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Vascular Ehlers‐Danlos, Marfan and Loeys‐Dietz syndromes have increased risk of aortic dilation and dissection. Previous early studies showed hypermobile Ehlers‐Danlos syndrome (hEDS) may also have increased risk, with echocardiography screening recommended; subsequent studies have not confirmed the risk or recommended echocardiography. This pediatric‐based study assessed aortic dilation prevalence in those with hEDS by serial echocardiographic examinations and assessed family history for aortic dissections. We retrospectively identified individuals with hEDS who had echocardiography studies from the electronic medical records at one pediatric center. Aortic root Z‐scores >2.0 were found in 15/225 subjects (average age 12.9 years) on initial echocardiograms, with no Z‐score >3.0. Subsequent studies (n = 68) found statistically significant decline in aortic root Z‐scores. Repeat echocardiography in those with initial aortic root Z‐score >2.0 (n = 10) demonstrated a decline in Z score <2.0 in seven. On final examination, 9/225 (4.0%) had a Z‐score >2.0, not statistically different from the general population. No aortic dissection occurred in first‐ or second‐degree relatives. In conclusion, aortic root dilation rate in hEDS is likely not different from the general population. We propose that in the absence of other cardiac findings or suspicion for another disorder, echocardiography is not required in hEDS. [ABSTRACT FROM AUTHOR]

Lung cancer in women is a modern epidemic and represents a global health crisis. Cigarette smoking remains the most important risk factor for lung cancer in all patients and, among women globally, rates of smoking continue to increase. Although some data exist supporting sex‐based differences across the continuum of lung cancer, there is currently a dearth of research exploring the differences in risk, biology, and treatment outcomes in women. Consequently, the American Cancer Society National Lung Cancer Roundtable recognizes the urgent need to promote awareness and future research that will close the knowledge gaps regarding lung cancer in women. To this end, the American Cancer Society National Lung Cancer Roundtable Task Group on Lung Cancer in Women convened a summit undertaking the following to: (1) summarize existing evidence and identify knowledge gaps surrounding the epidemiology, risk factors, biologic differences, and outcomes of lung cancer in women; (2) develop and prioritize research topics and questions that address research gaps and advance knowledge to improve quality of care of lung cancer in women; and (3) propose strategies for future research. Plain language summary: Lung cancer is the leading cause of cancer mortality in women, and, despite comparatively lower exposures to occupational and environmental carcinogens compared with men, disproportionately higher lung cancer rates in women who ever smoked and women who never smoked call for increased awareness and research that will close the knowledge gaps regarding lung cancer in women. The rising incidence and mortality of lung cancer among certain populations have resulted in a major health crisis worldwide. Despite comparatively less exposure to occupational and environmental carcinogens than their male counterparts, disproportionately high lung cancer rates in women who ever smoked and women who never smoked suggests other mechanisms influencing risk that warrant better understanding. [ABSTRACT FROM AUTHOR]

Accurate repair of DNA damage is critical for maintenance of genomic integrity and cellular viability. Because damage occurs non-uniformly across the genome, single-cell resolution is required for proper interrogation, but sensitive detection has remained challenging. Here, we present a comprehensive analysis of repair protein localization in single human cells using DamID and ChIC sequencing techniques. This study reports genome-wide binding profiles in response to DNA double-strand breaks induced by AsiSI, and explores variability in genomic damage locations and associated repair features in the context of spatial genome organization. By unbiasedly detecting repair factor localization, we find that repair proteins often occupy entire topologically associating domains, mimicking variability in chromatin loop anchoring. Moreover, we demonstrate the formation of multi-way chromatin hubs in response to DNA damage. Notably, larger hubs show increased coordination of repair protein binding, suggesting a preference for cooperative repair mechanisms. Together, our work offers insights into the heterogeneous processes underlying genome stability in single cells.Accurate repair of DNA damage is crucial for genome stability and preventing disease. Here, the authors adapt single-cell omics technologies to map the location of repair proteins across the human genome, showing formation of multi-way chromatin hubs in response to damage. [ABSTRACT FROM AUTHOR]

Introduction: Spontaneous control of chronic-phase HIV/SIV viremia is often associated with the expression of specific MHC class I allotypes. HIV/SIV-specific CD8+ cytotoxic T lymphocytes (CTLs) restricted by these MHC class I allotypes appear to be critical for viremic control. Establishment of the elite controller (EC) phenotype is predictable in SIVmac239-infected Indian rhesus macaques (RMs), with approximately 50% of Mamu-B*08 + RMs and 20% of Mamu-B*17 + RMs becoming ECs. Despite extensive characterization of EC-associated CTLs in HIV/SIV-infected individuals, the precise mechanistic basis of elite control remains unknown. Because EC and non-EC viral load trajectories begin diverging by day 14 post-infection, we hypothesized that hyperacute innate immune responses may contribute to viremic control. Methods: To gain insight into the immunological factors involved in the determination of EC status, we vaccinated 16 Mamu-B*08 + RMs with Vif and Nef to elicit EC-associated CTLs, then subjected these 16 vaccinees and an additional 16 unvaccinated Mamu-B*08 + controls to repeated intrarectal SIVmac239 challenges. We then performed whole-blood transcriptomic analysis of all 32 SIVmac239-infected Mamu-B*08 + RMs and eight SIVmac239-infected Mamu-B*08 – RMs during the first 14 days of infection. Results: Vaccination did not provide protection against acquisition, but peak and setpoint viremia were significantly lower in vaccinees relative to controls. We did not identify any meaningful correlations between vaccine-induced CTL parameters and SIVmac239 acquisition rate or chronic-phase viral loads. Ultimately, 13 of 16 vaccinees (81%) and 7 of 16 controls (44%) became ECs (viremia ≤ 10,000 vRNA copies/mL plasma for ≥ 4 weeks). We identified subsets of immunomodulatory genes differentially expressed (DE) between RM groupings based on vaccination status, EC status, and MHC class I genotype. These DE genes function in multiple innate immune processes, including the complement system, cytokine/chemokine signaling, pattern recognition receptors, and interferon-mediated responses. Discussion: A striking difference in the kinetics of differential gene expression among our RM groups suggests that Mamu-B*08 -associated elite control is characterized by a robust, rapid innate immune response that quickly resolves. These findings indicate that, despite the association between MHC class I genotype and elite control, innate immune factors in hyperacute SIV infection preceding CTL response development may facilitate the establishment of the EC phenotype. [ABSTRACT FROM AUTHOR]

Purpose: As primary care (PC) clinics seek to integrate behavioral health (BH) services into patient care, it is crucial to understand the experiences of the clinic team and the impact on workflow and well-being. This study was designed to identify perspectives and experiences of nurse practitioner-led PC teams as they implemented a behavioral health integration (BHI) model into their Federally Qualified Health Center PC practices. Methods: We conducted in-depth qualitative interviews with staff members at three clinic sites that implemented BHI. Interviewees were asked questions about the benefits and challenges encountered in the new BHI workflow, the dynamics of the warm hand-off, the tools and resources they used and desired, and the changes they would like to see to promote efficient workflows. Results: We interviewed 21 staff members during May and June of 2020. An analysis of the qualitative data showed the most frequently reported experiences and attitudes focused on (a) the availability of behavioral health consultants (BHC); (b) procedural uses of the warm hand-off; (c) the organization's productivity goals; and (d) desired tools and resources that are generally unavailable to the clinicians but could make a difference to patient care. Conclusion: Our results can assist FQHCs and similar organizations to achieve both BHI and the Quintuple aim. Integrating BH services into PC clinics is valuable and may mitigate clinician-staff burnout. However, PC organizations desiring to integrate new sustainable care models should consider involving staff in every phase of the transitional process phase to increase staff buy-in and staff rapport. [ABSTRACT FROM AUTHOR]

Introduction: 5p deletion syndrome, also called Cri-du-chat syndrome 5p is a rare genetic syndrome with reports up to 36% of patients are associated with congenital heart defects. We investigated the association between left outflow tract obstruction and Cri-du-chat syndrome. Methods: A retrospective review of the abnormal microarray cases with congenital heart defects in Children's Hospital of Pittsburgh and the Cytogenomics of Cardiovascular Malformations Consortium. Results: A retrospective review at nine pediatric centers identified 4 patients with 5p deletions and left outflow tract obstruction (LVOTO). Three of these patients had additional copy number variants. We present data suggesting an association of LVOTO with 5p deletion with high mortality in the presence of additional copy number variants. Conclusion: A rare combination of 5p deletion and left ventricular outflow obstruction was observed in the registry of copy number variants and congenital heart defects. [ABSTRACT FROM AUTHOR]

Objective: Explore the experiences of people with knee osteoarthritis (OA) who received a very low energy diet (VLED) and exercise program from a physiotherapist. Methods: Mixed methods study involving questionnaires (n = 42) and semistructured interviews (n = 22) with randomized control trial participants with knee OA who had received a 6‐month physiotherapist‐delivered VLED weight loss and exercise intervention. Questionnaires measured participant satisfaction and perceptions about physiotherapist's skills/knowledge in delivery of the dietary intervention (measured on 5–7 point Likert scales). Interviews explored participant's experiences and were analyzed based on the principles of reflexive thematic analysis. Results: Questionnaire response: 90%. Participants were satisfied with the program (95%), confident their physiotherapist had the required skills (84%) and knowledge (79%) to deliver the dietary intervention, felt comfortable talking to the physiotherapist about weight (74%), and would recommend others see a physiotherapist for the intervention they undertook (71%). The following four themes were developed from the interviews: (1) one‐stop‐shop of exercise and diet; (2) physiotherapist‐delivered weight loss works (unsure initially; successfully lost weight); (3) physiotherapists knowledge and skills (exercise is forte; most thought physiotherapists had the necessary weight loss skills/knowledge, but some disagreed); and (4) physiotherapists have a role in weight loss (physiotherapists are intelligent, credible, and trustworthy; specific training in weight loss necessary). Conclusion: This study provides, to our knowledge, the first documented perspectives from people with OA who have received a physiotherapist‐delivered weight loss intervention. Findings suggest physiotherapists may have a role in delivering a protocolized dietary intervention for some people with knee OA with overweight and obesity. [ABSTRACT FROM AUTHOR]

Background: Vaccination against Streptococcus pneumoniae is advised for transplant recipients to reduce morbidity and mortality associated with invasive pneumococcal disease. However, data on alloantibodies after sequential vaccination (with a pneumococcal conjugate vaccine followed by a polysaccharide vaccine) are still lacking. Methods: In the current study, we determined HLA class I and II and major histocompatibility class I-related chain A (MICA) antibodies in 41 clinically stable kidney transplant recipients. These antibodies were measured prior to and post sequential pneumococcal vaccination over a period of 12 months. Alloantibodies were measured by Luminex bead-based assays, and pneumococcal IgG antibodies were measured by ELISA. Results: Over a 12-month period, the sequential analysis revealed no significant change in alloantibodies. One patient developed de novo donor-specific antibodies (DSA) 1.5 months after the first vaccination, with mean fluorescence intensities of up to 2300. These DSA became undetectable in the follow-up, and the patient showed no signs of allograft rejection. Another patient experienced a biopsy-proven borderline rejection 7 months after the first vaccination but did not develop de novo DSA. Both maintained stable kidney function. As expected, the pneumococcal antibodies increased significantly after vaccination (p < 0.0001). Conclusions: Given the overall risk of alloimmune responses in transplant recipients, we would not attribute the two noticeable patient courses to vaccination. Thus, we consider sequential vaccination immunologically safe. [ABSTRACT FROM AUTHOR]

Objective: It is increasingly recognised that social anxiety is underpinned by a bivalent fear of evaluation. The present study tested how well a core-beliefs measure developed for social anxiety was accounted for within this bivalent model. It was hypothesised that bivalent fear of evaluation would predict more variance in social anxiety symptoms than negative alone, and that known core beliefs would predict fear of negative more than fear of positive evaluation. Method: An online survey was completed by 346 undergraduates who were recruited in exchange for course credit, through a targeted strategy that ensured that they experienced social anxiety symptoms. The survey was completed on Qualtrics, with all questions appearing in a standardised order. Results: The hypothesised model explained 45.4% of social anxiety symptom variance. Core-beliefs explained unique variance in fear of positive and negative evaluation but had a larger relationship with fear of negative evaluation. Conclusions: These results suggest that different core-beliefs underpin fear of positive and negative evaluation. Better knowledge of the core-beliefs underpinning fear of positive evaluation may inform the development of more effective psychological treatments KEY POINTS: What is already known about this topic: Bivalent fear of evaluation is increasingly recognised in social anxiety. Fear of positive evaluation uniquely contributes beyond negative evaluation. Core belief measures exist based on fear of negative evaluation theories. What this topic adds: Established core beliefs do not well explain variance in positive evaluation. Only conditional beliefs explain variance in both fear of negative and positive evaluation. Further research is needed on core beliefs related to fear of positive evaluation. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is a chronic sleep-related breathing disorder that is highly prevalent in individuals with posttraumatic stress disorder (PTSD). The reason for this high prevalence remains unclear. We hypothesized that breathing instability, one of the key contributors to OSA, may be altered in PTSD and predispose OSA. Healthy participants (214 females, 98 males) aged 17 to 42 (M = 19.92; SD = 2.85) completed online questionnaires measuring PTSD symptomatology, sleep disturbances, and self-reported breathlessness. A subset of these participants (16 females, 14 males) aged 18 to 42 (M = 23.50; SD = 7.18) completed an in-lab breathing instability assessment, whereby they performed a series of 20-second and maximal duration breath-holds. PTSD severity positively predicted subjective perceptions of breathlessness (P < 0.001) but not objective measures of breathing instability, namely ventilation following 20-s breath-holds (P = 0.93) and maximal breath-hold duration (P = 0.41). These results suggest that breathing instability may not be the driving factor behind the high prevalence of OSA in PTSD. Instead, other factors such as a low arousal threshold, elevated ventilatory responses to arousal, or coexisting insomnia may explain the high rates of OSA in PTSD. One explanation for the discrepancy between subjective breathlessness and breathing stability measures relating to PTSD severity may be that hypervigilance and increased anxiety impacted self-perceptions of breathlessness while not altering breathing instability per se. NEW & NOTEWORTHY: Obstructive sleep apnea (OSA) is more common in individuals with posttraumatic stress disorder (PTSD) than the general population for unknown reasons. This study assessed one of the key contributors to OSA, respiratory control instability, in young students with a range of posttraumatic stress symptoms. Although individuals with high PTSD symptoms reported increased subjective breathlessness, objectively measured breathing instability was not altered, suggesting respiratory instability is unlikely to increase the risk of OSA in PTSD. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy has become an important treatment for hematological cancers, and its success has spurred research into CAR T cell therapies for other diseases, including solid tumor cancers and autoimmune diseases. Notably, the development of CAR-based treatments for autoimmune diseases has shown great progress recently. Clinical trials for anti-CD19 and anti-BCMA CAR T cells in treating severe B cell-mediated autoimmune diseases, like systemic lupus erythematosus (SLE), have shown lasting remission thus far. CAR T cells targeting autoreactive T cells are beginning clinical trials for treating T cell mediated autoimmune diseases. Chimeric autoantigen receptor (CAAR) T cells specifically target and eliminate only autoreactive B cells, and they have shown promise in treating mucosal pemphigus vulgaris and MuSK myasthenia gravis. Regulatory CAR T cells have also been developed, which show potential in altering autoimmune affected areas by creating a protective barrier as well as helping decrease inflammation. These new treatments are only the beginning of potential CAR T cell applications in treating autoimmune disease. Novel CAR technologies have been developed that increase the safety, potency, specificity, and efficacy of CAR T cell therapy. Applying these novel modifications to autoimmune CARs has the potential to enhance the efficacy and applicability of CAR therapies to autoimmune disease. This review will detail several recently developed CAR technologies and discuss how their application to autoimmune disease will improve this emerging field. These include logicgated CARs, soluble protein-secreting CARs, and modular CARs that enable CAR T cell therapies to be more specific, reach a wider span of target cells, be safer for patients, and give a more potent cytotoxic response. Applying these novel CAR technologies to the treatment of autoimmune diseases has the potential to revolutionize this growing application of CAR T cell therapies. [ABSTRACT FROM AUTHOR]

Neuroestrogens locally synthesized in the brain are known to play a role in sexual behaviors. However, the question of whether neuroestrogens are involved in the regulation of the gonadotropin‐releasing hormone (GnRH) release is just emerging. Because previous studies in this lab indicate that neuroestradiol is also important for the pulsatile release as well as the surge release of GnRH in female rhesus monkeys, in the present study, we examined whether neuroestradiol plays a role in the estrogen‐induced LH surge in orchidectomized (ORX) male rhesus monkeys. Unlike in rodents, it is known that a high dose of estrogen treatment can result in the LH surge in ORX male rhesus monkeys. Results that the administration of the aromatase inhibitor, letrozole, failed to attenuate the estrogen‐induced LH surge, suggest that unlike in ovariectomized females, neuroestrogens do not play a role in the LH surge experimentally induced by the exogenous estrogen treatment in ORX male monkeys. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic negatively affected physical and psychological health worldwide. Pregnant women were likely more vulnerable to mental health difficulties due to the significant social, psychological, and hormonal changes they experience. During the pandemic, higher rates of antenatal depression and anxiety were observed compared to pre-pandemic rates. Increased mental health symptoms in pregnancy have been associated with adverse outcomes for child development. Understanding pandemic-specific preventive behaviours (i.e., mask use, physical distancing) and concerns may also be linked to maternal psychological well-being. Purpose: To compare matched pregnant and non-pregnant women (N = 474) to assess COVID-19 psychosocial impacts, preventive behaviours, and concerns. Methods: This study used a matched analysis of data collected by the International COVID-19 Awareness and Responses Evaluation (iCARE) Study. Participants were matched on several demographic factors and analyses were adjusted for chronic illness and psychiatric disorder. Results: Linear regression analyses indicated that pregnant women did not significantly differ from matched non-pregnant women for psychosocial impacts (B = 0.11, SE = 0.08, p = 0.178). Those who reported a chronic illness (B=-0.19, SE = 0.09, p = 0.036) or a psychiatric disorder (B=-0.28, SE = 0.09, p = 0.003) were more likely to report more significant psychosocial impacts. Logistic regression analyses indicated that pregnant women were more likely to report staying at home rather than going to work (OR = 2.01, 95% CI 1.31–3.08, p = 0.002) and being concerned about being infected (OR = 1.61, 95% CI 1.05–2.46, p = 0.028). Conclusions: Our findings in the context of the COVID-19 pandemic highlight the need to consider interventions targeting women, with chronic illnesses or psychiatric disorders, as they are often the most vulnerable. [ABSTRACT FROM AUTHOR]

Host organisms can harbor microbial symbionts that defend them from pathogen infection in addition to the resistance encoded by the host genome. Here, we investigated how variation in defenses, generated from host genetic background and symbiont presence, affects the emergence of pathogen genetic diversity across evolutionary time. We passaged the opportunistic pathogen Pseudomonas aeruginosa through populations of the nematode Caenorhabditis elegans varying in genetic-based defenses and prevalence of a protective symbiont. After 14 passages, we assessed the amount of genetic variation accumulated in evolved pathogen lineages. We found that diversity begets diversity. An overall greater level of pathogen whole-genome and per-gene genetic diversity was measured in pathogens evolved in mixed host populations compared with those evolved in host populations composed of one type of defense. Our findings directly demonstrate that symbiont-generated heterogeneity in host defense can be a significant contributor to pathogen genetic variation. [ABSTRACT FROM AUTHOR]

Copyright of European Poultry Science / Archiv für Geflügelkunde is the property of Verlag Eugen Ulmer and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: To assess the knowledge levels and fertility preservation (FP) intentions of urban Chinese cancer patients. Methods: A cross-sectional study was conducted on Hong Kong Chinese male and female cancer patients aged 18–54 years (N = 325) who were recruited by a local non-governmental organization for cancer patients between July 2020 to January 2021. Patients completed a self-administered questionnaire on knowledge, perceptions, and intentions to use FP services/seek FP-related information. Multivariable logistic regression was used to explore the correlates of intention to seek additional FP information and intention to undergo FP treatments. Results: Although cancer patients demonstrated a good knowledge of the available FP treatment options, they were less knowledgeable about the legal restrictions of these procedures. Only one in seven cancer patients first became aware of FP through a health provider and the majority of cancer patients felt they did not have adequate knowledge about FP to make informed FP decisions at the current time. Yet, over one-third of cancer patients would consider FP options even if their cancer or cancer treatment had < 5% chance of causing infertility, and 13.4% of females and 14.6% of males would delay their cancer treatment by ≥ 3 months to undergo FP procedures. However, for both sexes, the main perceived barrier to obtaining FP was its financial cost. Patients with older-aged spouses were less likely to seek FP treatments or seek more information about FP. Conclusion: There is an unmet need for more FP information and FP services for reproductive-aged cancer patients in East Asian populations. Greater integration of FP services into cancer treatment requires a reduction of cost barriers, greater provision of timely FP information, and improved referral systems. [ABSTRACT FROM AUTHOR]

Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in a BAV cohort with late onset sporadic disease (n = 5040). We identified 3 large and rare (< 1,1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting with GATA4 and DSCAM were enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 9% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV. [ABSTRACT FROM AUTHOR]

X chromosome inactivation (XCI) is an epigenetic process that results in the transcriptional silencing of one X chromosome in the somatic cells of females. This phenomenon is common to both eutherian and marsupial mammals, but there are fundamental differences. In eutherians, the X chosen for silencing is random. DNA methylation on the eutherian inactive X is high at transcription start sites (TSSs) and their flanking regions, resulting in universally high DNA methylation. This contrasts XCI in marsupials where the paternally derived X is always silenced, and in which DNA methylation is low at TSSs and flanking regions. Here, we examined the DNA methylation status of the tammar wallaby X chromosome during spermatogenesis to determine the DNA methylation profile of the paternal X prior to and at fertilization. Whole genome enzymatic methylation sequencing was carried out on enriched flow-sorted populations of premeiotic, meiotic, and postmeiotic cells. We observed that the X displayed a pattern of DNA methylation from spermatogonia to mature sperm that reflected the inactive X in female somatic tissue. Therefore, the paternal X chromosome arrives at the egg with a DNA methylation profile that reflects the transcriptionally silent X in adult female somatic tissue. We present this epigenetic signature as a candidate for the long sought-after imprint for paternal XCI in marsupials. [ABSTRACT FROM AUTHOR]

Background/Objectives: Systemic lupus erythematosus (lupus) and B-cell lymphoma (lymphoma) co-occur at higher-than-expected rates and primarily depend on B cells for their pathology. These observations implicate shared inflammation-related B cell molecular mechanisms as a potential cause of co-occurrence. Methods: We consequently implemented a novel Immune Imbalance Transcriptomics (IIT) algorithm and applied IIT to lupus, lymphoma, and healthy B cell RNA-sequencing (RNA-seq) data to find shared and contrasting mechanisms that are potential therapeutic targets. Results: We observed 7143 significantly dysregulated genes in both lupus and lymphoma. Of those genes, we found 5137 to have a significant immune imbalance, defined as a significant dysregulation by both diseases, as analyzed by IIT. Gene Ontology (GO) term and pathway enrichment of the IIT genes yielded immune-related "Neutrophil Degranulation" and "Adaptive Immune System", which validates that the IIT algorithm isolates biologically relevant genes in immunity and inflammation. We found that 344 IIT gene products are known targets for established and/or repurposed drugs. Among our results, we found 48 known and 296 novel lupus targets, along with 151 known and 193 novel lymphoma targets. Known disease drug targets in our IIT results further validate that IIT isolates genes with disease-relevant mechanisms. Conclusions: We anticipate the IIT algorithm, together with the shared and contrasting gene mechanisms uncovered here, will contribute to the development of immune-related therapeutic options for lupus and lymphoma patients. [ABSTRACT FROM AUTHOR]

Introduction: Uptake of telehealth has surged, yet no previous studies have evaluated the clinimetric properties of clinician-administered performance-based tests of function, strength, and balance via telehealth in people with chronic lower limb musculoskeletal pain. This study investigated the: (i) test–retest reliability of performance-based tests via telehealth, and (ii) agreement between scores obtained via telehealth and in-person. Methods: Fifty-seven adults aged ≥45 years with chronic lower limb musculoskeletal pain underwent three testing sessions: one in-person and two via videoconferencing. Tests included 30-s chair stand, 5-m fast-paced walk, stair climb, timed up and go, step test, timed single-leg stance, and calf raises. Test–retest reliability and agreement were assessed via intraclass correlation coefficients (ICC; lower limit of 95% confidence interval (CI) ≥0.70 considered acceptable). ICCs were interpreted as poor (<0.5), moderate (0.5–0.75), good (0.75–0.9), or excellent (>0.9). Results: Test–retest reliability was good-excellent with acceptable lower CI for stair climb test, timed up and go, right leg timed single-leg stance, and calf raises (ICC = 0.84–0.91, 95% CI lower limit = 0.71–0.79). Agreement between telehealth and in-person was good-excellent with acceptable lower CI for 30-s chair stand, left leg single-leg stance, and calf raises (ICC = 0.82–0.91, 95% CI lower limit = 0.71–0.85). Discussion: Stair climb, timed up and go, right leg timed single-leg stance, and calf raise tests have acceptable reliability for use via telehealth in research and clinical practice. If re-testing via a different mode (telehealth/in-person), clinicians and researchers should consider using the 30-s chair stand test, left leg timed single-leg stance, and calf raise tests. [ABSTRACT FROM AUTHOR]

* OBJECTIVES: To explore (1) initial feelings of people with knee osteoarthritis who are unexpectedly offered telerehabilitation, and (2) if their experiences met their expectations, and their willingness to use telerehabilitation in the future. * DESIGN: Mixed-methods study of 122 people with knee osteoarthritis who were randomized to receive physiotherapist-delivered telerehabilitation in a clinical trial. * METHODS: At enrollment in the trial, participants were unaware care would be delivered via telerehabilitation. At completion, quantitative (Likert scales, analyzed descriptively) and qualitative (open-text, underwent content/thematic analysis) questions asked participants about their initial feelings when randomized to telerehabilitation, if experiences met expectations, and willingness to use telerehabilitation in the future. * RESULTS: Data were collected between October 2021 to March 2023. At enrollment, 44 (36% of 122) participants initially felt negative toward telerehabilitation (doubts about effectiveness, physiotherapist can't see/touch, believe in-person is better, can't communicate effectively, not good with technology), 18 (15%) were neutral, and 60 (49%) felt positive. After experiencing telerehabilitation, 43 (72%) people who were initially positive and 27 (61%) who were initially negative believed telerehabilitation exceeded their expectations (easier than expected, surprised by benefits/effectiveness, strong rapport with physiotherapist, convenience). Twenty-eight (23% of 122) people were not at all or slightly willing to use telerehabilitation in future (prefer hands-on, doesn't allow adequate assessment/observation, prefer in-person, don't like telerehabilitation). * CONCLUSION: One in 2 people were positive about telerehabilitation from the outset, and 6 in 10 people who initially felt negative about telerehabilitation found that their experiences were better than expected. One in 4 people were unwilling to use telerehabilitation in the future, even after they had experienced it. [ABSTRACT FROM AUTHOR]

OATP1B facilitates the uptake of xenobiotics into hepatocytes and is a prominent target for drug–drug interactions (DDIs). Reduced systemic exposure of OATP1B substrates has been reported following multiple‐dose rifampicin; one explanation for this observation is OATP1B induction. Non‐uniform hepatic distribution of OATP1B may impact local rifampicin tissue concentrations and rifampicin‐mediated protein induction, which may affect the accuracy of transporter‐ and/or metabolizing enzyme‐mediated DDI predictions. We incorporated quantitative zonal OATP1B distribution data from immunofluorescence imaging into a PBPK modeling framework to explore rifampicin interactions with OATP1B and CYP substrates. PBPK models were developed for rifampicin, two OATP1B substrates, pravastatin and repaglinide (also metabolized by CYP2C8/CYP3A4), and the CYP3A probe, midazolam. Simulated hepatic uptake of pravastatin and repaglinide increased from the periportal to the pericentral region (approximately 2.1‐fold), consistent with OATP1B distribution data. Simulated rifampicin unbound intracellular concentrations increased in the pericentral region (1.64‐fold) compared to simulations with uniformly distributed OATP1B. The absolute average fold error of the rifampicin PBPK model for predicting substrate maximal concentration (Cmax) and area under the plasma concentration–time curve (AUC) ratios was 1.41 and 1.54, respectively (nine studies). In conclusion, hepatic OATP1B distribution has a considerable impact on simulated zonal substrate uptake clearance values and simulated intracellular perpetrator concentrations, which regulate transporter and metabolic DDIs. Additionally, accounting for rifampicin‐mediated OATP1B induction in parallel with inhibition improved model predictions. This study provides novel insight into the effect of hepatic OATP1B distribution on site‐specific DDI predictions and the impact of accounting for zonal transporter distributions within PBPK models. [ABSTRACT FROM AUTHOR]

Bicuspid aortic valve (BAV) is the most common congenital heart malformation in adults, but it can also cause childhood-onset complications. The presentation and clinical course of young adults who present due to BAV complications are relatively uncharacterized. In a multicenter study, we found that young people who experience significant complications related to BAV disease before age 30 are distinguished from the majority of BAV cases that manifest after age 50 by a relatively severe clinical course, with higher rates of surgical interventions, more frequent second interventions, and a greater burden of congenital heart malformations. These observations highlight the need for prompt recognition, regular lifelong surveillance, and targeted interventions to address the significant health burdens of patients with early-onset BAV complications. [ABSTRACT FROM AUTHOR]

Background: Despite the wide‐ranging negative consequences of nonsuicidal self‐injury (NSSI), there are few evidence‐based treatments for NSSI among adolescents and little is known about what treatments that work best for whom. The objective of this study was to investigate moderators (i.e., for whom a specific treatment works) and predictors (i.e., factors associated with treatment outcome independent of treatment type) of treatment outcome in a randomized clinical trial comparing internet‐delivered emotion regulation individual therapy for adolescents (IERITA) plus treatment as usual (TAU) to TAU alone. Methods: Adolescents (N = 166; mean [SD] age = 15.0 [1.2] years) with NSSI disorder were randomized to IERITA plus TAU (n = 84) or TAU‐only (n = 82). Adolescent emotion regulation difficulties, suicidality, NSSI frequency, depressive symptoms, sleep difficulties, global functioning, and age, and parental invalidation, were measured pre‐treatment and investigated as moderators and predictors of treatment outcome (i.e., NSSI frequency during treatment and for 4 weeks post‐treatment). A zero‐inflated negative binomial generalized linear mixed effects regression model was used to estimate the rate of NSSI change as a function of both treatment condition and moderator/predictor. Results: No significant moderators of treatment outcome were found. Parental invalidation was a significant predictor of treatment outcome regardless of treatment condition, such that high levels of parental invalidation pre‐treatment were associated with a less favorable NSSI frequency. Conclusions: We did not find evidence of a differential treatment effect as a function of any of the examined client factors. Future research should investigate moderation in larger samples and with sufficient statistical power to detect moderation effects of smaller magnitude. Results suggest that parental invalidation may have a negative impact on treatment response and highlight the importance of further investigating parental invalidation in the context of NSSI treatments. [ABSTRACT FROM AUTHOR]

Rapidly evolving taxa are excellent models for understanding the mechanisms that give rise to biodiversity. However, developing an accurate historical framework for comparative analysis of such lineages remains a challenge due to ubiquitous incomplete lineage sorting (ILS) and introgression. Here, we use a whole-genome alignment, multiple locus-sampling strategies, and summary-tree and single nucleotide polymorphism-based species-tree methods to infer a species tree for eastern North American Neodiprion species, a clade of pine-feeding sawflies (Order: Hymenopteran; Family: Diprionidae). We recovered a well-supported species tree that—except for three uncertain relationships—was robust to different strategies for analyzing whole-genome data. Nevertheless, underlying gene-tree discordance was high. To understand this genealogical variation, we used multiple linear regression to model site concordance factors estimated in 50-kb windows as a function of several genomic predictor variables. We found that site concordance factors tended to be higher in regions of the genome with more parsimony-informative sites, fewer singletons, less missing data, lower GC content, more genes, lower recombination rates, and lower D -statistics (less introgression). Together, these results suggest that ILS, introgression, and genotyping error all shape the genomic landscape of gene-tree discordance in Neodiprion. More generally, our findings demonstrate how combining phylogenomic analysis with knowledge of local genomic features can reveal mechanisms that produce topological heterogeneity across genomes. [ABSTRACT FROM AUTHOR]

Steroid hormones are important modulators of many physiological processes, and measurements of steroids in blood, saliva, and urine matrices are widely used to assess endocrine pathologies and stress. However, these matrices cannot be used to retrospectively assess early-life stress and developmental endocrine pathologies, because they do not integrate steroid levels over the long term. A novel biological matrix in which to measure steroids is primary teeth (or "baby teeth"). Primary teeth develop early in life and accumulate various endogenous molecules during their gradual formation. Here, we developed and validated the first assay to measure steroids in human primary teeth using liquid chromatography-tandem spectrometry (LC-MS/MS). Our assay is highly sensitive, specific, accurate, and precise. It allows for the simultaneous quantification of 17 steroids in primary teeth (16 of which have not been examined previously in primary teeth). Overall, steroid levels in primary teeth were relatively low, and 8 steroids were quantifiable. Levels of dehydroepiandrosterone, cortisol, and progesterone were the highest of the 17 steroids examined. Next, we used this assay to perform steroid profiling in primary teeth from males and females. The same 8 steroids were quantifiable, and no sex differences were found. Levels of androgens (androstenedione and testosterone) were positively correlated, and levels of glucocorticoids (cortisol, cortisone, corticosterone, 11-dehydrocorticosterone) were also positively correlated. These data demonstrate that multiple steroids can be quantified by LC-MS/MS in human primary teeth, and this method potentially provides a powerful new way to retrospectively assess early-life stress and developmental endocrine pathologies. [ABSTRACT FROM AUTHOR]

Heteromorphic sex chromosomes (XY or ZW) present problems of gene dosage imbalance between sexes and with autosomes. A need for dosage compensation has long been thought to be critical in vertebrates. However, this was questioned by findings of unequal mRNA abundance measurements in monotreme mammals and birds. Here, we demonstrate unbalanced mRNA levels of X genes in platypus males and females and a correlation with differential loading of histone modifications. We also observed unbalanced transcripts of Z genes in chicken. Surprisingly, however, we found that protein abundance ratios were 1:1 between the sexes in both species, indicating a post-transcriptional layer of dosage compensation. We conclude that sex chromosome output is maintained in chicken and platypus (and perhaps many other non therian vertebrates) via a combination of transcriptional and post-transcriptional control, consistent with a critical importance of sex chromosome dosage compensation. [ABSTRACT FROM AUTHOR]

Suboptimal disease self-management among adults with type 2 diabetes is associated with greater risk of diabetes related health complications and mortality. Emotional distress has been linked with poor diabetes self-management; however, few studies have examined the role of emotion dysregulation in diabetes management. The purpose of this study was to examine the relations between different facets of emotion dysregulation and diabetes self-management behaviors among a sample of 373 adults with type 2 diabetes. Separate median regression and binary logistic regression models were used to examine the association of emotion dysregulation facets and each diabetes self-care behavior (i.e., medication nonadherence, diet, exercise, self-monitoring of blood glucose (SMBG), foot care, and smoking). Generally, greater difficulties in emotion regulation were associated with poorer self-management behaviors. However, several facets of emotion dysregulation were linked with better self-management behaviors. Addressing emotion dysregulation among adults with type 2 diabetes has the potential to improve diabetes related self-management. [ABSTRACT FROM AUTHOR]

Background: The kernel used in CT image reconstruction is an important factor that determines the texture of the CT image. Consistency of reconstruction kernel choice is important for quantitative CT‐based assessment as kernel differences can lead to substantial shifts in measurements unrelated to underlying anatomical structures. Purpose: In this study, we investigate kernel harmonization in a multi‐vendor low‐dose CT lung cancer screening cohort and evaluate our approach's validity in quantitative CT‐based assessments. Methods: Using the National Lung Screening Trial, we identified CT scan pairs of the same sessions with one reconstructed from a soft tissue kernel and one from a hard kernel. In total, 1000 pairs of five different paired kernel types (200 each) were identified. We adopt the pix2pix architecture to train models for kernel conversion. Each model was trained on 100 pairs and evaluated on 100 withheld pairs. A total of 10 models were implemented. We evaluated the efficacy of kernel conversion based on image similarity metrics including root mean squared error (RMSE), peak signal‐to‐noise ratio (PSNR), and structural similarity index measure (SSIM) as well as the capability of the models to reduce measurement shifts in quantitative emphysema and body composition measurements. Additionally, we study the reproducibility of standard radiomic features for all kernel pairs before and after harmonization. Results: Our approach effectively converts CT images from one kernel to another in all paired kernel types, as indicated by the reduction in RMSE (p < 0.05) and an increase in the PSNR (p < 0.05) and SSIM (p < 0.05) for both directions of conversion for all pair types. In addition, there is an increase in the agreement for percent emphysema, skeletal muscle area, and subcutaneous adipose tissue (SAT) area for both directions of conversion. Furthermore, radiomic features were reproducible when compared with the ground truth features. Conclusions: Kernel conversion using deep learning reduces measurement variation in percent emphysema, muscle area, and SAT area. [ABSTRACT FROM AUTHOR]

Background On-road driving skills can be impaired in older drivers and drivers with mild cognitive impairment (MCI) due to different driving-relevant deficits. Among these deficits, somatic factors have received little attention so far. Methods In a prospective observational on-road driving study, we examined whether somatic factors can predict on-road driving skills in a mixed sample of healthy older drivers and drivers with MCI (n  = 99) and whether the inclusion of age explains additional variance. Somatic factors included the number of prescribed drugs, visual acuity, peripheral visual field integrity, mobility of the cervical spine, and hearing impairment. A hierarchical regression analysis was used to predict on-road driving skills by adding the somatic factors in the first step and age in the second step. Results Results revealed that the combination of somatic factors significantly predicted on-road driving skills (R 2adjusted = 0.439). The inclusion of age led to a significant increase of explained variance (R 2adjusted = 0.466). Conclusions Our results suggest that somatic factors can accurately predict on-road driving skills in healthy older drivers and drivers with MCI. In addition, our results suggest that there is a significant but rather small effect of age beyond somatic changes. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) have become internationally recognized over the past three decades as persistent organic pollutants used in the production of various consumer and industrial goods. Research efforts continue to gauge the risk that historically used, and newly produced, PFAS may cause to human health. Numerous studies report toxic effects of PFAS on the human liver as well as increased serum cholesterol levels in adults. A major concern with PFAS, also dubbed "forever chemicals," is that they accumulate in the liver and kidney and persist in serum. The mechanisms responsible for their disposition and excretion in humans are poorly understood. A better understanding of the interaction of PFAS with liver transporters, as it pertains to the disposition of PFAS and other xenobiotics, could provide mechanistic insight into human health effects and guide efforts toward risk assessment of compounds in development. This review summarizes the current state of the literature on the emerging relationships (eg, substrates, inhibitors, modulators of gene expression) between PFAS and specific hepatic transporters. The adaptive and toxicological responses of hepatocytes to PFAS that reveal linkages to pathologies and epidemiological findings are highlighted. The evidence suggests that our understanding of the molecular landscape of PFAS must improve to determine their impact on the expression and function of hepatocyte transporters that play a key role in PFAS or other xenobiotic disposition. From here, we can assess what role these changes may have in documented human health outcomes. [ABSTRACT FROM AUTHOR]

Aims Cardiac energy metabolism is perturbed in ischaemic heart failure and is characterized by a shift from mitochondrial oxidative metabolism to glycolysis. Notably, the failing heart relies more on ketones for energy than a healthy heart, an adaptive mechanism that improves the energy-starved status of the failing heart. However, whether this can be implemented therapeutically remains unknown. Therefore, our aim was to determine if increasing ketone delivery to the heart via a ketogenic diet can improve the outcomes of heart failure. Methods and results C57BL/6J male mice underwent either a sham surgery or permanent left anterior descending coronary artery ligation surgery to induce heart failure. After 2 weeks, mice were then treated with either a control diet or a ketogenic diet for 3 weeks. Transthoracic echocardiography was then carried out to assess in vivo cardiac function and structure. Finally, isolated working hearts from these mice were perfused with appropriately 3H or 14C labelled glucose (5 mM), palmitate (0.8 mM), and β-hydroxybutyrate (β-OHB) (0.6 mM) to assess mitochondrial oxidative metabolism and glycolysis. Mice with heart failure exhibited a 56% drop in ejection fraction, which was not improved with a ketogenic diet feeding. Interestingly, mice fed a ketogenic diet had marked decreases in cardiac glucose oxidation rates. Despite increasing blood ketone levels, cardiac ketone oxidation rates did not increase, probably due to a decreased expression of key ketone oxidation enzymes. Furthermore, in mice on the ketogenic diet, no increase in overall cardiac energy production was observed, and instead, there was a shift to an increased reliance on fatty acid oxidation as a source of cardiac energy production. This resulted in a decrease in cardiac efficiency in heart failure mice fed a ketogenic diet. Conclusion We conclude that the ketogenic diet does not improve heart function in failing hearts, due to ketogenic diet-induced excessive fatty acid oxidation in the ischaemic heart and a decrease in insulin-stimulated glucose oxidation. [ABSTRACT FROM AUTHOR]

Simple Summary: Simple Summary: With the low demand for leather from sheepskin, New Zealand slaughterhouses dispose of most byproduct sheepskin from meat production as solid waste. This study aimed to develop a use for these sheepskins as a source of gelatin or collagen. Three extraction methods were evaluated. The extracted material was characterized for gelatin and collagen composition and structure. Sheepskin was found to be a useful alternative source of gelatin–collagen material. Abattoirs dispose of sheepskins as solid waste due to low price and poor demand for sheepskin leather. In principle, as an alternative to being disposed of in landfill, sheepskins can serve as a source of the protein collagen or the hydrolysis product, gelatin. In this research, sheepskins collected from abattoirs were used as a source of collagen. Three extraction methods were compared: acid extraction, acid with enzymes, and alkali extraction. The extracted material was characterized using scanning electron microscopy (SEM) and Fourier-transform infrared spectroscopy (FTIR), small angle X-ray scattering (SAXS), and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The collagen and gelatin extraction yield ranged from 3.1% to 4.8% with the product purity determined by hydroxyproline, ranging from 7.8% for the alkali process to 59% and 68% for the acid and acid-enzyme processes. SDS PAGE showed that the acid process produced fragments with molecular weights in the range 100 to >250 kDa, while acid–enzyme resulted in smaller fragments, below 30 kDa. The FTIR region of the amide I band at 1800–1550 cm−1, which was used as an indicator of the collagen and gelatin content, showed that the gelatin dominated in the acid extracts, and the alkaline extract contained a large portion of keratin. SAXS was found to be a sensitive method for showing the presence of intact collagen fibrils in materials from all of the extraction methods, albeit at low concentrations. Herein, sheepskin is shown to be a useful source for collagen–gelatin material of varying molecular weights. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to examine referral patterns for people with musculoskeletal complaints presenting to Australian general practitioners (GPs). Methods: This longitudinal analysis from the Population Level Analysis Reporting (POLAR) database includes 133,279 patients with low back (≥18 years old) or neck, shoulder, and/or knee (≥45 years old) complaints seen by 4,538 GPs across 269 practices from 2014 through 2018. Referrals to allied health and medical and/or surgical specialists were included. We determined the number of patients with referrals and GPs who made referrals and examined their timing, associations, and trends over time. Results: A total of 43,666 patients (33%) received and 3,053 GPs (67%) made at least one referral. Most referrals were to allied health (n = 25,830, 19%), followed by surgeons (n = 18,805, 14%). Surgical referrals were higher for knee complaints (n = 6,140, 24%) compared with low back, neck, and shoulder complaints (range 8%–15%). The referral category varied predominantly by body region followed by gender, socioeconomic status, and primary health network. Time to allied health referral ranged between median (interquartile range [IQR]) 14 days (0–125 days) for neck complaints and 56 days (5–177 days) for knee complaints. Surgical referrals occurred sooner for those with knee complaints (15 days, IQR 0–128 days). There was a 2.2% (95% confidence interval [CI] 1.9%–2.4%) annual increase in the proportion of allied health referrals and a 1.9% (95% CI 1.6%–2.1%) decrease in surgical referrals across all sites. Conclusion: One‐third of patients receive, and two‐thirds of GPs make, referrals for musculoskeletal complaints. Understanding the reasons for referral and differences between GPs who refer more and less frequently may identify factors that explain variations in practice. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to determine dose parameters for resistance exercise associated with improvements in pain and physical function in knee and hip osteoarthritis (OA) and whether these improvements were related to adherence. Methods: We searched six databases, from inception to January 28, 2023, for randomized controlled trials comparing land‐based, resistance exercise–only interventions with no intervention, or any other intervention. There were four subgroups of intervention duration: 0 to <3 months, 3 to 6 months, >6 to <12 months, ≥12 months. The between‐group effect was calculated for immediate postintervention pain and physical function (activities of daily living [ADL] and sports/recreation [SPORT]). Results: For both knee and hip, data from 280 studies showed moderate benefit for pain, physical function ADL, and physical function SPORT in favor of interventions 3 to 6 months. For the knee, there was also a moderate benefit for physical function ADL in favor of interventions >6 to <12 months. From 151 knee and hip studies that provided total exercise volume data (frequency, time, duration), there was no association between volume with the effect size for pain and physical function. A total of 74 studies (69 knee, 5 hip) reported usable adherence data. There was no association between adherence with the effect size for pain and physical function. Conclusion: In knee and hip OA, resistance exercise interventions 3 to 6 months (and for the knee >6 to <12 months) duration improve pain and physical function. Improvements do not depend on exercise volume or adherence, suggesting exercise does not require rigid adherence to a specific dose. [ABSTRACT FROM AUTHOR]

Objectives: Anxiety is a global problem that is readily treatable with psychosocial interventions, though many individuals do not benefit following participation in extant treatment protocols. Accordingly, clarification of process‐related variables that may be leveraged to enhance outcomes appears warranted. Emotion regulation (ER) is a robust correlate of anxiety symptoms and is often targeted in behavioural treatments applied to anxiety‐related problems. Yet, some evidence suggests ER difficulties may be a proxy variable for emotional avoidance (EA). Clarifying the relative influence of ER and EA on anxiety symptom severity may improve specificity in targeting behavioural processes within psychosocial treatments designed to alleviate anxiety‐related suffering. Accordingly, we examined relations of ER and EA to anxiety symptom severity after accounting for anxiety sensitivity and anxiolytic medication use in a community‐based treatment‐seeking sample. Design: A four‐step hierarchical linear regression analysis of cross‐sectional data provided by a community‐based treatment‐seeking sample. Methods: Totally, 120 participants (Mage = 39.18; Female = 58.3%) completed a questionnaire packet upon intake to an anxiety disorders clinic. Results: EA and ER were strongly correlated, and each accounted for significant variance over and above model covariates. EA was a dominant risk factor for anxiety symptom severity, as ER was not a significant predictor (p =.073) following the inclusion of EA in the model (p =.006). Conclusions: EA appears to be a dominant risk factor, and ER a proxy risk factor, for anxiety symptom severity. EA may be an avenue for greater treatment specificity for those with anxiety symptoms. [ABSTRACT FROM AUTHOR]

Immunology for all: Most scientific communication has historically been limited to visual imagery and the written or spoken word, often in the form of dense articles obscured by jargon. Clear communication of science is vital to enable the public to engage with important scientific discoveries and to limit medical distrust. However, scientific communication is often executed in a way which neglects people with blindness, low vision and diverse needs. Our aim for the exhibit at the Monash Sensory Science Exhibition on Autoimmunity 2023 at Monash University was to develop novel, tactile and informative models to help better communicate the scientific principles that underpin autoimmune disease and immunology. As B‐cell biologists, we decided to focus our exhibit for this workshop on antibody‐mediated autoimmunity. Antibodies are key components of the immune system, providing protection against a range of diverse pathogens. However, in the context of autoimmunity, they can also drive pathology. [ABSTRACT FROM AUTHOR]

The article discusses the need for innovative and adaptive behavioral interventions, particularly in the context of the COVID-19 pandemic. It highlights the limited focus on behavioral research in COVID-19 trials and emphasizes the importance of health behavior interventions in addressing chronic diseases. The International Behavioural Trials Network (IBTN) aims to improve the quality of behavioral interventions and trial implementation through sharing recommendations and tools. The article also explores the globalization of behavioral science, the importance of bridging theory and intervention design, the need for systems approaches in behavioral interventions, and the challenges of intervention adaptation and implementation. It concludes by emphasizing the significance of implementation science in the development and scaling up of interventions. [Extracted from the article]

Background: 1.8 million Veterans are estimated to need legal services, such as for housing eviction prevention, discharge upgrades, and state and federal Veterans benefits. While having one's legal needs met is known to improve one's health and its social determinants, many Veterans' legal needs remain unmet. Public Law 116–315 enacted in 2021 authorizes VA to fund legal services for Veterans (LSV) by awarding grants to legal service providers including nonprofit organizations and law schools' legal assistance programs. This congressionally mandated LSV initiative will award grants to about 75 competitively selected entities providing legal services. This paper describes the protocol for evaluating the initiative. The evaluation will fulfill congressional reporting requirements, and inform continued implementation and sustainment of LSV over time. Methods: Our protocol calls for a prospective, mixed-methods observational study with a repeated measures design, aligning to the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) and Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) frameworks. In 2023, competitively selected legal services-providing organizations will be awarded grants to implement LSV. The primary outcome will be the number of Veterans served by LSV in the 12 months after the awarding of the grant. The evaluation has three Aims. Aim 1 will focus on measuring primary and secondary LSV implementation outcomes aligned to RE-AIM. Aim 2 will apply the mixed quantitative-qualitative Matrixed Multiple Case Study method to identify patterns in implementation barriers, enablers, and other i-PARIHS-aligned factors that relate to observed outcomes. Aim 3 involves a mixed-methods economic evaluation to understand the costs and benefits of LSV implementation. Discussion: The LSV initiative is a new program that VA is implementing to help Veterans who need legal assistance. To optimize ongoing and future implementation of this program, it is important to rigorously evaluate LSV's outcomes, barriers and enablers, and costs and benefits. We have outlined the protocol for such an evaluation, which will lead to recommending strategies and resource allocation for VA's LSV implementation. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to evaluate the effectiveness of a three‐month physiotherapist‐delivered eHealth physical activity program compared with usual care to improve function in adults with low back pain or knee osteoarthritis in rural Australia. Methods: This was a parallel, two‐group, pragmatic, superiority, randomized controlled trial involving three‐ and six‐month posttreatment follow‐ups. There was a total of 156 adults with chronic nonspecific low back pain (n = 97) or knee osteoarthritis (n = 59) from rural Australia. The intervention involved an eHealth physical activity and an exercise program that included five to eight teleconsultations with a physiotherapist (primary time point three months) or usual care (eg, general practitioner, physiotherapy, and pain medication). The primary outcome was the Patient‐Specific Functional Scale (0–30), with a three‐point difference between groups being considered the minimum clinically important difference. Results: Participants receiving the eHealth intervention (n = 78) reported significantly greater and clinically worthwhile improvements in function (mean between‐group difference 3.6; 95% confidence interval [CI] 1.3–5.9) compared to participants receiving usual care (n = 78). Small but statistically significantly greater improvements in disability (7.2 of 100; 95% CI 2.1–12.3) and quality of life (4.5 of 100; 95% CI 0.0–9.0) also favored the eHealth group. No clinical or statistical differences between groups were found for the secondary outcomes of pain, coping skills, and physical activity levels. Conclusion: A physiotherapist‐delivered eHealth intervention is effective and provides clinically meaningful improvements in function compared to usual care for people with musculoskeletal pain in rural communities. These findings highlight the potential for eHealth‐based programs to improve access to evidence‐based exercise interventions for people with musculoskeletal pain in rural communities. [ABSTRACT FROM AUTHOR]

Symbiosis can benefit hosts in numerous ways, but less is known about whether interactions with hosts benefit symbionts—the smaller species in the relationship. To determine the fitness impact of host association on symbionts in likely mutualisms, we conducted a meta-analysis across 91 unique host-symbiont pairings under a range of spatial and temporal contexts. Specifically, we assess the consequences to symbiont fitness when in and out of symbiosis, as well as when the symbiosis is under suboptimal or varying environments and biological conditions (e.g., host age). We find that some intracellular symbionts associated with protists tend to have greater fitness when the symbiosis is under stressful conditions. Symbionts of plants and animals did not exhibit this trend, suggesting that symbionts of multicellular hosts are more robust to perturbations. Symbiont fitness also generally increased with host age. Lastly, we show that symbionts able to proliferate in- and outside host cells exhibit greater fitness than those found exclusively inside or outside cells. The ability to grow in multiple locations may thus help symbionts thrive. We discuss these fitness patterns in light of host-driven factors, whereby hosts exert influence over symbionts to suit their own needs. [ABSTRACT FROM AUTHOR]

Phenolic compounds are the main phytochemical constituents of many higher plants. They play an important role in synthesizing metal nanoparticles using green technology due to their ability to reduce metal salts and stabilize them through physical interaction/conjugation to the metal surface. Six pure phenolic compounds were isolated from licorice (Glycyrrhiza glabra) and employed in synthesizing gold nanoparticles (AuNPs). The isolated compounds were identified as liquiritin (1), isoliquiritin (2), neoisoliquiritin (3), isoliquiritin apioside (4), liquiritin apioside (5), and glabridin (6). The synthesized AuNPs were characterized using UV, zeta sizer, HRTEM, and IR and tested for their stability in different biological media. The phenolic isolates and their corresponding synthesized NP conjugates were tested for their potential in vitro cytotoxicity. The anti-inflammatory effects were investigated in both normal and inflammation-induced settings, where inflammatory biomarkers were stimulated using lipopolysaccharides (LPSs) in the RAW 264.7 macrophage cell line. LPS, functioning as a mitogen, promotes cell growth by reducing apoptosis, potentially contributing to observed outcomes. Results indicated that all six pure phenolic isolates inhibited cell proliferation. The AuNP conjugates of all the phenolic isolates, except liquiritin apioside (5), inhibited cell viability. LPS initiates inflammatory markers by binding to cell receptors and setting off a cascade of events leading to inflammation. All the pure phenolic isolates, except isoliquiritin, neoisoliquiritin, and isoliquiritin apioside inhibited the inflammatory activity of RAW cells in vitro. [ABSTRACT FROM AUTHOR]

Genetically engineered mouse models only capture a small fraction of the genetic lesions that drive human cancer. Current CRISPR–Cas9 models can expand this fraction but are limited by their reliance on error-prone DNA repair. Here we develop a system for in vivo prime editing by encoding a Cre-inducible prime editor in the mouse germline. This model allows rapid, precise engineering of a wide range of mutations in cell lines and organoids derived from primary tissues, including a clinically relevant Kras mutation associated with drug resistance and Trp53 hotspot mutations commonly observed in pancreatic cancer. With this system, we demonstrate somatic prime editing in vivo using lipid nanoparticles, and we model lung and pancreatic cancer through viral delivery of prime editing guide RNAs or orthotopic transplantation of prime-edited organoids. We believe that this approach will accelerate functional studies of cancer-associated mutations and complex genetic combinations that are challenging to construct with traditional models. Prime-editing mouse models enable the study of specific cancer mutations in vivo. [ABSTRACT FROM AUTHOR]