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Abstract We extend the results of arXiv:2209.12903 by studying local projective measurements performed on subregions of two copies of a CFT2 in the thermofield double state and investigating their consequences on the bulk double-sided black hole holographic dual. We focus on CFTs defined on an infinite line and consider measurements of both finite and semi-infinite subregions. In the former case, the connectivity of the bulk spacetime is preserved after the measurement. In the latter case, the measurement of two semi-infinite intervals in one CFT or of one semi-infinite interval in each CFT can destroy the Einstein-Rosen bridge and disconnect the bulk dual spacetime. In particular, we find that a transition between a connected and disconnected phase occurs depending on the relative size of the measured and unmeasured subregions and on the specific Cardy state the measured subregions are projected on. We identify this phase transition as an entangled/disentangled phase transition of the dual CFT system by computing the post-measurement holographic entanglement entropy between the two CFTs. We also find that bulk information encoded in one CFT in the absence of measurement can sometimes be reconstructed from the other CFT when a measurement is performed, or can be erased by the measurement. Finally, we show that a purely CFT calculation of the Renyi entropy using the replica trick yields results compatible with those obtained in our bulk analysis.

Abstract Traumatic events that affect physiology and behavior in the current generation may also impact future generations. We demonstrate that an ecologically realistic degree of predation risk prior to conception causes lasting changes in the first filial (F1) and second filial (F2) generations. We exposed male and female mice to a live rat (predator stress) or control (non-predator) condition for 5 min. Ten days later, stressed males and females were bred together as were control males and females. Adult F1 offspring from preconception-stressed parents responded to a mild stressor with more anxiety-like behavior and hyperarousal than offspring from control parents. Exposing these F1 offspring to the mild stressor increased neuronal activity (cFOS) in the hippocampus and altered glucocorticoid system function peripherally (plasma corticosterone levels). Even without the mild stressor, F1 offspring from preconception-stressed parents still exhibited more anxiety-like behaviors than controls. Cross-fostering studies confirmed that preconception stress, not maternal social environment, determined offspring behavioral phenotype. The effects of preconception parental stress were also unexpectedly persistent and produced similar behavioral phenotypes in the F2 offspring. Our data illustrate that a surprisingly small amount of preconception predator stress alters the brain, physiology, and behavior of future generations. A better understanding of the ‘long shadow’ cast by fearful events is critical for understanding the adaptive costs and benefits of transgenerational plasticity. It also suggests the intriguing possibility that similar risk-induced changes are the rule rather than the exception in free-living organisms, and that such multigenerational impacts are as ubiquitous as they are cryptic.

Abstract Background Comprehensive Behavioral Intervention for Tics (CBIT) is a first-line treatment for tic disorders that aims to improve controllability over tics that an individual finds distressing or impairing. However, it is only effective for approximately half of patients. Supplementary motor area (SMA)-directed neurocircuitry plays a strong role in motor inhibition, and activity in this region is thought to contribute to tic expression. Targeted modulation of SMA using transcranial magnetic stimulation (TMS) may increase CBIT efficacy by improving patients' ability to implement tic controllability behaviors. Methods The CBIT + TMS trial is a two-phase, milestone-driven early-stage randomized controlled trial. The trial will test whether augmenting CBIT with inhibitory, non-invasive stimulation of SMA with TMS modifies activity in SMA-mediated circuits and enhances tic controllability in youth ages 12–21 years with chronic tics. Phase 1 will directly compare two rTMS augmentation strategies (1 Hz rTMS vs. cTBS) vs. sham in N = 60 participants. Quantifiable, a priori “Go/No Go Criteria” guide the decision to proceed to phase 2 and the selection of the optimal TMS regimen. Phase 2 will compare the optimal regimen vs. sham and test the link between neural target engagement and clinical outcomes in a new sample of N = 60 participants. Discussion This clinical trial is one of few to date testing TMS augmentation of therapy in a pediatric sample. The results will provide insight into whether TMS is a potentially viable strategy for enhancing CBIT efficacy and reveal potential neural and behavioral mechanisms of change. Trial registration ClinicalTrials.gov NCT04578912 . Registered on October 8, 2020.

Abstract A 2-Q antiferromagnetic order of the ferromagnetic dimers was found below T N = 2.9 K in the Shastry-Sutherland lattice BaNd2ZnS5 by single crystal neutron diffraction. The magnetic order can be understood by the orthogonal arrangement of local Ising Nd spins, identified by polarized neutrons. A field was applied along [1 -1 0] to probe the observed metamagnetic transition in the magnetization measurement. The field decouples two magnetic sublattices corresponding to the propagation vectors q 1 = (½, ½, 0) and q 2 = (−½, ½, 0), respectively. Each sublattice shows a “stripe” order with a Néel-type arrangement in each single layer. The “stripe” order with q 1 remains nearly intact up to 6 T, while the other one with q 2 is suppressed at a critical field H c ~1.7 T, indicating a partial disorder. The H c varies with temperature and is manifested in the H-T phase diagram constructed by measuring the magnetization in BaNd2ZnS5.

Abstract Background Effective antiretroviral therapy (ART) in people living with HIV (PLWH) has improved life expectancy and increased risk of age-associated cardiometabolic comorbidities. At-risk alcohol use is more frequent among PLWH and increases the risk of health challenges. PLWH with at-risk alcohol use are more likely to meet criteria for prediabetes/diabetes and this is associated with impaired whole-body glucose-insulin dynamics. Methods The Alcohol & Metabolic Comorbidities in PLWH: Evidence Driven Interventions Study (ALIVE-Ex Study, NCT03299205) is a longitudinal, prospective, interventional study to determine the effects of an aerobic exercise protocol on improving dysglycemia among PLWH with at-risk alcohol use. The intervention is a moderate intensity aerobic exercise protocol implemented 3 days per week for 10 weeks at the Louisiana State University Health Sciences Center-New Orleans. Participants who have a fasting blood glucose level between 94 and 125 mg/dl will be enrolled in the study. Oral glucose tolerance tests, fitness assessments, and skeletal muscle biopsies will be performed pre- and post-exercise intervention. The primary outcome is to determine whether the exercise protocol improves measures of whole-body glucose-insulin dynamics, cardiorespiratory fitness, and skeletal muscle metabolic and bioenergetic function. Secondary outcomes are to determine whether the exercise intervention improves cognitive function and overall quality of life. Results generated will demonstrate the effect of exercise on glycemic measures in PLWH with subclinical dysglycemia and at-risk alcohol use. Conclusions The proposed intervention will also have the potential to be scalable to promote lifestyle changes among PLWH, particularly in underserved communities.

Summary: Coral reefs underpin the environmental, social, and economic fabrics of much of the world's tropical coast. Yet, the fine-scale distribution and composition of coral reefs have never been reported consistently across the planet. Here, we present new area estimates enabled by global geomorphic zone and benthic substrate maps at 5 m pixel resolution. We revise global coral reef estimates to 348,361 km2 of shallow coral reefs and 80,213 km2 (46,237–106,319 km2, 95% confidence interval) of coral habitat. The mapping used more than 1.5 million training samples supported by 480+ data contributions to deploy a coral reef classification of over 100 trillion pixels from the Sentinel-2 satellites and the Planet Dove CubeSat constellation. The publicly available maps are accessible via the Allen Coral Atlas and Google Earth Engine and are already being used by thousands of people to improve the conservation, management, and research of coral reef ecosystems. Science for society: Coral reefs possess a quarter of all marine life and contribute to the well-being and livelihoods of a billion people worldwide. Maps of ecosystems underpin many science and conservation activities, but until recently, there were no consistent high-resolution maps of the world’s coral reefs. In this paper, we describe new global coral reef maps from the Allen Coral Atlas, detailing the underlying methodology and our new understanding of the global distribution of coral reefs. The transparent and repeatable nature of our mapping framework allows the maps to be updated based on user feedback, and the ease of access has led to downstream applications such as coral bleaching monitoring and usage in scientific, management, and conservation activities. Hundreds of thousands of people have already accessed the maps, and they are already being used directly around the world for marine spatial planning, marine protected areas, environmental accounting and assessments, restoration, and education.

Influenza A virus (FLUAV) infects a wide range of hosts and human-to-swine spillover events are frequently reported. However, only a few of these human viruses have become established in pigs and the host barriers and molecular mechanisms driving adaptation to the swine host remain poorly understood. We previously found that infection of pigs with a 2:6 reassortant virus (hVIC/11) containing the hemagglutinin (HA) and neuraminidase (NA) gene segments from the human strain A/Victoria/361/2011 (H3N2) and internal gene segments of an endemic swine strain (sOH/04) resulted in a fixed amino acid substitution in the HA (A138S, mature H3 HA numbering). In silico analysis revealed that S138 became predominant among swine H3N2 virus sequences deposited in public databases, while 138A predominates in human isolates. To understand the role of the HA A138S substitution in the adaptation of a human-origin FLUAV HA to swine, we infected pigs with the hVIC/11A138S mutant and analyzed pathogenesis and transmission compared to hVIC/11 and sOH/04. Our results showed that the hVIC/11A138S virus had an intermediary pathogenesis between hVIC/11 and sOH/04. The hVIC/11A138S infected the upper respiratory tract, right caudal, and both cranial lobes while hVIC/11 was only detected in nose and trachea samples. Viruses induced a distinct expression pattern of various pro-inflammatory cytokines such as IL-8, TNF-α, and IFN-β. Flow cytometric analysis of lung samples revealed a significant reduction of porcine alveolar macrophages (PAMs) in hVIC/11A138S-infected pigs compared to hVIC/11 while a MHCIIlowCD163neg population was increased. The hVIC/11A138S showed a higher affinity for PAMs than hVIC/11, noted as an increase of infected PAMs in bronchoalveolar lavage fluid (BALF), and showed no differences in the percentage of HA-positive PAMs compared to sOH/04. This increased infection of PAMs led to an increase of granulocyte-monocyte colony-stimulating factor (GM-CSF) stimulation but a reduced expression of peroxisome proliferator-activated receptor gamma (PPARγ) in the sOH/04-infected group. Analysis using the PAM cell line 3D4/21 revealed that the A138S substitution improved replication and apoptosis induction in this cell type compared to hVIC/11 but at lower levels than sOH/04. Overall, our study indicates that adaptation of human viruses to the swine host involves an increased affinity for the lower respiratory tract and alveolar macrophages.

Background: Studies have linked autism spectrum disorder (ASD) to physiological abnormalities including mitochondrial dysfunction. Mitochondrial dysfunction may be linked to a subset of children with ASD who have neurodevelopmental regression (NDR). We have developed a cell model of ASD which demonstrates a unique mitochondrial profile with mitochondrial respiration higher than normal and sensitive to physiological stress. We have previously shown similar mitochondrial profiles in individuals with ASD and NDR.Methods: Twenty-six ASD individuals without a history of NDR (ASD-NoNDR) and 15 ASD individuals with a history of NDR (ASD-NDR) were recruited from 34 families. From these families, 30 mothers, 17 fathers and 5 typically developing (TD) siblings participated. Mitochondrial respiration was measured in peripheral blood mononuclear cells (PBMCs) with the Seahorse 96 XF Analyzer. PBMCs were exposed to various levels of physiological stress for 1 h prior to the assay using 2,3-dimethoxy-1,4-napthoquinone.Results: ASD-NDR children were found to have higher respiratory rates with mitochondria that were more sensitive to physiological stress as compared to ASD-NoNDR children, similar to our cellular model of NDR. Differences in mitochondrial respiration between ASD-NDR and TD siblings were similar to the differences between ASD-NDR and ASD-NoNDR children. Interesting, parents of children with ASD and NDR demonstrated patterns of mitochondrial respiration similar to their children such that parents of children with ASD and NDR demonstrated elevated respiratory rates with mitochondria that were more sensitive to physiological stress. In addition, sex differences were seen in ASD children and parents. Age effects in parents suggested that mitochondria of older parents were more sensitive to physiological stress.Conclusion: This study provides further evidence that children with ASD and NDR may have a unique type of mitochondrial physiology that may make them susceptible to physiological stressors. Identifying these children early in life before NDR occurs and providing treatment to protect mitochondrial physiology may protect children from experiencing NDR. The fact that parents also demonstrate mitochondrial respiration patterns similar to their children implies that this unique change in mitochondrial physiology may be a heritable factor (genetic or epigenetic), a result of shared environment, or both.

Improving relative strength is important for maintaining functionality with age, and outdoor exercise structures could be useful to facilitate this. A total of 29 adults aged 65+ participated in a non-randomized crossover study with a 6-week control followed by a 6-week resistance training intervention on an outdoor exercise structure (3x/week). Relative strength (predicted maximal leg press/lower body lean mass [Dual-energy X-ray Absorptiometry]) and physical function variables were measured at baseline, post-control, and post-intervention. Represented as median (25th–75th), lower body relative strength improved from 7.91 (7.01–9.35) post-control to 8.50 (7.99–9.72) post-intervention ( p = .002) in study completers ( n = 17). Maximum leg press ( p = .002), 30-second chair stand ( p < .001), one-leg stance ( p = .011), and maximum chest press ( p = .009) also improved significantly during the intervention. There were no significant changes in aerobic activity, grip strength, lean mass, or muscle power. This study demonstrates that there could be potential relative strength benefits associated with the use of outdoor exercise structures in older adults.

Summary: There is a broad diversity among Cas12a endonucleases that possess nucleic acid detection and gene-editing capabilities, but few are studied extensively. Here, we present an exhaustive investigation of 23 Cas12a orthologs, with a focus on their cis- and trans-cleavage activities in combination with noncanonical crRNAs. Through biochemical assays, we observe that some noncanonical crRNA:Cas12a effector complexes outperform their corresponding wild-type crRNA:Cas12a. Cas12a can recruit crRNA with modifications such as loop extensions and split scaffolds. Moreover, the tolerance of Cas12a to noncanonical crRNA is also observed in mammalian cells through the formation of indels. We apply the adaptability of Cas12a:crRNA complexes to detect SARS-CoV-2 in clinical nasopharyngeal swabs, saliva samples, and tracheal aspirates. Our findings further expand the toolbox for next-generation CRISPR-based diagnostics and gene editing.

ABSTRACT Many temperate phages encode prophage-expressed functions that interfere with superinfection of the host bacterium by external phages. Salmonella phage P22 has four such systems that are expressed from the prophage in a lysogen that are encoded by the c2 (repressor), gtrABC, sieA, and sieB genes. Here we report that the P22-encoded SieA protein is necessary and sufficient for exclusion by the SieA system and that it is an inner membrane protein that blocks DNA injection by P22 and its relatives, but has no effect on infection by other tailed phage types. The P22 virion injects its DNA through the host cell membranes and periplasm via a conduit assembled from three “ejection proteins” after their release from the virion. Phage P22 mutants that overcome the SieA block were isolated, and they have amino acid changes in the C-terminal regions of the gene 16 and 20 encoded ejection proteins. Three different single-amino acid changes in these proteins are required to obtain nearly full resistance to SieA. Hybrid P22 phages that have phage HK620 ejection protein genes are also partially resistant to SieA. There are three sequence types of extant phage-encoded SieA proteins that are less than 30% identical to one another, yet comparison of two of these types found no differences in phage target specificity. Our data strongly suggest a model in which the inner membrane protein SieA interferes with the assembly or function of the periplasmic gp20 and membrane-bound gp16 DNA delivery conduit.IMPORTANCEThe ongoing evolutionary battle between bacteria and the viruses that infect them is a critical feature of bacterial ecology on Earth. Viruses can kill bacteria by infecting them. However, when their chromosomes are integrated into a bacterial genome as a prophage, viruses can also protect the host bacterium by expressing genes whose products defend against infection by other viruses. This defense property is called “superinfection exclusion.” A significant fraction of bacteria harbor prophages that encode such protective systems, and there are many different molecular strategies by which superinfection exclusion is mediated. This report is the first to describe the mechanism by which bacteriophage P22 SieA superinfection exclusion protein protects its host bacterium from infection by other P22-like phages. The P22 prophage-encoded inner membrane SieA protein prevents infection by blocking transport of superinfecting phage DNA across the inner membrane during injection.

IntroductionFluid teams have become increasingly prevalent and necessary for modern-day issues, yet they differ from more traditional teams, on which much of the current teams literature is based. For example, fluid teams are often comprised of members from different disciplines or organizational divisions who do not have a shared history or future, as they come together to perform a critical, time-sensitive task, and then disband. For these reasons, the mechanisms through which they function and perform may differ from those of more traditional teams, and research is needed to better understand these differences.MethodsTo this end, this study utilized critical incident techniques and thematic analysis to examine fluid teams within healthcare, one of the primary contexts in which they are prevalent. Interdisciplinary faculty and students in the medical field who encounter fluid teams within simulation-based education were prompted to reflect on key factors that facilitate or hinder fluid team effectiveness.ResultsPrimary themes extracted pertained to the conditions fluid teams operate within (e.g., high-stress), the behaviors and emergent states that contribute to their success (e.g., communication), and the KSAO’s of value for members of fluid teams to possess (e.g., readiness). These themes were then compared to existing literature, yielding the identification of some similarities but also many important differences between fluid and traditional teams.DiscussionA series of practical recommendations for how to promote fluid team effectiveness is then presented.

Abstract Objectives: We evaluated SARS-CoV-2 anti-nucleocapsid (anti-N) seroconversion and seroreversion rates, risk factors associated with SARS-CoV-2 seroconversion, and COVID-19 risk perceptions among academic healthcare center employees in a rural state. Methods: Among employees aged ≥18 years who completed a screening survey (n = 1,377), we invited all respondents reporting previous COVID-19 (n = 85; 82 accepted) and a random selection of respondents not reporting previous COVID-19 (n = 370; 220 accepted) to participate. Participants completed surveys and provided blood samples at 3-month intervals (T0, T3, T6, T9). We used logistic regression to identify risk factors for seropositivity at T0. Results: The cohort was primarily direct patient caregivers (205/302; 67.9%), white (278/302; 92.1%), and female (212/302; 70.2%). At T0, 86/302 (28.4%) participants were seropositive. Of the seronegative participants, 6/198 (3.0%), 6/183 (3.3%), and 14/180 (7.8%) had seroconverted at T3, T6, and T9, respectively. The overall seroreversion rate was 6.98% at T9. At T0, nursing staff (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.08, 5.19) and being within six feet of a non-household member outside of work (OR, 2.91; 95% CI, 1.02, 8.33) had significantly higher odds of seropositivity. Vaccination (OR, 0.05; 95% CI, 0.02, 0.12) and face mask use (OR, 0.36; 95% CI, 0.17, 0.78) were protective. Conclusions: The seroconversion and seroreversion rates were low among participants. Public health and infection prevention measures implemented early in the COVID-19 pandemic – vaccination, face mask use, and social distancing – were associated with significantly lower odds of SARS-CoV-2 seropositivity among participants.

Heart Failure (HF) continues to be a complex public health issue with increasing world population prevalence. Although overall mortality has decreased for HF and hypertrophic cardiomyopathy (HCM), a precursor for HF, their prevalence continues to increase annually. Because the etiology of HF and HCM is heterogeneous, it has been difficult to identify novel therapies to combat these diseases. Isoproterenol (ISP), a non-selective β-adrenoreceptor agonist, is commonly used to induce cardiotoxicity and cause acute and chronic HCM and HF in mice. However, the variability in dose and duration of ISP treatment used in studies has made it difficult to determine the optimal combination of ISP dose and delivery method to develop a reliable ISP-induced mouse model for disease. Here we examined cardiac effects induced by ISP via subcutaneous (SQ) and SQ-minipump (SMP) infusions across 3 doses (2, 4, and 10mg/kg/day) over 2 weeks to determine whether SQ and SMP ISP delivery induced comparable disease severity in C57BL/6J mice. To assess disease, we measured body and heart weight, surface electrocardiogram (ECG), and echocardiography recordings. We found all 3 ISP doses comparably increase heart weight, but these increases are more pronounced when ISP was administered via SMP. We also found that the combination of ISP treatment and delivery method induces contrasting heart rate, RR interval, and R and S amplitudes that may place SMP treated mice at higher risk for sustained disease burden. Mice treated via SMP also had increased heart wall thickness and LV Mass, but mice treated via SQ showed greater increase in gene markers for hypertrophy and fibrosis. Overall, these data suggest that at 2 weeks, mice treated with 2, 4, or 10mg/kg/day ISP via SQ and SMP routes cause similar pathological heart phenotypes but highlight the importance of drug delivery method to induce differing disease pathways.

Summary: Intrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Here, we describe an in situ resistance assay (ISRA) that reliably models acquired resistance to RTK/RAS-pathway-targeted therapies across cell lines. Using osimertinib resistance in EGFR-mutated lung adenocarcinoma (LUAD) as a model system, we show that acquired osimertinib resistance can be significantly delayed by inhibition of proximal RTK signaling using SHP2 inhibitors. Isolated osimertinib-resistant populations required SHP2 inhibition to resensitize cells to osimertinib and reduce MAPK signaling to block the effects of enhanced activation of multiple parallel RTKs. We additionally modeled resistance to targeted therapies including the KRASG12C inhibitors adagrasib and sotorasib, the MEK inhibitor trametinib, and the farnesyl transferase inhibitor tipifarnib. These studies highlight the tractability of in situ resistance assays to model acquired resistance to targeted therapies and provide a framework for assessing the extent to which synergistic drug combinations can target acquired drug resistance.

IntroductionWithin two-parent households, the parent-couple subsystem (marital or romantic partner relationship) is posited to shape the mental health of both parents and children. Autistic children and their parents have an elevated-risk for mental health problems. The present study longitudinally examined the mediating role of the quality of the parent-couple relationship in time-ordered pathways between changes in the mental health problems of autistic children and in parent depression symptoms at a within-family level.MethodologyUsing four time points of data collected on 188 families of autistic children (aged 5–12 years) across 3 years, the bidirectional associations between parent-couple relationship satisfaction, parent depressive symptoms, and child internalizing and externalizing mental health problems were investigated. Two multi-group (grouped by parent gender) complete longitudinal mediation models in structural equation modeling using Mplus software were conducted.ResultsParent-couple relationship satisfaction mediated: (1) the association between higher parent depressive symptoms and higher child internalizing mental health problems 12 months later for both mothers and fathers, and (2) the association between higher child externalizing mental health problems and higher father depression symptoms 12 months later. Father depression symptoms mediated a pathway from lower parent-couple satisfaction to higher child internalizing mental health problems 12 months later, and mother depression symptoms mediated the pathway from higher child externalizing mental health problems to lower parent-couple satisfaction 12 months later.ConclusionFindings highlight the bidirectional and complex ways that parent and child mental health and the quality of the parent-couple relationship are entwined across time in families of autistic children. Family-wide interventions that address the needs of multiple family members and family systems are best suited to improve the mental health of parents and autistic children.

Abstract Objective: Invasive colonial influences and continuing neoliberal policies have a detrimental impact on Land, health, food and culture for Indigenous Communities. Food security and sovereignty have significant impacts on Indigenous well-being and, specifically, oral health. Aspects relating to food security, such as availability of nutritious foods, are a common risk factor of oral diseases. This scoping review aimed to collate existing evidence regarding the relationship between food sovereignty and/or food security and oral health for Indigenous Communities, globally. Design: Four databases were searched using keywords related to ‘Food security’ or ‘Food sovereignty,’ ‘Indigenous Peoples’ and ‘Oral health.’ Duplicates were removed, and two independent reviewers screened the titles and abstracts to identify articles for full-text review. Extracted data were summarised narratively, presenting a conceptual model which illustrates the findings and relationships between food security and/or food sovereignty and oral health. Results: The search identified 369 articles, with forty-one suitable for full-text review and a final nine that met inclusion criteria. The impact of food security and food sovereignty on oral health was discussed across different populations and sample sizes, ranging from eighteen Kichwa families in Brazil to 533 First Nations and Metis households in Canada. Pathways of influence between food sovereignty and/or food security are explored clinically, quantitatively and qualitatively across oral health outcomes, including early childhood caries, dental caries and oral health-related quality of life for Indigenous Communities. Conclusions: Innovative strategies underpinned by concepts of Indigenous food sovereignty are needed to promote oral health equity for Indigenous Communities. The nexus between oral health and Indigenous food sovereignty remains largely unexplored, but has immense potential for empowering Indigenous rights to self-determination of health that honour Indigenous ways of knowing, being and doing.

Basal cell carcinoma (BCC) is highly curable by surgical excision or radiation. In rare cases, BCC can be locally destructive or difficult to surgically remove. Hedgehog inhibition (HHI) with vismodegib or sonidegib induces a 50-60% response rate. Long-term toxicity includes muscle spasms and weight loss leading to dose decreases. This retrospective chart review also investigates the impact of CoQ10 and calcium supplementation in patients treated with HHI drugs at a single academic medical center from 2012 to 2022. We reviewed the charts of adult patients diagnosed with locally advanced or metastatic BCC treated with vismodegib or sonidegib primarily for progression-free survival (PFS). Secondary objectives included overall survival, BCC-specific survival, time to and reasons for discontinuation, overall response rate, safety and tolerability, use of CoQ10 and calcium supplements, and insurance coverage. Of 55 patients assessable for outcome, 34 (61.8%) had an overall clinical benefit, with 25 (45.4%) having a complete response and 9 (16.3%) a partial response. Stable disease was seen in 14 (25.4%) and 7 (12.7%) progressed. Of the 34 patients who responded to treatment, 9 recurred. Patients who were rechallenged with HHI could respond again. The median overall BCC-specific survival rate at 5 years is 89%. Dose reductions or discontinuations for vismodegib and sonidegib occurred in 59% versus 24% of cases, or 30% versus 9% of cases, respectively. With CoQ10 and calcium supplementation, only 17% required a dose reduction versus 42% without. HHI is highly effective for treating advanced BCC but may require dosing decreases. Sonidegib was better tolerated than vismodegib. CoQ10 and calcium supplementation can effectively prevent muscle spasms.

AimsExisting evidence shows that people who report Adverse Childhood Experiences (ACEs) are more likely to exhibit health-risk behaviors. However, limited research on this topic pertains to oncology population. We aim to address this knowledge gap by estimating the prevalence of ACEs and investigating their association with self-reported health-risk behaviors among adult cancer survivors living in the U.S.MethodsWe conducted a secondary analysis using cross-sectional data from the 2021 Behavioral Risk Factor Surveillance System ACE module. We included 4,126 adults, aged ≥18 years, with a history of cancer. The outcome variable was self-reported health-risk behaviors, which included cigarette smoking, e-cigarette use, and binge alcohol drinking. Self-reported ACEs history was the primary independent variable, comprised of 11 questions regarding child abuse and dysfunctional households. We conducted descriptive statistics and multivariable logistic regression to describe the relationship between the ACE history and health-risk behaviors.ResultsOverall, 84.2% of cancer survivors self-reported as White, 58.4% were women, and 76.6% were aged 65+ years. Nearly two-thirds of the sample (63.2%) self-reported at least one ACE (prior to age 18) and 21.7% engaged in ≥1 health-risk-behaviors, such as cigarette smoking, binge alcohol drinking, or e-cigarette use. Experiencing ≥3 ACEs was associated with 145% increased odds of reporting at least one health-risk behavior (OR = 2.45, 95% CI [1.78-3.38]) when compared to those without a history of ACEs. Besides, survivors who were younger, divorced, less educated, and had low income had higher odds of reporting at least one health-risk behavior.ConclusionsOverall, a history of ACEs is associated with health-risk behaviors. These all can negatively impact cancer survivors' overall well-being. Early screening for ACE during oncologic visits can be a protective measure for preventing health-risk behaviors among cancer survivors.

The increased fragmentation caused by harsher ionization methods used during mass spectrometry such as electron ionization can make interpreting the mass spectra of peptides difficult. Therefore, the development of tools to aid in this spectral analysis is important in utilizing these harsher ionization methods to study peptides, as these tools may be more accessible to some researchers. We have compiled fragmentation mechanisms described in the literature, confirmed them experimentally, and used them to create a Python-based fragment prediction model for peptides analyzed under direct exposure probe electron ionization mass spectrometry. This initial model has been tested using single amino acids as well as targeted libraries of short peptides. It was found that the model does well in predicting fragments of peptides composed of amino acids for which the model is well-defined, but several cases where additional mechanistic information needs to be incorporated have been identified.

IntroductionIntegrated time nanosecond pulse irreversible electroporation (INSPIRE) is a novel tumor ablation modality that employs high voltage, alternating polarity waveforms to induce cell death in a well-defined volume while sparing the underlying tissue. This study aimed to demonstrate the in vivo efficacy of INSPIRE against spontaneous melanoma in standing, awake horses.MethodsA custom applicator and a pulse generation system were utilized in a pilot study to treat horses presenting with spontaneous melanoma. INSPIRE treatments were administered to 32 tumors across 6 horses and an additional 13 tumors were followed to act as untreated controls. Tumors were tracked over a 43–85 day period following a single INSPIRE treatment. Pulse widths of 500ns and 2000ns with voltages between 1000 V and 2000 V were investigated to determine the effect of these variables on treatment outcomes.ResultsTreatments administered at the lowest voltage (1000 V) reduced tumor volumes by 11 to 15%. Higher voltage (2000 V) treatments reduced tumor volumes by 84 to 88% and eliminated 33% and 80% of tumors when 500 ns and 2000 ns pulses were administered, respectively.DiscussionPromising results were achieved without the use of chemotherapeutics, the use of general anesthesia, or the need for surgical resection in regions which are challenging to keep sterile. This novel therapeutic approach has the potential to expand the role of pulsed electric fields in veterinary patients, especially when general anesthesia is contraindicated, and warrants future studies to demonstrate the efficacy of INSPIRE as a solid tumor treatment.

Parvalbumin-expressing (PV+) inhibitory interneurons drive gamma oscillations (30–80 Hz), which underlie higher cognitive functions. In this review, we discuss two groups/aspects of fundamental properties of PV+ interneurons. In the first group (dubbed Before Axon), we list properties representing optimal synaptic integration in PV+ interneurons designed to support fast oscillations. For example: [i] Information can neither enter nor leave the neocortex without the engagement of fast PV+ -mediated inhibition; [ii] Voltage responses in PV+ interneuron dendrites integrate linearly to reduce impact of the fluctuations in the afferent drive; and [iii] Reversed somatodendritic Rm gradient accelerates the time courses of synaptic potentials arriving at the soma. In the second group (dubbed After Axon), we list morphological and biophysical properties responsible for (a) short synaptic delays, and (b) efficient postsynaptic outcomes. For example: [i] Fast-spiking ability that allows PV+ interneurons to outpace other cortical neurons (pyramidal neurons). [ii] Myelinated axon (which is only found in the PV+ subclass of interneurons) to secure fast-spiking at the initial axon segment; and [iii] Inhibitory autapses – autoinhibition, which assures brief biphasic voltage transients and supports postinhibitory rebounds. Recent advent of scientific tools, such as viral strategies to target PV cells and the ability to monitor PV cells via in vivo imaging during behavior, will aid in defining the role of PV cells in the CNS. Given the link between PV+ interneurons and cognition, in the future, it would be useful to carry out physiological recordings in the PV+ cell type selectively and characterize if and how psychiatric and neurological diseases affect initiation and propagation of electrical signals in this cortical sub-circuit. Voltage imaging may allow fast recordings of electrical signals from many PV+ interneurons simultaneously.

Despite being the highest value fruit crop in Australia, little is known about the types and condition or “health” of Australia’s apple growing soils. This study is unique in being the first to report the condition and characteristics of Australia’s apple growing soils; it provides essential baseline data for future monitoring of soil health in apple production systems, as well as soil physical and chemical data required for the development of perennial soil-tree-climate models. Soil chemical and physical properties were measured at 34 orchards, across five states. Soils were assessed for water retention, hydraulic conductivity, bulk density, macroporosity, organic carbon, CEC, ESP, pH, and EC. Despite high to very high levels of organic carbon, most topsoils were moderately to poorly structured. Around one-third to half of all sites showed evidence of poor aeration or impeded drainage, whilst 10 of the 34 sites were prone to nutrient leaching. Plant available soil water (PAWC) varied greatly between sites from 31 mm to 170 mm from 0 to 60 cm depth and between sites within the same soil order. Whilst topsoils had high to very high levels of organic carbon (average: 2.46%), they were otherwise poorly structured, with higher than expected bulk density (average: 1.32 g/cm3) and lower than expected air capacity (average: 9.97%) and macroporosity (average: 1.75%). Subsoils were also found to have little soil water availability (average: 15.39 mm/100 mm), low air capacity (average: 5.28%), and low CEC (average: 8.12 cmol (+) kg−1). Notably, 10 of the 34 sites had less than 6 cmol (+) kg−1 CEC throughout the entire soil profile, indicating potential risk of nutrient leaching. This study indicates that apple growing soils require careful management to improve topsoil structure, and to maintain or increase soil carbon, as well as use of soil moisture sensors to schedule irrigation. In addition, some sites also require improved subsoil drainage and care to ensure fertigation and irrigation do not result in leaching of nutrients beneath the root zone.

Golf carts are rising in popularity among older adults, not only for use on the course but also for traveling short distances. Studies focus on the increasing incidence of related injuries, giving limited attention to identifying who uses golf carts as a transportation mode. Using data from a survey of Floridians aged 50 and older conducted between December 2020 and April 2021 (n = 4199), we conducted OLS regression to examine factors predicting the frequency of golf cart use. We examine six sets of predictors: sociodemographics, health, self-perceptions of aging, social relationships, transportation experiences, and built environment. More frequent use is associated with being younger, male, and married or partnered, reporting less loneliness and older age identities, walking and biking more frequently, and interacting more often with friends – but less often with family members. It also is associated with living in an inland rather than coastal county and one with lower golf cart injury rates. Our findings indicate that predictors of more frequent golf cart use differ from those associated with transitioning from driving, suggesting that greater golf cart use is not part of this process. Our results instead allude to the possible role of golf carts in enhancing middle-aged and older adults’ friendships and well-being.

Radionuclide-mediated diagnosis and therapy have emerged as effective and low-risk approaches to treating breast cancer. Compared to traditional anatomic imaging techniques, diagnostic radionuclide-based molecular imaging systems exhibit much greater sensitivity and ability to precisely illustrate the biodistribution and metabolic processes from a functional perspective in breast cancer; this transitions diagnosis from an invasive visualization to a noninvasive visualization, potentially ensuring earlier diagnosis and on-time treatment. Radionuclide therapy is a newly developed modality for the treatment of breast cancer in which radionuclides are delivered to tumors and/or tumor-associated targets either directly or using delivery vehicles. Radionuclide therapy has been proven to be eminently effective and to exhibit low toxicity when eliminating both primary tumors and metastases and even undetected tumors. In addition, the specific interaction between the surface modules of the delivery vehicles and the targets on the surface of tumor cells enables radionuclide targeting therapy, and this represents an exceptional potential for this treatment in breast cancer. This article reviews the development of radionuclide molecular imaging techniques that are currently employed for early breast cancer diagnosis and both the progress and challenges of radionuclide therapy employed in breast cancer treatment.

IntroductionLearned helplessness often arises when an individual feels that a challenging situation is inescapable. Childhood trauma can lead to feelings of learned helplessness in youth and adulthood. Resiliency theory suggests that positive experiences in childhood and adulthood may counteract traumatic experiences in childhood and reduce learned helplessness and promote learned optimism, the antithesis of learned helplessness. The purpose of this study was to examine the relationship of adverse childhood experiences (ACEs) with learned helplessness and optimism in adulthood and whether positive childhood and adult experiences (PCEs and PAEs) can lessen learned helplessness even in the presence of ACEs and promote greater learned optimism.MethodsThe sample consisted of 435 adults who were recruited to participate in the study through Amazon Mechanical Turk (MTurk), a crowdsourcing recruitment service. Participants lived in the United States and were 18–56 years at the time of the study. Each participant completed a survey about their childhood and adulthood experiences and learned helplessness and optimism as an adult. Data were analyzed using structural equation modeling (SEM) in Mplus Version 7.ResultsThe learned helplessness scale had two factors which we termed learned helplessness and learned optimism. ACEs were associated with higher self-report of learned helplessness and lower learned optimism. When PCEs were added to the model, ACEs retained their relationship with learned helplessness but were no longer associated with learned optimism. PCEs were positively associated with learned optimism but were not associated with learned helplessness. PAEs were negatively correlated with learned helplessness and positively correlated with learned optimism. Learned optimism and learned helplessness in adults were inversely correlated.DiscussionPotentially traumatic experiences in childhood, as measured by ACEs, may lead to more learned helplessness throughout life. However, positive experiences in both childhood and adulthood can increase learned optimism, which was correlated with lower learned helplessness, even when childhood trauma was experienced.

Background: Social anhedonia is common within major depressive disorder (MDD) and associated with worse treatment outcomes. The orbitofrontal cortex (OFC) is implicated in both reward (medial OFC) and punishment (lateral OFC) in social decision making. Therefore, to understand the biology of social anhedonia in MDD, medial/lateral OFC metabolism, volume, and thickness, as well as structural connectivity to the striatum, amygdala, and ventral tegmental area/nucleus accumbens were examined. A positive relationship between social anhedonia and these neurobiological outcomes in the lateral OFC was hypothesized, whereas an inverse relationship was hypothesized for the medial OFC. The association between treatment-induced changes in OFC neurobiology and depression improvement were also examined. Methods: 85 medication-free participants diagnosed with MDD were assessed with Wisconsin Schizotypy Scales to assess social anhedonia and received pretreatment simultaneous fluorodeoxyglucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI), including structural and diffusion. Participants were then treated in an 8-week randomized placebo-controlled double-blind course of escitalopram. PET/MRI were repeated following treatment. Metabolic rate of glucose uptake was quantified from dynamic FDG-PET frames using Patlak graphical analysis. Structure (volume and cortical thickness) was quantified from structural MRI using Freesurfer. To assess structural connectivity, probabilistic tractography was performed on diffusion MRI and average FA was calculated within the derived tracts. Linear mixed models with Bonferroni correction were used to examine the relationships between variables. Results: A significantly negative linear relationship between pretreatment social anhedonia score and structural connectivity between the medial OFC and the amygdala (estimated coefficient: −0.006, 95 % CI: −0.0108 – −0.0012, p-value = 0.0154) was observed. However, this finding would not survive multiple comparisons correction. No strong evidence existed to show a significant linear relationship between pretreatment social anhedonia score and metabolism, volume, thickness, or structural connectivity to any of the regions examined. There was also no strong evidence to suggest significant linear relationships between improvement in depression and percent change in these variables. Conclusions: Based on these multimodal findings, the OFC likely does not underlie social anhedonia in isolation and therefore should not be the sole target of treatment for social anhedonia. This is consistent with previous reports that other areas of the brain such as the amygdala and the striatum are highly involved in this behavior. Relatedly, amygdala-medial OFC structural connectivity could be a future target. The results of this study are crucial as, to our knowledge, they are the first to relate structure/function of the OFC with social anhedonia severity in MDD. Future work may need to involve a whole brain approach in order to develop therapeutics for social anhedonia.

CD47-SIRPa is a myeloid check point pathway that inhibits phagocytosis of cells lacking markers for self-recognition. Tumor cells can overexpress CD47 and bind to SIRPa on macrophages, preventing phagocytosis. CD47 expression is enhanced and correlated with a negative prognosis in Acute Myeloid Leukemia (AML), with its blockade leading to cell clearance. ALX90 is an engineered fusion protein with high-affinity for CD47. Composed of the N-terminal D1 domain of SIRPα genetically linked to an inactive Fc domain from human IgG, ALX90 is designed to avoid potential toxicity of CD47-expressing red blood cells. Venetoclax (VEN) is a specific B-cell lymphoma-2 (BCL-2) inhibitor that can restore apoptosis in malignant cells. In AML VEN is combined with azanucleosides to induce superior remission rates, however treatment for refractory/relapse is an unmet need. We questioned whether the anti-tumor activity of a VEN based regimen can be augmented through CD47 inhibition (CD47i) in AML. Human AML cell lines were sensitive to ALX90 and its addition increased efficacy of a VEN+AZA regimen in vivo. However, CD47i failed to clear bone marrow tumor burden in PDX models. We hypothesized that in cases of high medullary tumor burden, loss of resident macrophages reduced ALX efficiency. Therefore, we attempted to enhance this medullary macrophage population with agonism of TLR3 via Poly(I:C), which led to expansion and activation of medullary macrophages in in vivo AML PDX models and potentiated CD47i. In summary, the addition of Poly(I:C) can enhance medullary macrophage populations to potentiate the phagocytosis merited by therapeutic inhibition of CD47.

Improving the shelf life of steaks from beef chuck rolls and bone-in short ribs, items commonly exported, will increase the demand of beef in international markets. Our objectives were to determine the effect of topically applying combinations of acerola cherry powder and rosemary extract on steak color and lipid oxidation of beef chuck roll and bone-in short rib. USDA Choice beef chuck rolls (Institutional Meat Purchase Specifications [IMPS] 116A; N=9) andbone-in short ribs (IMPS 123A; N=18) were aged (0°C) 28 d and cut into 1.0 cm-thick steaks. Steak treatments included the following: untreated control (C) or topically sprayed (2 mL) with an acerola cherry powder solution (0.05% A), rosemary extract solution (0.10% R), or mixture of acerola cherry powder and rosemary extract (M1=0.05% A+0.1% R; M2=0.1% A+0.1% R; M3=0.05% A+0.2% R; M4=0.1% A+0.2% R). On day 0 of retail display, oxygen consumption, metmyoglobin-reducing activity, and lipid oxidation were measured. Lipid oxidation was evaluated again following 4 d of retail display. Chuck roll steak color was scored twice daily, whereas short rib lean and bone marrow color were scored once daily throughout 4 d of retail display. Treating chuck roll steaks with M2, M3, and M4 decreased lipid oxidation compared to C and A (P=0.004). In short rib steaks, lipid oxidation remained constant from day 0 to 4 treated with M4 but increased for all other treatments (P

This duoethnography weaves the experiences and perspectives of disabled activists, poverty scholars, community scholars of color, and university-based scholars partnering on a teacher preparation professional development project that (re)centers disability and its intersections by (a) reconsidering who creates knowledge, (b) positioning disabled activists, poverty scholars, and community scholars of color as experts with pedagogical authority, and (c) providing opportunities for teacher candidates (current and future teachers) to learn from activists and scholars in accessible, online spaces. The experiences and perspectives of multiply marginalized disabled youth and adults are often ignored and/or discounted in teacher preparation programs. However, one way to re-zone and re-people disability studies in teacher education is by teaching and learning at the intersections of critical race studies and disability studies through cross-coalitional community-university partnerships.

Abstract Background Vertebral endplate sclerosis and facet osteoarthritis have been documented in animals and humans. However, it is unclear how these adjacent pathologies engage in crosstalk with the intervertebral disc. This study sought to elucidate this crosstalk by assessing each compartment individually in response to acute disc injury. Methods Eleven New Zealand White rabbits underwent annular disc puncture using a 16G or 21G needle. At 4 and 10 weeks, individual compartments of the motion segment were analyzed. Discs underwent T1 relaxation mapping with MRI contrast agent gadodiamide as well T2 mapping. Both discs and facets underwent mechanical testing via vertebra—disc—vertebra tension‐compression creep testing and indentation testing, respectively. Endplate bone density was quantified via μCT. Discs and facets were sectioned and stained for histology scoring. Results Intervertebral discs became more degenerative with increasing needle diameter and time post‐puncture. Bone density also increased in endplates adjacent to both 21G and 16G punctured discs leading to reduced gadodiamide transport at 10 weeks. The facet joints, however, did not follow this same trend. Facets adjacent to 16G punctured discs were less degenerative than facets adjacent to 21G punctured discs at 10 weeks. 16G facets were more degenerative at 4 weeks than at 10, suggesting the cartilage had recovered. The formation of severe disc osteophytes in 16G punctured discs between 4 and 10 weeks likely offloaded the facet cartilage, leading to the recovery observed. Conclusions Overall, this study supports that degeneration spans the whole spinal motion segment following disc injury. Vertebral endplate thickening occurred in response to disc injury, which limited the diffusion of small molecules into the disc. This work also suggests that altered disc mechanics can induce facet degeneration, and that extreme bony remodeling adjacent to the disc may promote facet cartilage recovery through offloading of the articular cartilage.

In central nervous system (CNS) injury and disease, peripherally derived myeloid cells infiltrate the CNS parenchyma and interact with resident cells, propagating the neuroinflammatory response. Because peripheral myeloid populations differ profoundly depending on the type and phase of injury, their crosstalk with CNS resident cells, particularly microglia, will lead to different functional outcomes. Thus, understanding how peripheral myeloid cells affect the phenotype and function of microglia in different disease conditions and phases may lead to a better understanding of disease-specific targetable pathways for neuroprotection and neurorepair. To this end, we set out to develop an in vitro system to investigate the communication between peripheral myeloid cells and microglia, with the goal of uncovering potential differences due to disease type and timing. We isolated peripheral myeloid cells from mice undergoing experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, or acute cerebral ischemia by permanent middle cerebral artery occlusion (pMCAO) at different times after disease and probed their ability to change the phenotype of primary microglia isolated from the brain of adult mice. We identified changes not only dependent on the disease model, but also on the timepoint after disease onset from which the myeloid cells were isolated. Peripheral myeloid cells from acute EAE induced morphological changes in microglia, followed by increases in expression of genes involved in inflammatory signaling. Conversely, it was the peripheral myeloid cells from the chronic phase of pMCAO that induced gene expression changes in genes involved in inflammatory signaling and phagocytosis, which was not followed by a change in morphology. This underscores the importance of understanding the role of infiltrating myeloid cells in different disease contexts and phases. Furthermore, we showed that our assay is a valuable tool for investigating myeloid cell interactions in a range of CNS neuroinflammatory conditions.

BackgroundTobacco smoking remains the leading cause of preventable morbidity and mortality in the United States, with significant rural-urban disparities. Adults who live in rural areas of the United States have among the highest tobacco smoking rates in the nation and experience a higher prevalence of smoking-related deaths and deaths due to chronic diseases for which smoking is a causal risk factor. Barriers to accessing tobacco use cessation treatments are a major contributing factor to these disparities. Adults living in rural areas experience difficulty accessing tobacco cessation services due to geographical challenges, lack of insurance coverage, and lack of health care providers who treat tobacco use disorders. The use of digital technology could be a practical answer to these barriers. ObjectiveThis report describes a protocol for a study whose main objectives are to develop and beta test an innovative intervention that uses a private, moderated Facebook group platform to deliver peer support and faith-based cessation messaging to enhance the reach and uptake of existing evidence-based smoking cessation treatment (EBCT) resources (eg, state quitline coaching programs) for rural adults who smoke. MethodsWe will use the Integrated Theory of Health Behavior Change, surface or deep structure frameworks to guide intervention development, and the community-based participatory research (CBPR) approach to identify and engage with community stakeholders. The initial content library of moderator postings (videos and text or image postings) will be developed using existing EBCT material from the Centers for Disease Control and Prevention Tips from Former Smokers Campaign. The content library will feature topics related to quitting smoking, such as coping with cravings and withdrawal and using EBCTs with faith-based message integration (eg, Bible quotes). A community advisory board and a community engagement studio will provide feedback to refine the content library. We will also conduct a beta test of the intervention with 15 rural adults who smoke to assess the recruitment feasibility and preliminary intervention uptake such as engagement, ease of use, usefulness, and satisfaction to further refine the intervention based on participant feedback. ResultsThe result of this study will create an intervention prototype that will be used for a future randomized controlled trial. ConclusionsOur CBPR project will create a prototype of a Facebook-delivered faith-based messaging and peer support intervention that may assist rural adults who smoke to use EBCT. This study is crucial in establishing a self-sufficient smoking cessation program for the rural community. The project is unique in using a moderated social media platform providing peer support and culturally relevant faith-based content to encourage adult people who smoke to seek treatment and quit smoking. International Registered Report Identifier (IRRID)PRR1-10.2196/52398

Abstract Background Adolescence is a developmental period during which youth experience vulnerability to psychopathology. To build the foundation for a parsimonious psychopathology risk calculator while capturing the complexity and dynamic nature of the environment, the current study aimed to identify distinct risk and resilience profiles with a wide range of environmental factors guided by Bronfenbrenner's biopsychosocial ecological system theory. The association between the early‐mid childhood risk profiles and psychopathology in adolescence were examined. Moreover, the predictive utility of early childhood irritability was evaluated in addition to the risk profiles. Methods The data from Future of Families and Child Wellbeing Study a nation‐wide longitudinal study, were used in the latent profile analyses to identify the risk profiles with family, school, and neighborhood characteristics from 3 to 9 years old. To capture the socio‐environmental and cultural nuances, we extracted three subsamples, including Black/African American (n = 2587), Hispanic/Latinx (n = 1577), and White (n = 776) for separate analyses. Risk profile memberships were used to predict adolescence psychopathology, including depression, anxiety, attention deficits, oppositional defiant disorder, and conduct disorder symptoms. The predictive utility of early childhood irritability above and beyond environmental risk profiles was evaluated using stepwise regression. Results Three risk profiles were identified in the Hispanic/Latinx and Black/African American subsamples, while four profiles were identified in White subsample. Almost all risk profile membership predicted both internalizing and externalizing psychopathology, while some profiles are predictive of externalizing symptoms only. Higher level of irritability predicted higher symptomatology in all five mental health outcomes above and beyond the environmental profiles. Conclusions Distinct risk and resilience profiles primarily driven by parent and family characteristics were identified for all three major race/ethnicity groups. Our findings lay the foundation for a more efficient multi‐tiered information gathering process in mental health clinical settings to aid the decision making for intervention and prevention.

Background: Multiple etiologies exist for neonatal intestinal obstruction with similar presenting symptoms. While single etiology is the most common cause, concomitant surgical diagnoses exist requiring unique peri‑operative considerations. We present a retrospective review of 5 patients with a rare association of Hirschsprung disease (HD) and intestinal malrotation. Methods: After IRB approval, patients were identified utilizing Data Direct and Electronic Medical Records ID with pathologically confirmed HD and intestinal malrotation from a single institution and retrospective review was performed. Results: Five patients were identified with the concomitant malrotation and HD diagnoses over a 15-year period. Intestinal malrotation was confirmed by intra-operative findings. HD was confirmed in all patients by rectal biopsy. Feeding intolerance was the most common chief complaint. A contrast enema was the initial diagnostic test of choice in 3 of 5 of patients. All patients underwent a Ladd procedure, including appendectomy, during the index admission. Two of 5 patients underwent surgical management for HD during the index admission, while surgery was delayed in the remaining 3. Conclusions: Association between HD and malrotation causing intestinal obstruction has been previously described, albeit rare. The two diagnoses can present similarly in neonatal patients; although, the underlying pathophysiology, work up and surgical management is quite different. Traditionally, a Ladd procedure is performed utilizing an open approach and includes an appendectomy. However, patients undergoing a Ladd procedure with high suspicion of HD pre-operatively pose unique considerations. We present data of 5 patients to highlight unique considerations regarding diagnostic work up and operative planning.

Infection with Marburg virus (MARV), the causative agent of Marburg virus disease (MVD), results in haemorrhagic disease and high case fatality rates (>40%) in humans. Despite its public health relevance, there are no licensed vaccines or therapeutics to prevent or treat MVD. A vesicular stomatitis virus (VSV)-based vaccine expressing the MARV glycoprotein (VSV-MARV) is currently in clinical development. Previously, a single 10 million PFU dose of VSV-MARV administered 1–5 weeks before lethal MARV challenge conferred uniform protection in nonhuman primates (NHPs), demonstrating fast-acting potential. Additionally, our group recently demonstrated that even a low dose VSV-MARV (1000 PFU) protected NHPs when given 7 days before MARV challenge. In this study, we longitudinally profiled the transcriptional responses of NHPs vaccinated with this low dose of VSV-MARV either 14 or 7 days before lethal MARV challenge. NHPs vaccinated 14 days before challenge presented with transcriptional changes consistent with an antiviral response before challenge. Limited gene expression changes were observed in the group vaccinated 7 days before challenge. After challenge, genes related to lymphocyte-mediated immunity were only observed in the group vaccinated 14 days before challenge, indicating that the length of time between vaccination and challenge influenced gene expression. Our results indicate that a low dose VSV-MARV elicits distinct immune responses that correlate with protection against MVD. A low dose of VSV-MARV should be evaluated in clinical rails as it may be an option to deliver beneficial public health outcomes to more people in the event of future outbreaks.

Taï Forest virus (TAFV) is a lesser-known ebolavirus that causes lethal infections in chimpanzees and is responsible for a single human case. Limited research has been done on this human pathogen; however, with the recent emergence of filoviruses in West Africa, further investigation and countermeasure development against this virus is warranted. We developed a vesicular stomatitis virus (VSV)-based vaccine expressing the TAFV glycoprotein as the viral antigen and assessed it for protective efficacy in nonhuman primates (NHPs). Following a single high-dose vaccination, NHPs developed antigen-specific binding and neutralizing antibodies as well as modest T cell responses. Importantly, all vaccinated NHPs were uniformly protected from disease after lethal TAFV challenge while the naïve control group succumbed to the disease. Histopathologic lesions consistent with filovirus disease were present in control NHPs but were not observed in vaccinated NHPs. Transcriptional analysis of whole blood samples obtained after vaccination and challenge was performed to gain insight into molecular underpinnings conferring protection. Differentially expressed genes (DEG) detected 7 days post-vaccination were enriched to processes associated with innate immunity and antiviral responses. Only a small number of DEG was detected in vaccinated NHPs post-challenge while over 1,000 DEG were detected in control NHPs at end-stage disease which mapped to gene ontology terms indicative of defense responses and inflammation. Taken together, this data demonstrates the effective single-dose protection of the VSV-TAFV vaccine, and its potential for use in outbreaks.

Objective: Transmission of antimicrobial resistant bacteria between people and household pets, such as dogs and cats, is an emerging global public health problem. This scoping review synthesized existing evidence of human-pet bacteria transmission to understand the magnitude and breadth of this issue. Methods: The search included specific and generic terms for bacteria, resistance, transmission, pets, and humans. Searches were conducted through PubMed, Scopus, Web of Science, CABI Global Health, Networked Digital Library of Theses and Dissertations, Google Scholar. All studies published in English and Mandarin that isolated bacteria from pets (cats and dogs) and humans who had contact with the pets, and reported phenotypic or genotypic antimicrobial sensitivity test results, were included in this review. In cases of bacterial species that are commonly associated with pets, such as Staphylococcus pseudintermedius and Pasteurella multocida, we also included studies that only isolated bacteria from humans. Results: After removing duplication, the search captured 9355 studies. A total of 1098 papers were screened in the full-text review, and 562 studies were identified as eligible according to our inclusion criteria. The primary reason for exclusion was the lack of sensitivity testing. The included studies were published between 1973 and 2021. The most common study location was the United States (n = 176, 31.3%), followed by the United Kingdom (n = 53, 9.4%), Japan (n = 29, 5.2%), and Canada (n = 25, 4.4%). Most of the included studies were case reports (n = 367, 63.4%), cross-sectional/prevalence studies (n = 130, 22.4%), and case series (n = 51, 8.8%). Only few longitudinal studies (n = 14, 2.4%), case-control studies (n = 12, 2.1%), and cohort studies (n = 5, 0.9%) were included in our review. Most studies focused on Pasteurella multocida (n = 221, 39.3%), Staphylococcus aureus (n = 81, 14.4%), and Staphylococcus pseudintermedius (n = 52, 8.9%). For the 295 studies that used strain typing methods to compare bacteria from humans and pets, most used DNA banding pattern-based methods (n = 133, 45.1%) and DNA sequencing-based methods (n = 118, 40.0%). Conclusion: Transmission of bacteria could occur in both directions: pets to humans (e.g., S. pseudintermedius and P. multocida) and humans to pets (e.g., S. aureus). The majority of studies provided a low level of evidence of transmission (e.g., case reports), suggesting that more rigorous longitudinal, cohort, or case-control studies are needed to fully understand the risk of human-pet resistant bacterial transmission.

Objectives Emergency general surgery (EGS) conditions, such as perforated intestines or complicated hernias, can lead to significant postoperative morbidity and mortality. We sought to understand the recovery experience of older patients at least 1 year after EGS to identify key factors for a successful long-term recovery.Methods We conducted semi-structured interviews to explore recovery experiences of patients and their caregivers after admission for an EGS procedure. We screened patients who were aged 65 years or older at the time of an EGS operation, admitted at least 7 days, and still alive and able to consent at least 1 year postoperatively. We interviewed the patients, their primary caregiver, or both. Interview guides were developed to explore medical decision making, patient goals and expectations surrounding recovery after EGS, and to identify barriers and facilitators of recovery. Interviews were recorded and transcribed, and we used an inductive thematic approach to analysis.Results We performed 15 interviews (11 patients and 4 caregivers). Patients wanted to return to their prior quality of life, or ‘get back to normal.’ Family was key in providing both instrumental support (eg, for daily tasks such as cooking, driving, wound care) and emotional support. Provision of temporary support was key to the recovery of many patients. Although most patients returned to their prior lifestyle, some also experienced depression, persistent abdominal effects, pain, or decreased stamina. When asked about medical decision making, patients expressed viewing the decision for having an operation not as a choice but, rather, the only rational option to treat a severe symptom or life-threating illness.Conclusions There is an opportunity in healthcare to provide better education for older patients and their caregivers around instrumental and emotional support to bolster successful recovery after emergency surgery.Level of evidence Qualitative study, level II.

AbstractBackground: The Canadian healthcare system bares a long legacy of colonisation and assimilation of Indigenous values and approaches to health and wellness. This system often perpetuates social and health inequities through systemic racism, underfunding, lack of culturally appropriate care and barriers to access care. Current funding legislation policies enacted across federal, provincialand territorial governments do not necessarily uphold Indigenous Peoples’ rights to self-determination, health and wellness. We summarise literature on promising Indigenous health systems and practices that prioritise and/or improve rural Indigenous Peoples’ health and wellness. Objective: The impetus for this review was to provide information on promising health systems, while Dehcho First Nations developed a health and wellness vision. Methods: Documents were gathered from indexed and non-indexed databases to obtain literature from peer-reviewed and non-peer reviewed sources. Two reviewers independently 1) screened titles, abstracts and full texts to ensure they met the inclusion criteria, 2) gathered relevant data from all included documents and 3) identified major themes and sub-themes. Reviewers then discussed and reached consensus on the themes. Results: Thematic analysis revealed six themes for effective health systems for rural and remote Indigenous communities: 1) access to primary care, 2) multi-directional knowledge exchange, 3) culturally appropriate care, 4) training and building community capacity, 5) integrated care and 6) health system funding. Conclusion: Effective health and wellness systems must support Indigenous ways of knowing and doing in healthcare models based on collaborative partnerships with community members, health providers and government agencies.

Objective: There are limited studies exploring the support and education needs of individuals at-risk for or diagnosed with hereditary frontotemporal degeneration (FTD) and/or amyotrophic lateral sclerosis (ALS). This study evaluated a novel conference for this population to assess conference efficacy, probe how participants assessed relevant resources, and identify outstanding needs of persons at-risk/diagnosed. Methods: We implemented a post-conference electronic survey that probed participants' satisfaction, prior experience with resources, and unmet needs. Along with multiple-choice, free-text items were included to gather qualitative context. Results: Survey completion rate was 31% (115/376 attendees who were emailed the survey). There was positive interest in pursuing genetic counseling among eligible responders: 61% indicated they planned to seek genetic counseling because of the conference, which was significantly more than those who were undecided (21%) or did not plan to seek genetic counseling (18%). Qualitative data demonstrated need for additional education, support, and research opportunities. Conclusion: Conference reactions indicate this is a valued resource. Results indicated the importance of raising awareness about existing resources, and the need for further resource development, especially for at-risk communities. Innovation: While most resources are developed for caregivers' needs, this unique program targets at-risk individuals and unites ALS and FTD communities.

Abstract Visual art has been used to revamp the portrayal of climate change with the aims of engaging emotions and expanding nonexperts’ psychological capacity to perceive its relevance. However, empirical evidence supporting the effectiveness of artistic representation of data as a tool for public communication is lacking. Using controlled experiments with two national samples of U.S. adults (total N = 671), here we found that artistic visualizations elicited stronger positive emotions than informationally equivalent data graphs but did not differ in their perceived credibility or effectiveness as visual aids for learning. When used to prompt individual reflection, artistic visualizations appeared to mitigate the political division in viewers’ perceived relevance of climate change that could otherwise be exacerbated by exposure to data graphs.

Abstract Background The HMGA2:c.83G>A variant was identified in Welsh ponies having pleiotropic effects on height and insulin concentration. Objective Determine whether the HMGA2:c.83G>A variant is associated with decreased height and higher basal insulin concentrations across pony breeds. Animals Two hundred thirty‐six ponies across 6 breeds. Methods Cross‐sectional study. Ponies were genotyped for the HMGA2:c.83G>A variant and phenotyped for height and basal insulin concentrations. Stepwise regression was performed for model analysis using a linear regression model for height and mixed linear model for insulin with farm as a random effect. Coefficient of determination, pairwise comparison of the estimated marginal means and partial correlation coefficients (parcor) were calculated to assess the relationship between HMGA2 genotype and height or insulin. Results Breed and genotype accounted for 90.5% of the variation in height across breeds, and genotype explained 21% to 44% of the variation within breeds. Breed, genotype, cresty neck score, sex, age, and farm accounted for 45.5% of the variation in insulin, with genotype accounting for 7.1%. The HMGA2 A allele frequency was 62% and correlated with both height (parcor = −0.39; P 10 cm shorter than other genotypes. Compared with G/G individuals, A/A and G/A individuals had 4.3 μIU/mL (95% confidence interval [CI]: 1.8‐10.5) and 2.7 μIU/mL (95% CI: 1.4‐5.3) higher basal insulin concentrations, respectively. Conclusions and Clinical Importance These data demonstrate the pleiotropic effects of the HMGA2:c.83G>A variant and its role in identifying ponies at increased risk for insulin dysregulation.

Abstract Background COVID-19 disproportionately affects those with preexisting conditions, but little research has determined whether those with chronic diseases view the pandemic itself differently - and whether there are differences between chronic diseases. We theorized that while individuals with respiratory disease or autoimmune disorders would perceive greater threat from COVID-19 and be more supportive of non-pharmaceutical interventions (NPIs), those with autoimmune disorders would be less likely to support vaccination-based interventions. Methods We conducted a two-wave online survey conducted in February and November 2021 asking respondents their beliefs about COVID-19 risk perception, adoption and support of interventions, willingness to be vaccinated against COVID-19, and reasons for vaccination. Regression analysis was conducted to assess the relationship of respondents reporting a chronic disease and COVID-19 behaviors and attitudes, compared to healthy respondents adjusting for demographic and political factors. Results In the initial survey, individuals reporting a chronic disease had both stronger feelings of risk from COVID-19 as well as preferences for NPIs than healthy controls. The only NPI that was still practiced significantly more compared to healthy controls in the resample was limiting trips outside of the home. Support for community-level NPIs was higher among individuals reporting a chronic disease than healthy controls and remained high among those with respiratory diseases in sample 2. Vaccine acceptance produced more divergent results: those reporting chronic respiratory diseases were 6% more willing to be vaccinated than healthy controls, while we found no significant difference between individuals with autoimmune diseases and healthy controls. Respondents with chronic respiratory disease and those with autoimmune diseases were more likely to want to be vaccinated to protect themselves from COVID-19, and those with an autoimmune disease were more likely to report fear of a bad vaccine reaction as the reason for vaccine hesitancy. In the resample, neither those with respiratory diseases nor autoimmune diseases reported being more willing to receive a booster vaccine than healthy controls. Conclusions It is not enough to recognize the importance of health in determining attitudes: nuanced differences between conditions must also be recognized.

La ciencia es una actividad social que debe ser evaluada para determinar su desempeño. El objetivo de este trabajo fue evaluar el desempeño institucional de la productividad científica de ECOSUR utilizando información de la Web of Science (WoS) de 1995 a 2020. Durante este periodo, ECOSUR produjo 3 753 publicaciones, en su mayoría orientadas a las ciencias naturales. Hubo una tendencia creciente en el número de trabajos de investigación producidos durante el periodo de estudio. 2018 fue el año con el mayor número de publicaciones (336 artículos). Un alto porcentaje (>70%) se publicó en inglés, un 26% en español y el resto en otros idiomas. Más del 60% de los artículos fueron publicados en revistas con un factor de impacto (FI) superior a uno. El FI más alto fue de 10.464 pero con pocos artículos. La productividad no fue homogénea: el 38% de los investigadores publicaron más de 50 trabajos de investigación, y muchos otros, menos de 20.

Abstract Background Cancer supportive care interventions often have limited generalizability, goal misalignment, and high costs. We developed and piloted a health coaching intervention, UNC HealthScore, in patients undergoing cancer treatment (ClinicalTrials.gov identifier NCT04923997). We present feasibility, acceptability, and preliminary outcome data. Methods HealthScore is a six‐month, theory‐based, multicomponent intervention delivered through participant‐driven coaching sessions. For the pilot study, participants were provided a Fitbit, responded to weekly symptom and physical function digital surveys, and met with a health coach weekly to develop and monitor goals. Coaching notes were discussed in weekly interdisciplinary team meetings and provided back to the treating oncology team. Symptom alerts were monitored and triaged through a study resource nurse to relevant supportive care services. Feasibility was determined based on intervention enrollment and completion. Acceptability was based on satisfaction with coaching and Fitbit‐wearing and was informed by semistructured exit interviews. Outcomes evaluated for signs of improvement included several PROMIS (Patient‐Reported Outcomes Measurement Information System) measures, including the primary intervention target, physical function. Results From May 2020 to March 2022, 50 participants completed the single‐arm pilot. Feasibility was high: 66% enrolled and 71% completed the full intervention. Participants reported an average of 4.8 and 4.7 (out of 5) on the acceptability of coaching calls and using the Fitbit, respectively. Physical function scores rose 3.1 points (SE = 1.1) from baseline to 3 months, and 4.3 (SE = 1.0) from baseline to 6 months, above established minimal clinically important difference (MCID). Improvements above MCID were also evident in anxiety and depression, and smaller improvements were demonstrated for emotional support, social isolation, cognitive function, symptom burden, and self‐efficacy. Discussion HealthScore shows feasibility, acceptability, and promising preliminary outcomes. Randomized studies are underway to determine the efficacy of preserving physical function in patients with advanced cancer.

Inherited arrhythmia syndromes are rare genetic conditions that predispose seemingly healthy individuals to sudden cardiac arrest and death. The Hearts in Rhythm Organization is a multidisciplinary Canadian network of clinicians, researchers, patients, and families that aims to improve care for patients and families with inherited cardiac conditions, focused on those that confer predisposition to arrhythmia and sudden cardiac arrest and/or death. The field is rapidly evolving as research discoveries increase. A streamlined, practical guide for providers to diagnose and follow pediatric and adult patients with inherited cardiac conditions represents a useful tool to improve health system utilization, clinical management, and research related to these conditions. This review provides consensus care pathways for 7 conditions, including the 4 most common inherited cardiac conditions that confer predisposition to arrhythmia, with scenarios to guide investigation, diagnosis, risk stratification, and management. These conditions include Brugada syndrome, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy and related arrhythmogenic cardiomyopathies, and catecholaminergic polymorphic ventricular tachycardia. In addition, an approach to investigating and managing sudden cardiac arrest, sudden unexpected death, and first-degree family members of affected individuals is provided. Referral to specialized cardiogenetic clinics should be considered in most cases. The intention of this review is to offer a framework for the process of care that is useful for both experts and nonexperts, and related allied disciplines such as hospital management, diagnostic services, coroners, and pathologists, in order to provide high-quality, multidisciplinary, standardized care. Résumé: Les syndromes d’arythmie héréditaires sont des troubles génétiques rares qui prédisposent des personnes en apparence en bonne santé à un arrêt cardiaque soudain et à la mort. L’organisation Hearts in Rhythm Organization est un réseau multidisciplinaire canadien qui regroupe des cliniciens, des chercheurs ainsi que des patients et leurs proches dans le but d’améliorer les soins prodigués aux patients atteints de maladies cardiaques héréditaires et à leur famille, en particulier dans le cas des maladies qui entraînent une prédisposition à l’arythmie et à un arrêt cardiaque soudain et/ou à la mort. Puisque ce champ de recherche évolue rapidement, la mise au point d’un guide pratique et simple à l’intention des professionnels de la santé pour le diagnostic et le suivi des patients enfants et adultes présentant une maladie cardiaque héréditaire serait donc un outil intéressant pour améliorer l’utilisation du système de santé et la prise en charge clinique de ces maladies tout en orientant la recherche à ce propos. La présente synthèse expose les trajectoires de soins faisant l’objet d’un consensus pour sept maladies, dont les quatre maladies cardiaques héréditaires les plus courantes qui prédisposent à l’arythmie. Elle présente aussi des scénarios pour orienter les examens, le diagnostic, la stratification du risque et la prise en charge des patients. Ces maladies sont le syndrome de Brugada, le syndrome du QT long, la cardiomyopathie arythmogénique du ventricule droit et les cardiomyopathies arythmogènes associées, et la tachycardie ventriculaire polymorphe catécholaminergique. En outre, une approche pour la prise en charge de l’arrêt cardiaque soudain, de mort subite inattendue et des membres de la famille immédiate de la personne touchée est proposée. L’orientation vers des cliniques spécialisées en cardiogénétique doit être envisagée dans la plupart des cas. L’objectif est d'établir un cadre de soins qui soit utile pour les experts et les non-experts ainsi que pour les professionnels des domaines connexes, par exemple le personnel de l’administration hospitalière et des services diagnostiques, les coroners et les pathologistes, en vue d’offrir des soins multidisciplinaires normalisés de grande qualité.