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Abstract Aims Hospitalized patients with heart failure (HF) are a heterogeneous population, with multiple phenotypes proposed. Prior studies have not examined the biological phenotypes of critically ill patients with HF admitted to the contemporary cardiac intensive care unit (CICU). We aimed to leverage unsupervised machine learning to identify previously unknown HF phenotypes in a large and diverse cohort of patients with HF admitted to the CICU. Methods We screened 6008 Mayo Clinic CICU patients with an admission diagnosis of HF from 2007 to 2018 and included those without missing values for common laboratory tests. Consensus k‐means clustering was performed based on 10 common admission laboratory values (potassium, chloride, anion gap, blood urea nitrogen, haemoglobin, red blood cell distribution width, mean corpuscular volume, platelet count, white blood cell count and neutrophil‐to‐lymphocyte ratio). In‐hospital mortality was evaluated using logistic regression, and 1 year mortality was evaluated using Cox proportional hazard models after multivariable adjustment. Results Among 4877 CICU patients with HF who had complete admission laboratory data (mean age 69.4 years, 38.4% females), we identified five clusters with divergent demographics, comorbidities, laboratory values, admission diagnoses and use of critical care therapies. We labelled these clusters based on the characteristic laboratory profile of each group: uncomplicated (25.7%), iron‐deficient (14.5%), cardiorenal (18.4%), inflamed (22.3%) and hypoperfused (19.2%). In‐hospital mortality occurred in 10.7% and differed between the phenotypes: uncomplicated, 2.7% (reference); iron‐deficient, 8.1% [adjusted odds ratio (OR) 2.18 (1.38–3.48), P

The syntheses and characterization (NMR and XRD) of two substituted [2.2.2]bicyclooctene ring systems are described here. The cyclohexene rings of these systems adopt a nearly perfect boat conformation according to analysis using Cremer–Pople parameters. Both structures contain a nearly planar imide ring that is oriented endo relative to a bridgehead cyclopropyl ring. 4-(2-Phenylethyl)-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione, C19H19NO2, is substituted with a phenylethyl group that hosts C—H...π interactions in the crystal. 4-[2-(4-Hydroxyphenyl)ethyl]-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione, C19H19NO3, bears a 4-hydroxyphenylethyl group on the imide ring and contains O—H...O and C—H...O hydrogen bonds.

Abstract Background Community health workers (CHWs) can support patient engagement in care for a variety of health conditions, including HIV. This paper reports on the experiences of HIV clinics and health departments that integrated CHWs into their health systems as part of a capacity-building initiative to address HIV-related disparities in the United States. Methods Semi-structured interviews were conducted with key informants (n = 14) in two Ryan White HIV/AIDS program jurisdictions: Mississippi (jurisdiction covers the entire state) and the city of New Orleans, Louisiana. This work was part of a larger evaluation of an initiative that used a Learning Collaborative model to facilitate the implementation of evidence-informed interventions to address HIV care continuum gaps in four jurisdictions. The two jurisdictions that focused on integrating CHWs into HIV care clinics and support service agencies were selected for this sub-analysis. Interview participants included HIV clinic leaders and staff, health department leaders, and other Learning Collaborative leaders. Interview transcripts were coded and analyzed for themes related to the acceptability, feasibility, and perceived impact of CHW integration. Results Overall, participants expressed interest in having support from CHWs at HIV clinics and service agencies to assist with patient retention and engagement efforts. However, there were challenges integrating CHWs into existing systems (e.g., gaining access to electronic health records, changing policies to conduct home visits, and clarifying roles and scope of work). Negotiating contracts and accessing funding for CHW positions presented major challenges that often contributed to turnover and conflicts around scope of practice. When health departments leveraged existing funding streams to support CHW positions, the clinics and agencies where the CHWs worked had limited flexibility over the hiring process. Conclusions Our findings reinforce the value and acceptability of CHWs as part of the workforce in HIV clinical and support service settings; however, integrating CHWs into clinics and service agencies required effort. Training the CHWs was not sufficient; other staff and clinicians had to understand the role of CHWs to facilitate their integration into health systems. Resources are needed to support organizations in incorporating CHWs effectively, and long-term, flexible sources of funding are necessary for these positions.

Abstract Background Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood. Methods APOEε4 carriers and APOEε3 homozygotes enrolled in the Women’s Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß42/40) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank. Results A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß42/40/tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P

Abstract Maternal smoking during pregnancy (MSDP), driven by nicotine crossing the placenta, causes lifelong decreases in offspring pulmonary function and vitamin C supplementation during pregnancy prevents some of those changes. We have also shown in animal models of prenatal nicotine exposure that vitamin C supplementation during pregnancy improves placental function. In this study we examined whether vitamin C supplementation mitigates the effects of MSDP on placental structure, function, and gene expression in pregnant human smokers. Doppler ultrasound was performed in a subset of 55 pregnant smokers participating in the “Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function” (VCSIP) randomized clinical trial (NCT01723696) and in 33 pregnant nonsmokers. Doppler ultrasound measurements showed decreased umbilical vein Doppler velocity (Vmax) in placebo-treated smokers that was significantly improved in smokers randomized to vitamin C, restoring to levels comparable to nonsmokers. RNA-sequencing demonstrated that vitamin C supplementation to pregnant smokers was associated with changes in mRNA expression in genes highly relevant to vascular and cardiac development, suggesting a potential mechanism for vitamin C supplementation in pregnant smokers to improve some aspects of offspring health.

Abstract Background Champions are integral across research in cancer, yet studies exploring their roles are limited and have produced mixed results. The current review examines and synthesizes descriptions of how champions emerged and the types of activities they most often performed. By examining evidence from across the translational research continuum, this scoping review aims to characterize the role of champions and strategies that facilitate their involvement in the implementation of cancer care interventions in both clinical and community-based settings. Methods This scoping review was designed and implemented in compliance with PRISMA-ScR. The review focused on peer-reviewed articles in English-language journals. We searched five databases: PubMed (including MEDLINE), Scopus (including EMBASE), CINAHL, PsycINFO, and the Cochrane Library. Articles published from 1971 to 2022 were included. Two members of the team reviewed in duplicate each article and then a single member of the team extracted the data in Covidence, with a second member comparing the extraction to the original article. Qualitative and quantitative data were extracted and then synthesized. These data were used to summarize core champion activities and implementation strategies and to characterize barriers and facilitators to using champions in research. Results A total of 74 articles were included in the review. The qualitative synthesis highlighted facilitators and barriers to the effective use of champions. Facilitators included consideration of an individual’s characteristics when identifying champions, time spent planning for the specific responsibilities of champions, working within a supportive environment, and identifying champions embedded in the target setting. Major barriers included constrained time, low self-efficacy among champions, inadequate training, high turnover rates of champions, and a lack of buy-in from organizational leadership toward the intervention. Champions also were mostly assigned their roles, had varied core activities, and used complementary strategies to empower their target populations. Champions’ most frequent core activities include facilitation, outreach/promotion, and recruitment of participants into studies. Conclusions Champions were used in research of many cancer types and often serve similar roles regardless of where they are located within the translational research process. Despite their critical role, evidence is lacking on the impact of champions specifically on outcomes of many of the research studies that include them. Future research is needed to understand the nuances of champion-driven approaches across diverse cancer care settings.

Abstract Background Medical training can be a challenging time for residents both professionally and personally. Resident support programs must be able to address a range of potential experiences, be accessible and easy to navigate, and consider the unique context of residency. Rigorous evaluation of resident support programs is needed to determine whether these programs are meeting these goals. Methods The Directors of Resident Support (DRS) program, launched in January 2021 at the Cumming School of Medicine at the University of Calgary, is a near-peer support model consisting of three faculty physicians, trained in peer support, who receive contacts from residents needing support for any issue. DRS physicians provide empathetic listening, referral to existing resources, and peer support for residents. A multisource evaluation of the DRS program, including field notes, data collection forms, and surveys, was guided by the Donabedian framework. Results There were 62 total contacts in the 2-year evaluation period which required a median 2 h to address (range 5 min to more than 40 h). The most common topic for contact was to discuss feedback or evaluation (n = 10, 24.4%) and the most common response was listening and support (n = 29, 70.7%). Residents also contacted DRS to discuss experiences of racism, physical assault, sexual harassment, and mental health crises. Residents (n = 13) rated a median score of 74 out of possible 100 for usefulness (interquartile range [IQR] 1-100, with higher scores suggesting greater usefulness). Free text survey responses suggested that residents felt validated by contact with the program though some residents felt that additional follow-up would have been helpful. Conclusion The DRS program has been well-utilized by residents for a variety of issues. Postgraduate Medical Education offices seeking to create resident support programs may anticipate that about 3% of residents may use a similar program per year and that the typical interaction would last 2 h, with a wide range. Feedback suggested that similar programs should have a formal process for follow-up with residents to ensure their concern was addressed and that resident supporters should have diverse lived experiences.

Complex malignant hematology (CMH) shared-care programs have been established to support patients with access to care closer to home. This integrative review examined what is known about CMH shared-care using the RE-AIM evaluation framework. We searched five electronic databases for articles published until 16 January 2024. Articles were included if they were qualitative or quantitative studies, reviews or discussion papers, and reported on an experience with shared-care (defined as a reciprocal, ongoing patient-sharing relationship between a specialist centre and community hospital) for patients with hematological malignancies, and examined one or more aspects of the RE-AIM framework. The search yielded 6523 articles; 10 articles describing eight shared-care experiences. Indicators of reach were reported for 65% of the programs, and emphasized some patient eligibility criteria. Effectiveness indicators were reported for 28% of programs, and suggested favourable survival outcomes within a shared-care model; however, health system impact and quality of life studies were lacking. Indicators of adoption and implementation were reported for 56% and 42% of programs, respectively, and emphasized multidisciplinary teams, infrastructure support, and communication strategies. Maintenance was not reported. Common elements contribute to the implementation of existing CMH shared-care programs; however, a formal evaluation remains an area of need.

Abstract Background A genotype-by-environment (G × E) interaction is defined as genotypes responding differently to different environments. In salmonids, G × E interactions can occur in different rearing conditions, including changes in salinity or temperature. However, water flow, an important variable that can influence metabolism, has yet to be considered for potential G × E interactions, although water flows differ across production stages. The salmonid industry is now manipulating flow in tanks to improve welfare and production performance, and expanding sea pen farming offshore, where flow dynamics are substantially greater. Therefore, there is a need to test whether G × E interactions occur under low and higher flow regimes to determine if industry should consider modifying their performance evaluation and selection criteria to account for different flow environments. Here, we used genotype-by-sequencing to create a genomic-relationship matrix of 37 Chinook salmon, Oncorhynchus tshawytscha, families to assess possible G × E interactions for production performance under two flow environments: a low flow regime (0.3 body lengths per second; bl s−1) and a moderate flow regime (0.8 bl s−1). Results Genetic correlations for the same production performance trait between flow regimes suggest there is minimal evidence of a G × E interaction between the low and moderate flow regimes tested in this study, for Chinook salmon reared from 82.9 ± 16.8 g ( $${\overline{\text{x}}}$$ x ¯ ± s.d.) to 583.2 ± 117.1 g ( $${\overline{\text{x}}}$$ x ¯ ± s.d.). Estimates of genetic and phenotypic correlations between traits did not reveal any unfavorable trait correlations for size- (weight and condition factor) and growth-related traits, regardless of the flow regime, but did suggest measuring feed intake would be the preferred approach to improve feed efficiency because of the strong correlations between feed intake and feed efficiency, consistent with previous studies. Conclusion This new information suggests that Chinook salmon families do not need to be selected separately for performance across different flow regimes. However, further studies are needed to confirm this across a wider range of fish sizes and flows. This information is key for breeding programs to determine if separate evaluation groups are required for different flow regimes that are used for production (e.g., hatchery, post smolt recirculating aquaculture system, or offshore).

Abstract Background Lymphatic filariasis (LF) is a globally significant, vector-borne, neglected tropical disease that can result in severe morbidity and disability. As the World Health Organization (WHO) Global Programme to Eliminate Lymphatic Filariasis makes progress towards LF elimination, there is greater need to develop sensitive strategies for post-intervention surveillance. Molecular xenomonitoring (MX), the detection of pathogen DNA in vectors, may provide a sensitive complement to traditional human-based surveillance techniques, including detection of circulating filarial antigen and microfilaraemia (Mf). This study aims to explore the relationship between human Mf prevalence and the prevalence of polymerase chain reaction (PCR)-positive mosquitoes using MX. Methods This study compared Mf and MX results from a 2019 community-based survey conducted in 35 primary sampling units (PSUs) in Samoa. This study also investigated concordance between presence and absence of PCR-positive mosquitoes and Mf-positive participants at the PSU level, and calculated sensitivity and negative predictive values for each indicator using presence of any Mf-positive infection in humans or PCR-positive mosquitoes as a reference. Correlation between prevalence of filarial DNA in mosquitoes and Mf in humans was estimated at the PSU and household/trap level using mixed-effect Bayesian multilevel regression analysis. Results Mf-positive individuals were identified in less than half of PSUs in which PCR-positive mosquito pools were present (13 of 28 PSUs). Prevalence of PCR-positive mosquitoes (each species separately) was positively correlated with Mf prevalence in humans at the PSU level. Analysed at the species level, only Aedes polynesiensis demonstrated strong evidence of positive correlation (r) with human Mf prevalence at both PSU (r: 0.5, 95% CrI 0.1–0.8) and trap/household levels (r: 0.6, 95% CrI 0.2–0.9). Conclusions Findings from this study demonstrate that MX can be a sensitive surveillance method for identifying residual infection in low Mf prevalence settings. MX identified more locations with signals of transmission than Mf-testing. Strong correlation between estimated PCR-positive mosquitoes in the primary vector species and Mf in humans at small spatial scales demonstrates the utility of MX as an indicator for LF prevalence in Samoa and similar settings. Further investigation is needed to develop MX guidelines to strengthen the ability of MX to inform operational decisions. Graphical abstract

Abstract During conversation, people often endeavor to convey information in an understandable way (finding common ground) while also sharing novel or surprising information (exploring new ground). Here, we test how friends and strangers balance these two strategies to connect with each other. Using fMRI hyperscanning, we measure a preference for common ground as convergence over time and exploring new ground as divergence over time by tracking dyads’ neural and linguistic trajectories over the course of semi-structured intimacy-building conversations. In our study, 60 dyads (30 friend dyads) engaged in a real-time conversation with discrete prompts and demarcated turns. Our analyses reveal that friends diverge neurally and linguistically: their neural patterns become more dissimilar over time and they explore more diverse topics. In contrast, strangers converge: neural patterns and language become more similar over time. The more a conversation between strangers resembles the exploratory conversations of friends, the more they enjoy it. Our results highlight exploring new ground as a strategy for a successful conversation.

Abstract Background Venous thromboembolism (VTE) in pregnancy is a major cause of maternal morbidity and mortality, and the use of preventive low-molecular-weight heparin (LMWH) can be challenging. Clinical guidelines recommend eliciting pregnant individuals’ preferences towards the use of daily injections of LMWH and discussing the best option through a shared decision-making (SDM) approach. Our aim was to identify individuals’ preferences concerning each of the main clinical outcomes, and categorize attributes influencing the use of LMWH during pregnancy. Methods Design: Convergent mixed-methods. Participants: Pregnant women or those planning a pregnancy with VTE recurrence risk. Intervention: A SDM intervention about thromboprophylaxis with LMWH in pregnancy. Analysis: Quantitatively, we report preference scores assigned to each of the health states. Qualitatively, we categorized preference attributes using Burke’s pentad of motives framework: act (what needs to be done), scene (patient’s context), agent (perspectives and influence of people involved in the decision), agency (aspects of the medication), and purpose (patient’s goals). We use mixed-method convergent analysis to report findings using side-by-side comparison of concordance/discordance. Results We comprehensively determined preferences for using LMWH by pregnant individuals at risk of VTE: through value elicitation exercises we found that the least valued health state was to experience a pulmonary embolism (PE), followed by major obstetrical bleeding (MOB), deep vein thrombosis (DVT), and using daily injections of LMWH (valued as closest to a ‘healthy pregnancy’); through interviews we found that: previous experiences, access to care (scene) and shared decision-making (agent) affected preferences. LMWH's benefits were noted, but substantial drawbacks were described (agency). For participants, the main goal of using LMWH was avoiding any risks in pregnancy (purpose). Side-by-side comparisons revealed concordance and discordance between health states and motives. Conclusions Mixed-methods provide a nuanced understanding of LMWH preferences, by quantifying health states preferences and exploring attributes qualitatively. Incorporating both methods may improve patient-centered care around preference-sensitive decisions in thromboprophylaxis during pregnancy.

Abstract Background Despite recent therapeutic advances, combating cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 infection and acts as a critical host factor. Recently, we discovered cardiac glycosides (CGs) as novel suppressors of GRP78 stress induction through a high-throughput screen of clinically relevant compound libraries. This study aims to test the possibility that agents capable of blocking stress induction of GRP78 could dually suppress cancer and COVID-19. Results Here we report that oleandrin (OLN), is the most potent among the CGs in inhibiting acute stress induction of total GRP78, which also results in reduced cell surface and nuclear forms of GRP78 in stressed cells. The inhibition of stress induction of GRP78 is at the post-transcriptional level, independent of protein degradation and autophagy and may involve translational control as OLN blocks stress-induced loading of ribosomes onto GRP78 mRNAs. Moreover, the human Na+/K+-ATPase α3 isoform is critical for OLN suppression of GRP78 stress induction. OLN, in nanomolar range, enhances apoptosis, sensitizes colorectal cancer cells to chemotherapeutic agents, and reduces the viability of patient-derived colon cancer organoids. Likewise, OLN, suppresses GRP78 expression and impedes tumor growth in an orthotopic breast cancer xenograft model. Furthermore, OLN blocks infection by SARS-CoV-2 and its variants and enhances existing anti-viral therapies. Notably, GRP78 overexpression mitigates OLN-mediated cancer cell apoptotic onset and suppression of virus release. Conclusion Our findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat cancer and COVID-19.

The molecular structure of the tripodal carbamoylmethylphosphine oxide compound diethyl {[(5-[2-(diethoxyphosphoryl)acetamido]-3-{2-[2-(diethoxyphosphoryl)acetamido]ethyl}pentyl)carbamoyl]methyl}phosphonate, C25H52N3O12P3, features six intramolecular hydrogen-bonding interactions. The phosphonate groups have key bond lengths ranging from 1.4696 (12) to 1.4729 (12) Å (P=O), 1.5681 (11) to 1.5811 (12) Å (P—O) and 1.7881 (16) to 1.7936 (16) Å (P—C). Each amide group adopts a nearly perfect trans geometry, and the geometry around each phophorus atom resembles a slightly distorted tetrahedron.

Abstract Background Adverse childhood experiences (ACEs) are important factors for population mental and physical health. While considerable public health literature demonstrates the global relevance of ACEs, more recent research shows that benevolent childhood experiences (BCEs) might be important to consider in their direct and mitigating roles for psychological distress and other mental health outcomes. There is little evidence of latent class examinations involving both ACEs and BCEs among adults in western nations. The present study sought to replicate and extend prior literature by: (1) assessing the extent to which past latent class groupings reproduce in present samples, and (2) analyzing the association of latent classes of childhood experiences with psychological distress and suicidal thoughts and behaviours (STBs). We examined psychological distress (i.e., depression, anxiety, post-traumatic stress, general wellbeing) and STBs (i.e., suicidal ideation, self-harm ideation and behaviour, entrapment, and defeat). Method Data were drawn from two nationwide cross-sectional online survey studies in the United Kingdom. The first sample (N = 488) was drawn from a study on suicidal behaviour, and the second sample (N = 447) was from a study concerning risk for interpersonal violence. Results Results largely replicated an existing four class solution of childhood experiences: Class 1 (Moderate ACEs/High BCEs; 17.6%), Class 2 (High ACEs/Moderate BCEs; 15.3%), Class 3 (Low ACEs/High BCEs; 48.3%), and Class 4 (Low ACEs/Moderate BCEs; 18.8%). Class 2 (High ACEs/Moderate BCEs) was associated with consistently worse psychological distress and STBs. Classes containing high BCEs (1 and 3) were characterized by generally lower levels of psychological distress and STBs. Conclusions Results affirm the potential value for jointly considering ACEs and BCEs to understand psychological distress and STBs. ACEs and BCEs may serve foundational roles in theories of suicide. The protective role of BCEs hypothesized in resiliency theory may be supported. Prevention practice and research implications are discussed.

Abstract Numbers of aggressive prostate cancer (aPC) cases are rising, but only a few risk factors have been identified. In this study, we introduce a systematic approach to integrate geospatial data into external exposome research using aPC cases from Pennsylvania. We demonstrate the association between several area-level exposome measures across five Social Determinants of Health domains (SDOH) and geographic areas identified as having elevated odds of aPC. Residential locations of Pennsylvania men diagnosed with aPC from 2005 to 2017 were linked to 37 county-/tract-level SDOH exosome measures. Variable reduction processes adopted from neighborhood-wide association study along with Bayesian geoadditive logistic regression were used to identify areas with elevated odds of aPC and exposome factors that significantly attenuated the odds and reduced the size of identified areas. Areas with significantly higher odds of aPC were explained by various SDOH exposome measures, though the extent of the reduction depended on geographic location. Some areas were associated with race (social context), health insurance (access), or tract-level poverty (economics), while others were associated with either county-level water quality or a combination of factors. Area-level exposome measures can guide future patient-level external exposome research and help design targeted interventions to reduce local cancer burden.

Abstract Retinitis Pigmentosa is a leading cause of severe vision loss. Retinitis Pigmentosa can present with a broad range of phenotypes impacted by disease age of onset, severity, and progression. This variation is influenced both by different gene mutations as well as unique variants within the same gene. Mutations in the nuclear hormone receptor 2 family e, member 3 are associated with several forms of retinal degeneration, including Retinitis Pigmentosa. In our previous studies we demonstrated that subretinal administration of one Nr2e3 dose attenuated retinal degeneration in rd7 mice for at least 3 months. Here we expand the studies to evaluate the efficacy and longitudinal impact of the NR2E3 therapeutic by examining three different doses administered at early or intermediate stages of retinal degeneration in the rd7 mice. Our study revealed retinal morphology was significantly improved 6 months post for all doses in the early-stage treatment groups and for the low and mid doses in the intermediate stage treatment groups. Similarly, photoreceptor function was significantly improved in the early stage for all doses and intermediate stage low and mid dose groups 6 months post treatment. This study demonstrated efficacy in multiple doses of NR2E3 therapy.

Abstract Venus, lacking an intrinsic global dipole magnetic field, serves as a textbook example of an induced magnetosphere, formed by interplanetary magnetic fields (IMF) enveloping the planet. Yet, various aspects of its magnetospheric dynamics and planetary ion outflows are complex and not well understood. Here we analyze plasma and magnetic field data acquired during the fourth Venus flyby of the Parker Solar Probe (PSP) mission and show evidence for closed topology in the nightside and downstream portion of the Venus magnetosphere (i.e., the magnetotail). The formation of the closed topology involves magnetic reconnection—a process rarely observed at non-magnetized planets. In addition, our study provides an evidence linking the cold Venusian ion flow in the magnetotail directly to magnetic connectivity to the ionosphere, akin to observations at Mars. These findings not only help the understanding of the complex ion flow patterns at Venus but also suggest that magnetic topology is one piece of key information for resolving ion escape mechanisms and thus the atmospheric evolution across various planetary environments and exoplanets.

Abstract While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy (“PRINCE”, NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.

Adverse Childhood Experiences (ACEs) are very common and presently implicated in 9 out of 10 leading causes of death in the United States. Despite this fact, our mechanistic understanding of how ACEs impact health is limited. Moreover, interventions for reducing stress presently use a one-size-fits-all approach that involves no treatment tailoring or precision. To address these issues, we developed a combined cross-sectional study and randomized controlled trial, called the California Stress, Trauma, and Resilience Study (CalSTARS), to (a) characterize how ACEs influence multisystem biological functioning in adults with all levels of ACE burden and current perceived stress, using multiomics and other complementary approaches, and (b) test the efficacy of our new California Precision Intervention for Stress and Resilience (PRECISE) in adults with elevated perceived stress levels who have experienced the full range of ACEs. The primary trial outcome is perceived stress, and the secondary outcomes span a variety of psychological, emotional, biological, and behavioral variables, as assessed using self-report measures, wearable technologies, and extensive biospecimens (i.e. DNA, saliva, blood, urine, & stool) that will be subjected to genomic, transcriptomic, proteomic, metabolomic, lipidomic, immunomic, and metagenomic/microbiome analysis. In this protocol paper, we describe the scientific gaps motivating this study as well as the sample, study design, procedures, measures, and planned analyses. Ultimately, our goal is to leverage the power of cutting-edge tools from psychology, multiomics, precision medicine, and translational bioinformatics to identify social, molecular, and immunological processes that can be targeted to reduce stress-related disease risk and enhance biopsychosocial resilience in individuals and communities worldwide.

IntroductionDespite continued improvement in post-sepsis survival, long term morbidity and mortality remain high. Chronic critical illness (CCI), defined as persistent inflammation and organ injury requiring prolonged intensive care, is a harbinger of poor long-term outcomes in sepsis survivors. Current dogma states that sepsis survivors are immunosuppressed, particularly in CCI. Investigation of this immune suppression in heterogeneous immune populations across distinct clinical trajectories and outcomes, along with limited sampling access, is accessible via single-cell RNA sequencing (scRNA-seq).MethodsscRNA-seq analysis was performed on healthy subjects (n=12), acutely septic patients at day 4 ± 1 (n=4), and those defined as rapid recovery (n=4) or CCI (n=5) at day 14-21. Differential gene expression and pathway analyses were performed on peripheral blood lymphocytes at both a population and annotated cell subset level. Cellular function was assessed via enzyme-linked immunosorbent spot (ELISpot), cytokine production analysis, and T-cell proliferation assays on an additional cohort of septic patients (19 healthy, 68 acutely septic, 27 rapid recovery and 20 classified as CCI 14-21 days after sepsis onset).ResultsSepsis survivors that developed CCI exhibited proportional shifts within lymphoid cell populations, with expanded frequency of CD8+ and NK cells. Differential expression and pathway analyses revealed continued activation in T cells and NK cells, with generalized suppression of B-cell function. Both T and NK cell subsets displayed transcriptomic profiles of exhaustion and immunosuppression in CCI, particularly in CD8+ T effector memory (TEM) cells and NK cells. Functional validation of T-cell behavior in an independent cohort demonstrated T cells maintained proliferative responses in vitro yet exhibited a marked loss of cytokine production. IFN-γ production at the acute phase (day 4 ± 1) was significantly reduced in subjects later classified as CCI.DiscussionSepsis patients exhibit unique T-, B-, and NK-cell transcriptional patterns that are both time- and clinical trajectory-dependent. These transcriptomic and pathway differences in sepsis patients that develop CCI are associated with exhaustion in CD8+ TEM cells and NK cells. Understanding the specific immune system patterns of different cell subsets after sepsis at a molecular level will be key to the development of personalized immunotherapy and drug-targeting intervention.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT02276417.

Summary: Background: The incidence of nosocomial meningitis, and utility of lumbar puncture, is unclear in hospitalized patients without preceding neurosurgery or head trauma. Aim: We planned for a systematic review and meta-analysis to evaluate accuracy of clinical features and diagnostic utility of lumbar puncture in nosocomial meningitis. Methods: We searched MEDLINE, MEDLINE In-Process/ePubs, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science from inception until June 5, 2024. We included studies evaluating utility of clinical features, or lumbar puncture, to rule out nosocomial meningitis in patients without preceding neurosurgery or head trauma. We excluded studies examining community acquired meningitis, outbreaks, HIV positive individuals, and case reports. Outcomes included incidence, risk factors and diagnostic accuracy of clinical features for nosocomial meningitis, and lumbar puncture complications. Given few included studies and heterogeneity, we could only summarize incidence of nosocomial meningitis. Findings: Of 13,302 citations, we reviewed 197 manuscripts and included 6. There were 23 of 333 (6.9%, very low certainty) positive lumbar punctures among individuals who underwent lumbar puncture to rule out nosocomial meningitis. Conclusions: There were insufficient data to evaluate the diagnostic accuracy of lumbar puncture in nosocomial meningitis in patients without preceding neurosurgery or head trauma. Very low certainty evidence indicates the incidence of nosocomial meningitis is low in this population. Given complications and costs associated with lumbar puncture, future studies should evaluate its utility in nosocomial meningitis. In the meantime, it may be reasonable to reserve lumbar puncture to instances of high suspicion.

Introduction There is growing interest in using electronic health records (EHRs) for chronic disease surveillance. However, these data are convenience samples of in-care individuals, which are not representative of target populations for public health surveillance, generally defined, for the relevant period, as resident populations within city, state or other jurisdictions. We focus on using EHR data for the estimation of diabetes prevalence among young adults in New York City, as the rising diabetes burden in younger ages calls for better surveillance capacity.Methods This article applies common non-probability sampling methods, including raking, post-stratification and multilevel regression with post-stratification, to real and simulated data for the cross-sectional estimation of diabetes prevalence among those aged 18–44 years. Within real data analyses, we externally validate city-level and neighbourhood-level EHR-based estimates to gold-standard estimates from a local health survey. Within data simulations, we probe the extent to which residual biases remain when selection into the EHR sample is non-ignorable.Results Within the real data analyses, these methods reduced the impact of selection biases in the citywide prevalence estimate compared with the gold standard. Residual biases remained at the neighbourhood-level, where prevalence tended to be overestimated, especially in neighbourhoods where a higher proportion of residents were captured in the sample. Simulation results demonstrated these methods may be sufficient, except when selection into the EHR is non-ignorable, depending on unmeasured factors or on diabetes status.Conclusions While EHRs offer the potential to innovate on chronic disease surveillance, care is needed when estimating prevalence for small geographies or when selection is non-ignorable.

Abstract BackgroundParticipatory surveillance involves at-risk populations reporting their symptoms using technology. In Lesotho, a landlocked country of 2 million people in Southern Africa, laboratory and case-based COVID-19 surveillance systems were complemented by a participatory surveillance system called “LeCellPHIA” (Lesotho Cell Phone Population-Based HIV Impact Assessment Survey). ObjectiveThis report describes the person, place, and time characteristics of influenza-like illness (ILI) in Lesotho from July 15, 2020, to July 15, 2021, and reports the risk ratio of ILI by key demographic variables. MethodsLeCellPHIA employed interviewers to call participants weekly to inquire about ILI. The average weekly incidence rate for the year-long period was created using a Quasi-Poisson model, which accounted for overdispersion. To identify factors associated with an increased risk of ILI, we conducted a weekly data analysis by fitting a multilevel Poisson regression model, which accounted for 3 levels of clustering. ResultsThe overall response rate for the year of data collection was 75%, which resulted in 122,985 weekly reports from 1776 participants. ILI trends from LeCellPHIA mirrored COVID-19 testing data trends, with an epidemic peak in mid to late January 2021. Overall, any ILI symptoms (eg, fever, dry cough, and shortness of breath) were reported at an average weekly rate of 879 per 100,000 (95% CI 782‐988) persons at risk. Compared to persons in the youngest age group (15‐19 years), all older age groups had an elevated risk of ILI, with the highest risk of ILI in the oldest age group (≥60 years; risk ratio 2.6, 95% CI 1.7‐3.8). Weekly data were shared in near real time with the National COVID-19 Secretariat and other stakeholders to monitor ILI trends, identify and respond to increases in reports of ILI, and inform policies and practices designed to reduce COVID-19 transmission in Lesotho. ConclusionsLeCellPHIA, an innovative and cost-effective system, could be replicated in countries where cell phone ownership is high but internet use is not yet high enough for a web- or app-based surveilance system.

Abstract BackgroundElectronic health records (EHRs) are increasingly used for epidemiologic research to advance public health practice. However, key variables are susceptible to missing data or misclassification within EHRs, including demographic information or disease status, which could affect the estimation of disease prevalence or risk factor associations. ObjectiveIn this paper, we applied methods from the literature on missing data and causal inference to assess whether we could mitigate information biases when estimating measures of association between potential risk factors and diabetes among a patient population of New York City young adults. MethodsWe estimated the odds ratio (OR) for diabetes by race or ethnicity and asthma status using EHR data from NYU Langone Health. Methods from the missing data and causal inference literature were then applied to assess the ability to control for misclassification of health outcomes in the EHR data. We compared EHR-based associations with associations observed from 2 national health surveys, the Behavioral Risk Factor Surveillance System (BRFSS) and the National Health and Nutrition Examination Survey, representing traditional public health surveillance systems. ResultsObserved EHR-based associations between race or ethnicity and diabetes were comparable to health survey-based estimates, but the association between asthma and diabetes was significantly overestimated (OREHRBRFSSMissingDataCausal ConclusionsFindings suggest that without bias adjustment, EHR analyses may yield biased measures of association, driven in part by subgroup differences in health care use. However, applying missing data or causal inference frameworks can help control for and, importantly, characterize residual information biases in these estimates.

Abstract Periodontitis affects billions of people worldwide. To address relationships of periodontal niche cell types and microbes in periodontitis, we generated an integrated single-cell RNA sequencing (scRNAseq) atlas of human periodontium (34-sample, 105918-cell), including sulcular and junctional keratinocytes (SK/JKs). SK/JKs displayed altered differentiation states and were enriched for effector cytokines in periodontitis. Single-cell metagenomics revealed 37 bacterial species with cell-specific tropism. Fluorescence in situ hybridization detected intracellular 16 S and mRNA signals of multiple species and correlated with SK/JK proinflammatory phenotypes in situ. Cell-cell communication analysis predicted keratinocyte-specific innate and adaptive immune interactions. Highly multiplexed immunofluorescence (33-antibody) revealed peri-epithelial immune foci, with innate cells often spatially constrained around JKs. Spatial phenotyping revealed immunosuppressed JK-microniches and SK-localized tertiary lymphoid structures in periodontitis. Here, we demonstrate impacts on and predicted interactomics of SK and JK cells in health and periodontitis, which requires further investigation to support precision periodontal interventions in states of chronic inflammation.

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the top infectious killers in the world. The only licensed vaccine against TB, Bacille Calmette-Guérin (BCG), provides variable protection against pulmonary TB, especially in adults. Hence, novel TB vaccine approaches are urgently needed. Both Th1 and Th17 responses are necessary for protection against TB, yet effective adjuvants and vaccine delivery systems for inducing robust Th1 and Th17 immunity are lacking. Herein we describe a synthetic Mincle agonist, UM-1098, and a silica nanoparticle delivery system that drives Th1/Th17 responses to Mtb antigens. Stimulation of human peripheral blood mononuclear cells (hPBMCs) with UM-1098 induced high levels of Th17 polarizing cytokines IL-6, IL-1β, IL-23 as well as IL-12p70, IL-4 and TNF-α in vitro. PBMCs from both C57BL/6 and BALB/c mice responded with a similar cytokine pattern in vitro and in vivo. Importantly, intramuscular (I.M.) vaccination with UM-1098-adjuvanted TB antigen M72 resulted in significantly higher antigen-specific IFN-γ and IL-17A levels in C57BL/6 wt mice than Mincle KO mice. Vaccination of C57BL/6 wt mice with immunodominant Mtb antigens ESAT6/Ag85B or M72 resulted in predominantly Th1 and Th17 responses and induced antigen-specific serum antibodies. Notably, in a virulent Mtb challenge model, vaccination with UM-1098 adjuvanted ESAT6/Ag85B or M72 significantly reduced lung bacterial burden when compared with unvaccinated mice and protection occurred in the absence of pulmonary inflammation. These data demonstrate that the synthetic Mincle agonist UM-1098 induces strong Th1 and Th17 immunity after vaccination with Mtb antigens and provides protection against Mtb infection in mice.

Abstract Bioadhesive materials and patches are promising alternatives to surgical sutures and staples. However, many existing bioadhesives do not meet the functional requirements of current surgical procedures and interventions. Here, we present a translational patch material that exhibits instant adhesion to tissues (2.5-fold stronger than Tisseel, an FDA-approved fibrin glue), ultra-stretchability (stretching to >300% its original length without losing elasticity), compatibility with rapid photo-projection (

Abstract Empirically supported treatments for posttraumatic stress disorder (PTSD) exist, but research suggests these therapies are less effective, acceptable, and feasible to deliver to active duty service members (SMs) compared to civilians. Stellate ganglion block (SGB) procedure, in which a local anesthetic is injected around the cervical sympathetic chain or stellate ganglion to temporarily inhibit sympathetic nervous activity, is gaining popularity as an alternative PTSD treatment in military settings. However, it is unknown whether certain PTSD symptoms are more responsive to SGB than others. The current study involved a secondary analysis of data collected from a previous randomized controlled trial of SGB compared to sham (normal saline) injection (N = 113 SMs). PTSD symptoms were assessed via clinical interview and self-report at baseline and 8 weeks post-SGB or sham. Logistic regression analyses showed that the marked alterations in arousal and reactivity PTSD symptom cluster demonstrated the greatest symptom severity reductions after SGB, relative to sham. The reexperiencing cluster also showed pronounced response to SGB in clinician-rated but not self-reported outcomes. Post-hoc item-level analyses suggested that arousal and reactivity cluster findings were driven by reductions in hypervigilance, concentration difficulties, and sleep disturbance, whereas clinician-rated reexperiencing cluster findings were driven by reductions in physiological reactions to trauma cues, emotional reactions to trauma cues, and intrusions. Our findings align with a burgeoning literature positioning SGB as a potential novel or adjunctive PTSD treatment. Results could guide future hypothesis-driven research on mediators of therapeutic change during SGB for PTSD symptoms in SMs.

Abstract Background Use of participatory research methods is increasing in research trials. Once partnerships are established with end-users, there is less guidance about processes research teams can use to successfully incorporate end-user feedback. The current study describes the use of a brief reflections process to systematically examine and evaluate the impact of end-user feedback on study conduct. Methods The Comparative Effectiveness of Trauma-Focused and Non-Trauma- Focused Treatment Strategies for PTSD among those with Co-Occurring SUD (COMPASS) study was a randomized controlled trial to determine the effectiveness of trauma-focused psychotherapy versus non-trauma-focused psychotherapy for Veterans with co-occurring posttraumatic stress disorder and substance use disorder who were entering substance use treatment within the Department of Veterans Affairs. We developed and paired a process of “brief reflections” with our end-user engagement methods as part of a supplemental evaluation of the COMPASS study engagement plan. Brief reflections were 30-minute semi-structured discussions with the COMPASS Team following meetings with three study engagement panels about feedback received regarding study issues. To evaluate the impact of panel feedback, 16 reflections were audio-recorded, transcribed, rapidly analyzed, and integrated with other study data sources. Results Brief reflections revealed that the engagement panels made recommended changes in eight areas: enhancing recruitment; study assessment completion; creating uniformity across Study Coordinators; building Study Coordinator connection to Veteran participants; mismatch between study procedures and clinical practice; therapist skill with patients with active substance use; therapist burnout; and dissemination of study findings. Some recommendations positively impact study conduct while others had mixed impact. Reflections were iterative and led to emergent processes that included revisiting previously discussed topics, cross-pollination of ideas across panels, and sparking solutions amongst the Team when the panels did not make any recommendations or recommendations were not feasible. Conclusions When paired with end-user engagement methods, brief reflections can facilitate systematic examination of end-user input, particularly when the engagement strategy is robust. Reflections offer a forum of accountability for researchers to give careful thought to end-user recommendations and make timely improvements to the study conduct. Reflections can also facilitate evaluation of these recommendations and reveal end-user-driven strategies that can effectively improve study conduct. Trial registration ClinicalTrials.gov (NCT04581434) on October 9, 2020; https://clinicaltrials.gov/ct2/show/study/NCT04581434?term=NCT04581434&draw=2&rank=1 .

Abstract Background Despite decades of anti-racism and equity, diversity, and inclusion (EDI) interventions in academic medicine, medical racism continues to harm patients and healthcare providers. We sought to deeply explore experiences and beliefs about medical racism among academic clinicians to understand the drivers of persistent medical racism and to inform intervention design. Methods We interviewed academically-affiliated clinicians with any racial identity from the Departments of Family Medicine, Cardiac Sciences, Emergency Medicine, and Medicine to understand their experiences and perceptions of medical racism. We performed thematic content analysis of semi-structured interview data to understand the barriers and facilitators of ongoing medical racism. Based on participant narratives, we developed a logic framework that demonstrates the necessary steps in the process of addressing racism using if/then logic. This framework was then applied to all narratives and the barriers to addressing medical racism were aligned with each step in the logic framework. Proposed interventions, as suggested by participants or study team members and/or identified in the literature, were matched to these identified barriers to addressing racism. Results Participant narratives of their experiences of medical racism demonstrated multiple barriers to addressing racism, such as a perceived lack of empathy from white colleagues. Few potential facilitators to addressing racism were also identified, including shared language to understand racism. The logic framework suggested that addressing racism requires individuals to understand, recognize, name, and confront medical racism. Conclusions Organizations can use this logic framework to understand their local context and select targeted anti-racism or EDI interventions. Theory-informed approaches to medical racism may be more effective than interventions that do not address local barriers or facilitators for persistent medical racism.

Purpose/objectives: The indications, techniques, and extent to which proton beam therapy (PBT) is employed for breast cancer are unknown. We seek to determine PBT utilization for breast cancer. Materials/methods: The Particle Therapy Co-Operative Group (PTCOG) Breast Subcommittee developed an IRB-approved 29-question survey and sent it to breast cancer radiation oncologists at all active PBT centers worldwide in June 2023. Descriptive statistics were used to summarize responses, and comparisons by continent were performed using Fisher’s exact tests. Results: Of 79 surveys distributed, 28 recipients submitted responses (35 % response rate) representing fifteen U.S., 8 European, and 5 Asian centers (continent response rate 50 %, 38 %, and 18 %, respectively). Overall, 93 % reported treating breast cancer patients with PBT; 13 (50 %) have treated ≥100 breast cancer patients at their center since opening. Most (89 %) have pencil beam scanning technology. Nearly half (46 %) use moderate hypofractionation (15–20 fractions) for regional nodal irradiation and 42 % conventional fractionation (25–30 fractions). More European centers prefer hypofractionation (88 %) vs. Asian (50 %) and U.S. (21 %) centers (p = 0.003). Common patient selection methods were practitioner determination/patient preference (n = 16) and comparative plan evaluation (n = 15). U.S. centers reported the most experience with breast PBT, with 71 % having treated ≥100 breast cancer patients vs. 38 % in Europe and none in Asia (p = 0.001). Of respondent centers, 39 % enrolled ≥75 % of breast PBT patients on a research study. Conclusion: Utilization, patient selection methods, and dose-fractionation approaches for breast cancer PBT vary worldwide. These survey data serve as a benchmark from which successor surveys can provide insight on practice pattern evolution.

Dietary modifications such as caloric restriction (CR) and intermittent fasting (IF) have gained popularity due to their proven health benefits in aged populations. In time restricted feeding (TRF), a form of intermittent fasting, the amount of time for food intake is regulated without restricting the caloric intake. TRF is beneficial for the central nervous system to support brain health in the context of aging. Therefore, we here ask whether TRF also exerts beneficial effects in the aged retina. We compared aged mice (24 months) on a TRF paradigm (access to food for six hours per day) for either 6 or 12 months against young control mice (8 months) and aged control mice on an ad libitum diet. We examined changes in the retina at the functional (electroretinography), structural (histology and fluorescein angiograms) and molecular (gene expression) level. TRF treatment showed amelioration of age-related reductions in both scotopic and photopic b-wave amplitudes suggesting benefits for retinal interneuron signaling. TRF did not affect age-related signs of retinal inflammation or microglial activation at either the molecular or histological level. Our data indicate that TRF helps preserve some aspects of retinal function that are decreased with aging, adding to our understanding of the health benefits that altered feeding patterns may confer.

The motoric cognitive risk syndrome (MCR) is a syndrome characterized by subjective memory complaints and slow walking speeds that can identify older adults at increased risk for developing Alzheimer’s disease or a related dementia (ADRD). To date, the feasibility of community-based physical activity (PA) programs for improving outcomes in MCR have yet to be examined. To address this knowledge gap, we conducted a translational randomized controlled trial (RCT) comparing 24-weeks of PA to a healthy aging education (HE) control intervention delivered within the infrastructure of an urban senior center in Greater Boston (clincaltrials.gov identifier: NCT03750682). An existing senior center employee was trained to administer the multimodal group-based PA program that included moderate-intensity aerobic walking, strength, flexibility and balance training. A total of 79 older adults attended the senior center for a screening visit, of whom 29 met the MCR criteria and 25 were randomized to PA or HE (mean age: 74.4 ± 7 years; BMI: 32.4 ± 7 kg/m2; 85% female; 3MSE score: 92.4 ± 7; gait speed: 0.52 ± 0.1 m/s; SPPB score 4.8 ± 1.9). Due to the Covid-19 pandemic the study was stopped prematurely. Participants could successfully adhere to the study interventions (overall attendance rate: PA: 69% vs. HE:70% at study termination). Participants also successfully completed baseline and follow-up study assessments that included a computerized cognitive testing battery and objective tests of physical performance and functional exercise capacity. No study-related adverse events occurred. Notable trends for improved cognitive performance, gait speed and 6-min walk distance were exhibited in PA compared to HE. Our study provides important preliminary information to aid the design of larger-scale RCTs of PA that may help to preserve the independence of vulnerable older adults at high risk for ADRD in community-based settings.

Abstract Children with pulmonary hypertension (PH) often demonstrate limited exercise capacity. Data support exercise as an effective nonpharmacologic intervention among adults with PH. However, data on exercise training in children and adolescents are limited, and characteristics of the optimal exercise program in pediatric PH have not been identified. Exercise programs may have multiple targets, including muscle deficits which are associated with exercise limitations in both adult and pediatric PH. Wearable accelerometer sensors measure physical activity volume and intensity in the naturalistic setting and can facilitate near continuous data transfer and bidirectional communication between patients and the study team when paired with informatics tools during exercise interventions. To address the knowledge gaps in exercise training in pediatric PH, we designed a prospective, single arm, nonrandomized pilot study to determine feasibility and preliminary estimates of efficacy of a 16‐week home exercise intervention, targeting lower extremity muscle mass and enriched by wearable mobile health technology. The exercIse Training in pulmONary hypertEnsion (iTONE) trial includes (1) semistructured exercise prescriptions tailored to the participant's baseline level of activity and access to resources; (2) interval goal setting fostering self‐efficacy; (3) real time monitoring of activity via wearable devices; (4) a digital platform enabling communication and feedback between participant and study team; (5) multiple avenues to assess participant safety. This pilot intervention will provide information on the digital infrastructure needed to conduct home‐based exercise interventions in PH and will generate important preliminary data on the effect of exercise interventions in youth with chronic cardiorespiratory conditions to power larger studies in the future.

IntroductionAtopic diseases have been steadily increasing over the past decades and effective disease-modifying treatment options are urgently needed. These studies introduce a novel synthetic Toll-like receptor 4 (TLR4) agonist, INI-2004, with remarkable efficacy as a therapeutic intranasal treatment for seasonal allergic rhinitis.MethodsUsing a murine airway allergic sensitization model, the impact of INI-2004 on allergic responses was assessed.ResultsOne or two intranasal doses of INI-2004 significantly reduced airway resistance, eosinophil influx, and Th2 cytokine production – providing strong evidence of allergic desensitization. Further investigations revealed that a liposomal formulation of INI-2004 exhibited better safety and efficacy profiles compared to aqueous formulations. Importantly, the liposomal formulation demonstrated a 1000-fold increase in the maximum tolerated intravenous dose in pigs. Pre-clinical GLP toxicology studies in rats and pigs confirmed the safety of liposomal INI-2004, supporting its selection for human clinical trials.DiscussionThese findings lay the groundwork for the ongoing clinical evaluation of INI-2004 in allergic rhinitis as a stand-alone therapy for individuals poly-sensitized to multiple seasonal allergens. The study underscores the significance of innovative immunotherapy approaches in reshaping the landscape of allergic rhinitis management.

IntroductionRecent minimum population estimates are critical for effective marine mammal conservation, yet such estimates are often lacking at the stock or management level. Throughout the Main Hawaiian Islands, pantropical spotted dolphins (PSD; Stenella attenuata attenuata) are comprised of a pelagic and three island-associated stocks (O‘ahu, 4-Islands, and Hawai‘i Island). The insular stocks, in particular, face multiple anthropogenic and natural threats such as vessel impacts, fisheries interactions, marine debris, climate change, and disease. Prior to this study, no abundance estimates of the 4-Islands (i.e., the Maui Nui region) PSD stock existed that were suitable for management use and inclusion in stock assessment report calculations.MethodsWe generated annual mark-recapture abundance estimates of naturally marked adults in a POPAN-framework using photo-identification data collected from small-boat surveys during 2014–2022 in the Maui Nui region. We extrapolated these estimates to the wider population using dorsal fin mark rates.Results and discussionWe collected data on 62 groups of PSD, throughout all months of the year, and with an average group size of 55.70 (SD = 17.31). We analyzed encounter histories of 174 distinct individuals. Annual recapture rate averaged 1.84 (SD = 1.32) with a maximum of 7. Individuals detected per year averaged 35.67 (SD = 21.16) with a maximum of 77 in 2017. Overall mark rate was 0.495 (SE = 0.010), resulting in total annual abundance estimates that averaged 154.87 (SE = 14.25) and ranged from 105 (SE = 13) in 2014 to 232 (SE = 31) in 2017. Although abundance estimates fluctuated, generally 250 animals or less used the study area each year and we found no overall evidence of a trend. Our benchmark results revealed a small population in need of monitoring given the numerous threats facing this stock, the uncertainty of their impacts, and the decreased resiliency and recovery potential of small populations to negative demographic and environmental stochastic events. Our findings, including documenting long-term site fidelity and year-round presence of PSD in Maui Nui, further signify this area as one of future research and conservation importance.

Background The epidemiology and pathophysiology of heart failure (HF) differ in women and men. Whether these differences extend to the subgroup of patients with advanced HF is not well defined. Methods and Results This is a retrospective cohort study of all adult Olmsted County, Minnesota residents with advanced HF (European Society of Cardiology criteria) from 2007 to 2017. Differences in survival and hospitalization risks in women and men following advanced HF development were examined using Cox proportional hazard regression and Andersen‐Gill models, respectively. Of 936 individuals with advanced HF, 417 (44.6%) were women and 519 (55.4%) were men (self‐reported sex). Time from development of HF to advanced HF was similar in women and men (median 3.2 versus 3.6 years). Women were older at diagnosis (mean age 79 versus 75 years), less often had coronary disease and hyperlipidemia, but more often had hypertension and depression (P

OBJECTIVES:. Although clinicians may use methylene blue (MB) in refractory septic shock, the effect of MB on patient-important outcomes remains uncertain. We conducted a systematic review and meta-analysis to investigate the benefits and harms of MB administration in patients with septic shock. DATA SOURCES:. We searched six databases (including PubMed, Embase, and Medline) from inception to January 10, 2024. STUDY SELECTION:. We included randomized clinical trials (RCTs) of critically ill adults comparing MB with placebo or usual care without MB administration. DATA EXTRACTION:. Two reviewers performed screening, full-text review, and data extraction. We pooled data using a random-effects model, assessed the risk of bias using the modified Cochrane tool, and used Grading of Recommendations Assessment, Development, and Evaluation to rate certainty of effect estimates. DATA SYNTHESIS:. We included six RCTs (302 patients). Compared with placebo or no MB administration, MB may reduce short-term mortality (RR [risk ratio] 0.66 [95% CI, 0.47–0.94], low certainty) and hospital length of stay (mean difference [MD] –2.1 d [95% CI, –1.4 to –2.8], low certainty). MB may also reduce duration of vasopressors (MD –31.1 hr [95% CI, –16.5 to –45.6], low certainty), and increase mean arterial pressure at 6 hours (MD 10.2 mm Hg [95% CI, 6.1–14.2], low certainty) compared with no MB administration. The effect of MB on serum methemoglobin concentration was uncertain (MD 0.9% [95% CI, –0.2% to 2.0%], very low certainty). We did not find any differences in adverse events. CONCLUSIONS:. Among critically ill adults with septic shock, based on low-certainty evidence, MB may reduce short-term mortality, duration of vasopressors, and hospital length of stay, with no evidence of increased adverse events. Rigorous randomized trials evaluating the efficacy of MB in septic shock are needed. REGISTRATION:. Center for Open Science (https://osf.io/hpy4j).

Abstract Spatial ability is defined as a cognitive or intellectual skill used to represent, transform, generate, and recall information of an object or the environment. Individual differences across spatial tasks have been strongly linked to science, technology, engineering, and mathematics (STEM) interest and success. Several variables have been proposed to explain individual differences in spatial ability, including affective factors such as one’s confidence and anxiety. However, research is lacking on whether affective variables such as confidence and anxiety relate to individual differences in both a mental rotation task (MRT) and a perspective-taking and spatial orientation task (PTSOT). Using a sample of 100 college students completing introductory STEM courses, the present study investigated the effects of self-reported spatial confidence, spatial anxiety, and general anxiety on MRT and PTSOT. Spatial confidence, after controlling for effects of general anxiety and biological sex, was significantly related to performance on both the MRT and PTSOT. Spatial anxiety, after controlling for effects of general anxiety and biological sex, was not related to either PTSOT or MRT scores. Together these findings suggest some affective factors, but not others, contribute to spatial ability performance to a degree that merits advanced investigation in future studies.

The 2020 moment magnitude (Mw) 6.5 Stanley, Idaho, earthquake raised questions about the history and extent of complex faulting in the northwestern Centennial Tectonic Belt (CTB) and its relation to the Sawtooth normal fault and Eocene Trans-Challis fault system (TCFS). To explore faulting in this area, we excavated a paleoseismic trench across the Sawtooth fault along the western margin of the CTB, and compared an early Holocene (9.1 ± 2.1 ka, 1σ) rupture at the site with lacustrine paleoseismic data and fault mapping in the 2020 epicentral region. We find: (1) a history of partial to full rupture of the Sawtooth fault (Mw 6.8–7.4), (2) that shorter ruptures (Mw≤6.9) are likely along distributed and discontinuous faults in the epicentral region, (3) that this complex system that hosted the 2020 earthquake is not directly linked to the Sawtooth fault, (4) that the northeast-trending TCFS likely plays a role in controlling fault length and rupture continuity for adjacent faults, and (5) that parts of the TCFS may facilitate displacement transfer between normal faults that accommodate crustal extension and rotation. Our results help unravel complex faulting in the CTB and imply that relict structures can help inform regional seismic hazard assessments.

Abstract Background Although mammography can significantly reduce breast cancer mortality, many women do not receive their annual breast cancer screening. Differences in screening adherence exist by race/ethnicity, socioeconomic status (SES), and insurance status. However, more detailed investigations into the impact of neighborhood disadvantage and access to resources on screening adherence are lacking. Methods We comprehensively examined the effect of individual social, economic, and demographic factors (n = 34 variables), as well as neighborhood level SES (nSES) indicators (n = 10 variables) on breast cancer screening adherence across a multi-ethnic population (n = 472). In this cross-sectional study, participants were surveyed from 2017 to 2018. The data was analyzed using univariate regression and LASSO for variable reduction. Significant predictors were carried forward into final multivariable mixed-effect logistic regression models where odds ratios (OR), 95% confidence intervals and p-values were reported. Results Nineteen percent of participants were non-adherent to breast screening guidelines. Race/ethnicity was not associated with adherence; however, increasing age (OR = 0.97, 95%CI = 0.95–0.99, p = 0.01), renting a home (OR = 0.53, 95%CI = 0.30–0.94, p = 0.04), food insecurity (OR 0.46, 95%CI = 0.22–0.94, p = 0.01), and overcrowding (OR = 0.58, 95% CI = 0.32–0.94, p = 0.01) were significantly associated with lower breast cancer screening adherence. Conclusion Socioeconomic indicators at the individual and neighborhood levels impact low breast cancer screening adherence and may help to inform future screening interventions.

Abstract Climate change has led to an alarming increase in the frequency and severity of wildfires worldwide. While it is known that amphibians have physiological characteristics that make them highly susceptible to fire, the specific impacts of wildfires on their symbiotic skin bacterial communities (i.e., bacteriomes) and infection by the deadly chytrid fungus, Batrachochytrium dendrobatidis, remain poorly understood. Here, we address this research gap by evaluating the effects of fire on the amphibian skin bacteriome and the subsequent risk of chytridiomycosis. We sampled the skin bacteriome of the Neotropical species Scinax squalirostris and Boana leptolineata in fire and control plots before and after experimental burnings. Fire was linked with a marked increase in bacteriome beta dispersion, a proxy for skin microbial dysbiosis, alongside a trend of increased pathogen loads. By shedding light on the effects of fire on amphibian skin bacteriomes, this study contributes to our broader understanding of the impacts of wildfires on vulnerable vertebrate species.

Harmful algal blooms (HABs) are a reoccurring threat to subsistence and recreational shellfish harvest in Southeast Alaska. Recent Tribally led monitoring programs have enhanced understanding of the environmental drivers and toxicokinetics of shellfish toxins in the region; however, there is considerable variability in shellfish toxins in some species, which cannot be easily explained by seasonal bloom dynamics. Persistent concentrations of paralytic shellfish toxins (PSTs) in homogenized butter clam samples (n > 6, Saxidomus gigantea) have been observed in several communities, and relatively large spikes in concentrations are sometimes seen without Alexandrium observations or increased toxin concentrations in other species. In order to investigate potential sources of variability in PST concentrations from this subsistence species, we assessed individual concentrations of PSTs across a size gradient of butter clams during a period of relatively stable PST concentrations. We found that increasing concentrations of PSTs were significantly associated with larger clams using a log-linear model. We then simulated six clams randomly sampled from three size distributions, and we determined large clams had an outsized probability of contributing a significant proportion of the total toxicity in a six-clam homogenized sample. While our results were obtained during a period of low HAB activity and cannot be extrapolated to periods of intoxication or rapid detoxification, they have significant ramifications for both monitoring programs as well as subsistence and recreational harvesters.

Inherited retinal degeneration (IRD) can cause a wide range of different forms of vision loss and blindness, and in spite of extensive advancements in gene therapy research, therapeutic approaches for targeting IRDs are still lacking. We have recently developed an approach for the intravitreal co-delivery of hyaluronic-acid nanospheres (HA-NSs) with sulfotyrosine (ST), effectively reaching the outer retina from the vitreal cavity. Here, our goal was to understand whether DNA-filled HA-NSs could generate gene expression in the outer retina. TxRed-labeled HA-NSs were compacted with plasmid DNA carrying a GFP reporter gene and intravitreally injected into the mouse retina. Follow-up at 4 weeks showed widespread gene expression in the outer retina and reduced, albeit present, expression at 8 weeks post-injection. Further analysis revealed this expression to be largely localized to the retinal pigment epithelium (RPE). These data show that intravitreal delivery of HA-NSs is a promising non-viral platform for the delivery of therapeutic genes and can generate pan-tissue, persistent gene expression in the RPE.

Background:. Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by deep-seated, painful lesions most frequently occurring in intertriginous areas of the skin. HS leads to poor quality of life in affected individuals and is difficult to diagnose and treat. Objective:. Understanding the genetics associated with familial inheritance may lead to a better understanding of the pathogenesis of this debilitating disease. Methods:. Articles published until March 9, 2023, were identified in PubMed using the following search terms: hidradenitis suppurativa and gene* or acne inversa and gene*. Results:. The rate of monogenic mutations associated with HS is less than 7%, with the most common genetic mutations reported in sporadic and familial HS cases being in NCSTN and less frequently in PSENEN. Individuals with mutations in the gamma-secretase complex tended to have more severe HS and an early age of onset. Limitations:. This study was limited to the case studies available in PubMed, the majority of which used targeted gene panels to detect genetic mutations. Conclusion:. Approximately 30% of individuals diagnosed with HS report having a positive family history; however, very few studies demonstrate monogenic familial transmission of HS. The case studies of syndromic HS reported a variety of genetic mutations associated with HS, some of which were familial, while others were sporadic, suggesting that other pathways may be involved in the pathogenesis of HS and other potential mutations that have yet to be evaluated. More research is needed to understand the genetic mutations in HS.

BackgroundChronic stress is an important risk factor in the development of obesity. While research suggests chronic stress is linked to excess weight gain in children, the biological or behavioral mechanisms are poorly understood. ObjectiveThe objectives of the Family Stress Study are to examine behavioral and biological pathways through which chronic stress exposure (including stress from COVID-19) may be associated with adiposity in young children, and to determine if factors such as child sex, caregiver-child relationship quality, caregiver education, and caregiver self-regulation moderate the association between chronic stress and child adiposity. MethodsThe Family Stress Study is a prospective cohort study of families recruited from 2 Canadian sites: the University of Guelph in Guelph, Ontario, and McMaster University in Hamilton, Ontario. Participants will be observed for 2 years and were eligible to participate if they had at least one child (aged 2-6 years) and no plans to move from the area within the next 3 years. Study questionnaires and measures were completed remotely at baseline and will be assessed using the same methods at 1- and 2-year follow-ups. At each time point, caregivers measure and report their child’s height, weight, and waist circumference, collect a hair sample for cortisol analysis, and fit their child with an activity monitor to assess the child’s physical activity and sleep. Caregivers also complete a web-based health and behaviors survey with questions about family demographics, family stress, their own weight-related behaviors, and their child’s mental health, as well as a 1-day dietary assessment for their child. ResultsEnrollment for this study was completed in December 2021. The final second-year follow-up was completed in April 2024. This study’s sample includes 359 families (359 children, 359 female caregivers, and 179 male caregivers). The children’s mean (SD) age is 3.9 years (1.2 years) and 51% (n=182) are female. Approximately 74% (n=263) of children and 80% (n=431) of caregivers identify as White. Approximately 34% (n=184) of caregivers have a college diploma or less and nearly 93% (n=499) are married or cohabiting with a partner. Nearly half (n=172, 47%) of the families have an annual household income ≥CAD $100,000 (an average exchange rate of 1 CAD=0.737626 USD applies). Data cleaning and analysis are ongoing as of manuscript publication. ConclusionsDespite public health restrictions from COVID-19, the Family Stress Study was successful in recruiting and using remote data collection to successfully engage families in this study. The results from this study will help identify the direction and relative contributions of the biological and behavioral pathways linking chronic stress and adiposity. These findings will aid in the development of effective interventions designed to modify these pathways and reduce obesity risk in children. Trial RegistrationClinicalTrials.gov NCT05534711; https://clinicaltrials.gov/study/NCT05534711 International Registered Report Identifier (IRRID)DERR1-10.2196/48549

Habitat fragmentation can negatively impact wildlife populations by simplification of ecological interactions, but little is known about how these impacts extend to host-associated symbiotic communities. The symbiotic communities of amphibians play important roles in anti-pathogen defences, particularly against the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd). In this study, we analyse the role of macroparasitic helminth communities in concert with microbial communities in defending the host against Bd infection within the context of forest fragmentation. We found that skin microbial and helminth communities are disrupted at fragmented habitats, while gut microbiomes appear more resilient to environmental change. We also detected potential protective roles of helminth diversity and anti-pathogen microbial function in limiting Bd infection. Microbial network analysis revealed strong patterns of structure in both skin and gut communities, with helminths playing central roles in these networks. We reveal consistent roles of microbial and helminth diversity in driving host–pathogen interactions and the potential implications of fragmentation on host fitness.