes.Design Secondary analysis of National Epidemiologic Survey on Alcohol and Related Conditions-III, a nationally representative cross-sectional study of 36 309 non-institutionalised US citizens aged 18 years or older.Primary outcome measures We assessed the effect of interactions among race/ethnicity, disability status, sexual orientation and income level on a self-reported health outcome with three approaches: non-intersectional multivariate regression, intersectional multivariate regression with a single multicategorical predictor variable and intersectional multivariate regression with two-way interactions.Results Multivariate regression with a single multicategorical predictor variable allows for more flexibility in a logistic regression problem. In the fully fitted model, compared with individuals who were white, above the poverty level, had no disability and were heterosexual (referent), only those who were white, above the poverty level, had no disability and were gay/lesbian/bisexual/not sure (LGBQ+) demonstrated no significant difference in the odds of reporting excellent/very good health (aOR=0.90, 95% CI=0.71 to 1.13, p=0.36). Multivariate regression with two-way interactions modelled the extent that the relationship between each predictor and outcome depended on the value of a third predictor variable, allowing social position variation at several intersections. For example, compared with heterosexual individuals, LGBQ+ individuals had lower odds of reporting better health among whites (aOR=0.94, 95% CI=0.93 to 0.95) but higher odds of reporting better health among Black Indigenous People of Color (BIPOC) individuals (aOR=1.13, 95% CI=1.11 to 1.15).Conclusion These quantitative approaches help us to understand compounding intersectional experiences within healthcare, to plan interventions and policies that address multiple needs simultaneously.

Summary: The composite material-like extracellular matrix (ECM) in the sinoatrial node (SAN) supports the native pacemaking cardiomyocytes (PCMs). To test the roles of SAN ECM in the PCM phenotype and function, we engineered reconstructed-SAN heart tissues (rSANHTs) by recellularizing porcine SAN ECMs with hiPSC-derived PCMs. The hiPSC-PCMs in rSANHTs self-organized into clusters resembling the native SAN and displayed higher expression of pacemaker-specific genes and a faster automaticity compared with PCMs in reconstructed-left ventricular heart tissues (rLVHTs). To test the protective nature of SAN ECMs under strain, rSANHTs and rLVHTs were transplanted onto the murine thoracic diaphragm to undergo constant cyclic strain. All strained-rSANHTs preserved automaticity, whereas 66% of strained-rLVHTs lost their automaticity. In contrast to the strained-rLVHTs, PCMs in strained-rSANHTs maintained high expression of key pacemaker genes (HCN4, TBX3, and TBX18). These findings highlight the promotive and protective roles of the composite SAN ECM and provide valuable insights for pacemaking tissue engineering.

Introduction The prevalence of burnout among anesthesiology residents is 41%–51%. Burnout is associated with medical errors, physician turnover, and substance use disorder. Social support and wellness may reduce burnout, but a barrier is support persons’ lack of understanding of an anesthesiologist's work demands. We developed the Family Anesthesia Experience (FAX) to help support persons best support their resident. Methods FAX consisted of a 4-hour event with hands-on experience, didactics portion, and panel discussion. Participants learned about a typical day in the life of an anesthesiology resident, wellness, burnout, substance use disorder, and available support resources, and had hands-on experience with procedures. The panel discussion offered logistical information about anesthesiology residency and allowed support persons to ask panel members questions. A postevent survey collected feedback on the event. Results Fifty-one participants (first-year anesthesiology residents and their support persons) attended the event. Eight of 11 residents (73%) and 32 of 40 support persons (80%) completed the survey. All enjoyed the event, would recommend it to other anesthesiology resident support persons, and felt the event would improve communication and support. Most learned a moderate (35%) to large amount (50%) from the event. Qualitative feedback suggested most support persons found the event helpful in improving their understanding of anesthesiology residents’ work demands. Discussion The FAX was well liked by participants. Although we did not assess specific knowledge gained and long-term effects of the 2022 event, evaluations of previous years’ events suggest that the event improved participants’ understanding of anesthesiology residents’ work and stressors.

Constructing a written scientific explanation is a science practice that is fundamental in supporting students developing understanding of the natural world in which we live. Engaging in the practice of constructing valid scientific explanations supports students in developing science disciplinary literacy. Yet, writing a scientific explanation can be challenging for diverse and exceptional learners because it requires coordinating multiple, complex skills. This conceptual analysis explores the purpose of constructing written scientific explanations by focusing on the constituent elements and structures of a constructed scientific explanation. These findings are then integrated into a framework to assist Individual Education Program (IEP) teams in planning and implementing successful supports and instruction for diverse and exceptional learners in middle- and high-school, general education, science classrooms.

Abstract Background Both internet addiction (IA) and non-suicidal self-injury (NSSI) are major public health concerns among adolescents, however, the association between IA and NSSI was not well understood. We aimed to investigate the association between IA and NSSI within a cohort study, and explore the mediated effect of depressive symptoms and the moderating effect of social support in the association. Methods A total of 1530 adolescents aged 11–14 years who completed both the baseline (T1) and 14-month follow-up (T2) survey of the Chinese Adolescent Health Growth Cohort were included for the current analysis. IA, NSSI, depressive symptoms and social support were measured at T1; depressive symptoms and NSSI were measured again at T2. Structural equation models were employed to estimate the mediated effect of depressive symptoms and the moderating effect of social support in the association between IA and NSSI at T2. Results IA was independently associated with an increased risk of NSSI at T2, with the total effect of 0.113 (95%CI 0.055–0.174). Depressive symptoms mediated the association between IA and NSSI at T2, and social support moderated the indirect but not the direct effect of IA on NSSI at T2. Sex differences were found on the mediated effect of depressive symptoms and the moderated mediation effect of social support. Conclusions Interventions that target adolescents’ NSSI who also struggle with IA may need to focus on reducing depressive symptoms and elevating social support.

Abstract Background Releasing timely and relevant clinical guidelines is challenging for organizations globally. Priority-setting is crucial, as guideline development is resource-intensive. Our aim, as a national organization responsible for developing cardiovascular clinical guidelines, was to develop a method for generating and prioritizing topics for future clinical guideline development in areas where guidance was most needed. Methods Several novel processes were developed, adopted and evaluated, including (1) initial public consultation for health professionals and the general public to generate topics; (2) thematic and qualitative analysis, according to the International Classification of Diseases (ICD-11), to aggregate topics; (3) adapting a criteria-based matrix tool to prioritize topics; (4) achieving consensus through a modified-nominal group technique and voting on priorities; and (5) process evaluation via survey of end-users. The latter comprised the organization’s Expert Committee of 12 members with expertise across cardiology and public health, including two citizen representatives. Results Topics (n = 405; reduced to n = 278 when duplicates removed) were identified from public consultation responses (n = 107 respondents). Thematic analysis synthesized 127 topics that were then categorized into 37 themes using ICD-11 codes. Exclusion criteria were applied (n = 32 themes omitted), resulting in five short-listed topics: (1) congenital heart disease, (2) valvular heart disease, (3) hypercholesterolaemia, (4) hypertension and (5) ischaemic heart diseases and diseases of the coronary artery. The Expert Committee applied the prioritization matrix to all five short-listed topics during a consensus meeting and voted to prioritize topics. Unanimous consensus was reached for the topic voted the highest priority: ischaemic heart disease and diseases of the coronary arteries, resulting in the decision to update the organization’s 2016 clinical guidelines for acute coronary syndromes. Evaluation indicated that initial public consultation was highly valued by the Expert Committee, and the matrix tool was easy to use and improved transparency in priority-setting. Conclusion Developing a multistage, systematic process, incorporating public consultation and an international classification system led to improved transparency in our clinical guideline priority-setting processes and that topics chosen would have the greatest impact on health outcomes. These methods are potentially applicable to other national and international organizations responsible for developing clinical guidelines.

ABSTRACTIn Poverty, Solidarity, and Poor-Led Social Movements, Monique Deveaux builds a political theory of poverty as relational and responsibility for injustice as solidaristic. Identifying the ways that poor-led movements have politically theorized and acted, Deveaux develops a theory of relational poverty that entails politicizing poverty which requires local-level organizing, consciousness-raising, resisting injustice and developing and demanding alternatives, and engaging in public debate and discourse. She goes on to argue that the praxis of poor-led movements reveals normative commitments to mutuality, deference and deep listening, and risk taking. These enable movements of people in poverty to take on the injustice of poverty together across difference, privilege, and other obstacles to transformative (solidaristic) politics. Deveaux provides a mode for doing grounded normative theory (GNT) by relying on secondary literature. GNT is a methodology for doing political theory that destabilizes the epistemological authority of the political theory of the academy by treating lived experience – words and actions – as providing relevant text for analysis. The methodology is particularly important for theories related to justice. Deveaux demonstrates how this can be done with secondary sources thus enabling comprehensive engagement without avoiding burdening social movement actors with interviews or other modes of accommodating researchers.

Several organic geochemical proxies within a sediment core from Lake Petén Itzá, Guatemala, suggest intense human-induced degradation of the aquatic environment during the Maya Preclassic period from around 700 BCE to 200 CE

Abstract Background Rearranged during transfection (RET) tyrosine kinase signaling has been previously implicated in endocrine resistant breast cancer, however the mechanism by which this signaling cascade promotes resistance is currently not well described. We recently reported that glial cell-derived neurotrophic factor (GDNF)-RET signaling appears to promote a positive feedback loop with the transcription factor early growth response 1 (EGR1). Here we investigate the mechanism behind this feedback loop and test the hypothesis that GDNF-RET signaling forms a regulatory loop with EGR1 to upregulate cyclin D1 (CCND1) transcription, leading to cell cycle progression and tamoxifen resistance. Methods To gain a better understanding of the GDNF-RET-EGR1 resistance mechanism, we studied the GDNF-EGR1 positive feedback loop and the role of GDNF and EGR1 in endocrine resistance by modulating their transcription levels using CRISPR-dCAS9 in tamoxifen sensitive (TamS) and tamoxifen resistant (TamR) MCF-7 cells. Additionally, we performed kinetic studies using recombinant GDNF (rGDNF) treatment of TamS cells. Finally, we performed cell proliferation assays using rGDNF, tamoxifen (TAM), and Palbociclib treatments in TamS cells. Statistical significance for qPCR and chromatin immunoprecipitation (ChIP)-qPCR experiments were determined using a student’s paired t-test and statistical significance for the cell viability assay was a one-way ANOVA. Results GDNF-RET signaling formed a positive feedback loop with EGR1 and also downregulated estrogen receptor 1 (ESR1) transcription. Upregulation of GDNF and EGR1 promoted tamoxifen resistance in TamS cells and downregulation of GDNF promoted tamoxifen sensitivity in TamR cells. Additionally, we show that rGDNF treatment activated GDNF-RET signaling in TamS cells, leading to recruitment of phospho-ELK-1 to the EGR1 promoter, upregulation of EGR1 mRNA and protein, binding of EGR1 to the GDNF and CCND1 promoters, increased GDNF protein expression, and subsequent upregulation of CCND1 mRNA levels. We also show that inhibition of cyclin D1 with Palbociclib, in the presence of rGDNF, decreases cell proliferation and resensitizes cells to TAM. Conclusion Outcomes from these studies support the hypotheses that GDNF-RET signaling forms a positive feedback loop with the transcription factor EGR1, and that GDNF-RET-EGR1 signaling promotes endocrine resistance via signaling to cyclin D1. Inhibition of components of this signaling pathway could lead to therapeutic insights into the treatment of endocrine resistant breast cancer.

Abstract Background Transition-age youth (TAY) with chronic health conditions frequently experience co-occurring mental health conditions. However, little is known about the perspectives of TAY with co-occurring diagnoses preparing to exit pediatric health and mental health services. Research is needed to understand the impact of a mental health condition on transition readiness and self-management in TAY with chronic health conditions. Methods TAY (aged 16–20 years) with co-occurring chronic health and mental health conditions were recruited in Alberta, Canada. Nine semi-structured individual interviews were completed by phone or videoconference, and transcribed verbatim. Guided by qualitative description, we analyzed the data using thematic analysis in partnership with five young adults with lived experience in the health/mental health systems. Results Participants shared their experiences living with simultaneous physical and mental health concerns and preparing for transition to adult care. Our analysis revealed three overarching themes: 1) “they’re intertwined”: connections between chronic health and mental health conditions in TAY, 2) impact of mental health on transition readiness and self-management, and 3) recommendations for service provision from the perspectives of TAY. Conclusions Our findings highlighted the myriad ways in which physical and mental health are connected as TAY prepare for service transitions using specific examples and powerful metaphors. TAY endorsed the importance of providers discussing these connections in routine clinical care. Future research should involve co-designing and evaluating educational material addressing this topic with diverse TAY, caregivers, and service providers.

Crutch walking, especially when using a swing-through gait pattern, is associated with high, repetitive joint forces, hyperextension/ulnar deviation of the wrist, and excessive palmar pressure that compresses the median nerve. To reduce these adverse effects, we designed a pneumatic sleeve orthosis that utilized a soft pneumatic actuator and secured to the crutch cuff for long-term Lofstrand crutch users. Eleven non-disabled young adult participants performed both swing-through and reciprocal crutch gait patterns with and without the custom orthosis for comparison. Wrist kinematics, crutch forces, and palmar pressures were analyzed. Significantly different wrist kinematics, crutch kinetics, and palmar pressure distribution were observed in swing-through gait trials with orthosis use (p