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Abstract Background Early reports showed that patients with COVID-19 had recrudescence of previously resolved coccidioidomycosis (Valley fever, VF), and there were indications that coinfection had more severe outcomes. We therefore investigated serial infection of Coccidioides posadasii and SARS-CoV-2 in a K18-hACE2 mouse model to assess disease outcomes. Methods In our model, we challenged K18-hACE2 mice sequentially with a sub-lethal dose of SARS-CoV-2 and 24 hours later with low virulence strain of Coccidioides posadasii, and vice versa, compared to mice that only received a single infection challenge. We performed survival and pathogenesis mouse studies as well as looked at the systemic immune response differences between treatment groups. Results Here we show that co-infected groups have a more severe disease progression as well as a decrease in survival. Importantly, results differ depending on the SARS-CoV-2 variant (WA-1, Delta, or Omicron) and infection timing (SARS-CoV-2 first, C. posadasii second or vice versa). We find that groups that are infected with the virus first had a decrease in survival, increased morbidity and weight loss, increased fungal and viral burdens, differences in immune responses, and the amount and size of fungal spherules. We also find that groups coinfected with C. posadasii first have a decrease fungal burden and inflammatory responses. Conclusions This is the first in vivo model investigation of a coinfection of SARS-CoV-2 and Coccidioides. Because of the potential for increased severity of disease in a coinfection, we suggest populations that live in areas of high coccidioidomycosis endemicity may experience higher incidence of complicated disease progression with COVID-19.

Measurements of sphingolipid metabolism are most accurately performed by LC-MS. However, this technique is expensive, not widely accessible, and without the use of specific probes, it does not provide insight into metabolic flux through the pathway. Employing the fluorescent ceramide analogue NBD-C6-ceramide as a tracer in intact cells, we developed a comprehensive HPLC-based method that simultaneously measures the main nodes of ceramide metabolism in the Golgi. Hence, by quantifying the conversion of NBD-C6-ceramide to NBD-C6-sphingomyelin, NBD-C6-hexosylceramides, and NBD-C6-ceramide-1-phosphate (NBD-C1P), the activities of Golgi resident enzymes sphingomyelin synthase 1, glucosylceramide synthase, and ceramide kinase (CERK) could be measured simultaneously. Importantly, the detection of NBD-C1P allowed us to quantify CERK activity in cells, a usually difficult task. By applying this method, we evaluated the specificity of commonly used sphingolipid inhibitors and discovered that 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, which targets glucosylceramide synthase, and fenretinide (4HPR), an inhibitor for dihydroceramide desaturase, also suppress CERK activity. This study demonstrates the benefit of an expanded analysis of ceramide metabolism in the Golgi, and it provides a qualitative and easy-to-implement method.

Teenage siblings of children with autism spectrum disorder (ASD) are at risk of worse mental health outcomes than their peers, yet there have been few interventions focused on improving their psychosocial wellbeing. This study explored the acceptability of an 8-session virtual group mind-body resiliency intervention for teen siblings of children with ASD. We used mixed methods to assess quantitative and qualitative survey results. Participants reported that the intervention had the right amount of sessions (88%), structure (74%), and duration (89%). Most participants felt comfortable during sessions (74%), found it helpful to learn mind-body exercises (74%), and that the intervention helped in coping with stress (71%). Though participants were satisfied with the opportunity to meet peers, they desired more social connection.

Abstract Transcriptional mechanisms controlling developmental processes establish and maintain proteomic networks, which can govern the levels of intracellular small molecules. Although dynamic changes in bioactive small molecules can link transcription factor and genome activity with cell state transitions, many mechanistic questions are unresolved. Using quantitative lipidomics and multiomics, we discover that the hematopoietic transcription factor GATA1 establishes ceramide homeostasis during erythroid differentiation by regulating genes encoding sphingolipid metabolic enzymes. Inhibiting a GATA1-induced sphingolipid biosynthetic enzyme, delta(4)-desaturase, or disrupting ceramide homeostasis with cell-permeable dihydroceramide or ceramide is detrimental to erythroid, but not myeloid, progenitor activity. Coupled with genetic editing-based rewiring of the regulatory circuitry, we demonstrate that ceramide homeostasis commissions vital stem cell factor and erythropoietin signaling by opposing an inhibitory protein phosphatase 2A-dependent, dual-component mechanism. Integrating bioactive lipids as essential components of GATA factor mechanisms to control cell state transitions has implications for diverse cell and tissue types.

Previous studies have revealed that adverse childhood experiences (ACEs) create a significant and lasting effect of increased anxiety. However, few studies have examined the mediating and moderating mechanisms underlying this relation. The present study aimed to explore the mediating role of self-compassion and moderating role of social support in ACEs-anxiety relationship among Chinese adolescents. In this cross-sectional study, 1,764 middle school students completed questionnaires measuring their levels of ACEs, anxiety, self-compassion (SC), and social support. Correlations of variables were computed using Pearson's r. Mediation and moderated mediation models were tested using PROCESS macro with the regression bootstrapping method. After covariates (age and gender) were controlled, results showed that: (1) ACEs were positively associated with anxiety symptoms; (2) self-compassion partially mediated the ACEs-anxiety association; (3) both ACEs-anxiety and SC-anxiety relationships were moderated by social support. Specifically, social support was associated with lower anxiety, particularly among students with fewer ACEs or lower level of self-compassion. Reducing possible adversities existing in environment may help to reduce risk of anxiety for adolescents. Cultivating self-compassion is crucial for adolescents' mental health, since it may play a role in ACEs-anxiety relationship. Social support would operate as a buffer to ACEs in the relation with anxiety, under the circumstances of mild adversities, and a promoter to self-compassion in the relation with anxiety, under the circumstances of low self-compassion., Author(s): Xinli Chi [sup.1] , Weiwei Jiang [sup.1] , Tianyou Guo [sup.1] , Daniel L. Hall [sup.2] [sup.3] , Christina M. Luberto [sup.2] [sup.3] , Liye Zou [sup.1] Author Affiliations: [...]

Adolescent and young adult (AYA) siblings of individuals with autism experience unique challenges that can promote both growth and emotional maladjustment. This study explored sibling and parent reports of siblings' lived experiences and identified learning, stressors, and concerns from those experiences. 20 neurotypical (NT) AYA siblings (ages 13-24), and 21 parents were interviewed. Themes that emerged from the data analysis included: (1) learning, empathy, and compassion (2) relationship between the degree of functional impairment and the nature of the sibling relationship; (3) reluctance to share information about siblings with peers; (4) hypervigilance associated with unpredictable behavior; (5) worries and concerns about the future. These findings contribute to the existing literature on the impact and nature of neurotypical siblings' lived experience.

Objectives: To evaluate long-term outcomes after an 8-week mindfulness intervention, Mindfulness for Interdisciplinary Health Care Professionals (MIHP), and investigate relationships between outcomes overtime. Design/Methods: In this single-arm study, 35 participants received MIHP and completed measures of burnout, perceived stress, activity impairment, and dispositional mindfulness at baseline, post-MIHP, and a 3-month follow-up. Changes over time were evaluated using repeated-measures analysis of variance (ANOVA) and reliable change indices (RCIs). Then, correlations between dispositional mindfulness and distress/impairment outcomes were evaluated. Results: At follow-up, aspects of burnout and several mindfulness skills demonstrated maintained improvements. RCIs showed that a higher percentage of participants improved on all outcomes at each time period than declined?all outcomes showed little to no deterioration. However, most participants did not reliably change, and this was more pronounced at the follow-up. Changes in two mindfulness skills (acting with awareness and nonjudging of inner experience) were consistently negatively correlated with distress and impairment outcomes. Conclusions: Acquired mindfulness skills during MIHP were maintained at the follow-up. RCI analyses demonstrated that MIHP may protect against worsening stress and burnout during training. Two mindfulness skills, acting with awareness and nonjudging of inner experience, showed potential mechanistic effects on work-relevant outcomes. Booster sessions to encourage maintained mindfulness practices and skills should be investigated in future trials. This study was registered on clinicaltrials.gov (#NCT03403335) on January 11, 2018.

The COVID-19 pandemic, once a global crisis, is now largely under control, a testament to the extraordinary global efforts involving vaccination and public health measures. However, the relentless evolution of SARS-CoV-2, leading to the emergence of new variants, continues to underscore the importance of remaining vigilant and adaptable. Monoclonal antibodies (mAbs) have stood out as a powerful and immediate therapeutic response to COVID-19. Despite the success of mAbs, the evolution of SARS-CoV-2 continues to pose challenges and the available antibodies are no longer effective. New variants require the ongoing development of effective antibodies. In the present study, we describe the generation and characterization of neutralizing mAbs against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein by combining plasmid DNA and recombinant protein vaccination. By integrating genetic immunization for rapid antibody production and the potent immune stimulation enabled by protein vaccination, we produced a rich pool of antibodies, each with unique binding and neutralizing specificities, tested with the ELISA, BLI and FACS assays and the pseudovirus assay, respectively. Here, we present a panel of mAbs effective against the SARS-CoV-2 variants up to Omicron BA.1 and BA.5, with the flexibility to target emerging variants. This approach ensures the preparedness principle is in place to address SARS-CoV-2 actual and future infections.

Parents of children with Autism experience high levels of stress. Resiliency is the ability to cope and adapt when faced with stressful events. This randomized, waitlist controlled pilot trial examines the feasibility, acceptability, and preliminary efficacy of an adapted virtual mind--body group intervention for parents of children with ASD. The intervention was feasible and acceptable. The immediate treatment group showed no difference in distress and greater improvement in resiliency and stress reactivity/coping relative to the delayed treatment group, (M difference 5.78; p = 0.038 and M difference 7.78; p = 0.001 respectively). Findings showed promising feasibility, acceptability, and preliminary efficacy for parents of children with ASD.

Despite the advances in medical treatment of Crohn’s disease (CD), most of the patients require one or more surgical bowel resections during their life for complicated disease. Surgery for CD has gone through progressive technical refinement over time. Minimally invasive surgery and bowel-sparing techniques have been validated with regard to surgical trauma reduction, and their role has been clearly defined in the current guidelines. Nevertheless, continuous technology advancement has further expanded the surgical tools with single-access and robotic-assisted surgery. With the aim of further reducing the impact of surgery, the concept of “strategic surgery” has been explored. On the one hand, patients’ optimization before surgery has the potential to reduce post-operative complications. On the other, early intervention for the uncomplicated disease before medical therapy escalation has been demonstrated equally reliable with respect to biologics in terms of quality of life and advantageous in terms of health-care costs. Ultimately, a better comprehension of the pathological mechanisms underlying the disease is the key to radically changing the surgical management of both abdominal and perianal CDs. In fact, novel surgical strategies aiming at reducing disease recurrence which take into account the anastomotic configuration and the role of the mesentery as an active player in the disease process have been pursued in the past decade. The purpose of this review is to describe the recent innovations in the surgical treatment of CD focusing on their potential impact on the short- and long-term outcomes.

Background Stress-related disease is increasing, with high resilience proposed as protective. Whilst the Current Experiences Scale (CES) shows promise as a measure of resilience, its psychological correlates and relationship to psychological stress remain unclear. Objectives (1) Further explore the psychometric properties of the CES, (2) identify modifiable psychological factors associated with the CES and (3) test a previously published model for the influence of adaptive strategies and stress management factors on resiliency and stress. Methods N = 455 individuals (mean age = 47.8, 65.1% female) completed measures of adaptive strategies: mindfulness (Cognitive and Affective Mindfulness Scale-Revised), positive affect (Positive and Negative Affect Schedule) and gratitude (The Gratitude Questionnaire), stress management skills: coping (Measure of Current Status-A), depression (Patient Health Questionnaire-8) and anxiety (General Anxiety Disorder Assessment) and outcomes: resilience (CES) and stress (Perceived Stress Scale). Cronbach’s alpha and confirmatory factor analysis (CFA) examined the psychometric properties of the CES. Multivariable regression identified psychological variables associated with resilience. Structural equation modelling (SEM) tested the previously published model for resilience. Results The CES and its subscales showed good internal consistency (ɑ = .75-.93). The 23-item CES produced excellent results for model fit (Root Mean Square Error of Approximation (RMSEA) = .07, Standardized Root Mean Square Residual (SRMR) = .06, Comparative Fit Index (CFI) = .99; Tucker-Lewis Index (TLI) = .99). Higher gratitude (P < .0001), mindfulness (P < .0001), positive affect (P < .0001) and coping (P < .0001) were associated with higher resilience. Depression (P = .23) and anxiety (P = .34) were not. A model of resilience which included gratitude, mindfulness, positive affect and coping as determinants of resilience and perceived stress performed well (RMSEA = .03, SRMR = .02, CFI = .99; TLI = .99). Conclusions The CES was validated in a large sample. The association of gratitude, mindfulness, positive affect and coping with resilience may guide practitioners seeking to design resilience-enhancing programs.

Background: Following acute coronary syndrome (ACS), up to 40% of patients report elevated depressive symptoms which is associated with a two-fold increase in mortality risk due to behavioral and biological mechanisms. Mindfulness-Based Cognitive Therapy (MBCT) delivered via synchronous group videoconferencing could help reduce depressive symptoms. Objective: To guide MBCT adaptation for ACS patients for a future clinical trial, this qualitative study aimed to explore ACS patients' (1) symptoms after ACS, (2) needs for behavioral health treatment, (3) perspectives on mindfulness intervention and group videoconference delivery, and (4) willingness to self-collect dried blood spots in a research study. Methods: We compared ACS patients with and without depressive symptoms to highlight particularly relevant treatment topics for patients developing depression following ACS experience. From 2/2019-11/2019, we conducted semi-structured individual telephone interviews with N = 23 patients after ACS (N = 13 with and N = 10 without elevated depressive symptoms; 63.4 (SD = 8.5) years, 87% male, 96% non-Hispanic white, 7.1 (SD = 7.5) years since ACS). In qualitative content analyses, four independent coders coded each interview. Results: Participants with depressive symptoms experienced emotional, physical, social, and health behavior problems, while those without depressive symptoms made positive health behavior changes and struggled with anxiety symptoms. Both groups were interested in a behavioral health treatment for emotional and social support. Most were willing to participate in a mindfulness group via videoconferencing; some preferred in-person, but accessibility and convenience outweighed these cons. Almost all were willing to self-collect dried blood spots and some were already familiar with this technique. Conclusion: ACS patients, especially those with depressive symptoms, need help managing a multitude of quality of life concerns that can be targeted with an adapted MBCT approach. A videoconference-delivered MBCT approach is of interest. Suggestions for adapting MBCT to target the needs of ACS patients are discussed. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by the predisposition to develop tumors such as malignant peripheral nerve sheath tumors (MPNSTs) which represents the primary cause of death for NF1-affected patients. Regardless of the high incidence and mortality, the molecular mechanisms underneath MPNST growth and metastatic progression remain poorly understood. In this proof-of-concept study, we performed somatic whole-exome sequencing (WES) to profile the genomic alterations in four samples from a patient with NF1-associated MPNST, consisting of a benign plexiform neurofibroma, a primary MPNST, and metastases from lung and skin tissues. By comparing genomic patterns, we identified a high level of variability across samples with distinctive genetic changes which allow for the definition of profiles of the early phase with respect to the late metastatic stages. Pathogenic and likely pathogenic variants were abundant in the primary tumor, whereas the metastatic samples exhibited a high level of copy-number variations (CNVs), highlighting a possible genomic instability in the late phases. The most known MPNST-related genes, such as TP53 and SUZ12, were identified in CNVs observed within the primary tumor. Pathway analysis of altered early genes in MPNST pointed to a potential role in cell motility, division and metabolism. Moreover, we employed survival analysis with the TCGA sarcoma genomic dataset on 262 affected patients, in order to corroborate the predictive significance of the identified early and metastatic MPNST driver genes. Specifically, the expression changes related to the mutated genes, such as in RBMX, PNPLA6 and AGAP2, were associated with reduced patient survival, distinguishing them as potential prognostic biomarkers. This study underlines the relevance of integrating genomic results with clinical information for early diagnosis and prognostic understanding of tumor aggressiveness. [ABSTRACT FROM AUTHOR]

Sphingolipids (SLs) constitute a discrete subdomain of metabolism, and they display both structural and signaling functions. Accumulating evidence also points to intimate connections between intermediary metabolism and SL metabolism. Given that many SLs exhibit bioactive properties (i.e. transduce signals), these raise the possibility that an important function of SLs is to relay information on metabolic changes into specific cell responses. This could occur at various levels. Some metabolites are incorporated into SLs, whereas others may initiate regulatory or signaling events that, in turn, modulate SL metabolism. In this review, we elaborate on the former as it represents a poorly appreciated aspect of SL metabolism, and we develop the hypothesis that the SL network is highly sensitive to several specific metabolic changes, focusing on amino acids (serine and alanine), various fatty acids, choline (and ethanolamine), and glucose. [ABSTRACT FROM AUTHOR]

Abstract Aims Tai chi exercise has been shown in a prior randomized controlled trial to improve depression symptoms and quality of life (QoL) in patients with heart failure (HF), but correlates of these improvements are not well known. The purpose of this secondary analysis was to explore whether tai chi is associated with improvements in biopsychosocial and behavioural measures and whether such improvements are correlated with improved depression and QoL. Methods and results Participants were n = 100 adults with chronic systolic HF (mean age = 67.4, SD = 12.0; 64% male; 96% White; New York Heart Association class = 1–3) randomized to a 12 week tai chi exercise intervention or health education control. Constructs of interest included social support, exercise self‐efficacy, activity engagement, sense of coherence, and inflammatory biomarkers. Tai chi was associated with increased everyday activity engagement compared with the health education group (P

Introduction: Adults with congenital heart disease (ACHD) often experience elevated health anxiety. The SMART-3RP is an eight-week, mind-body group resiliency intervention with evidence to reduce health anxiety in other medical populations. The aims of this waitlist-controlled, randomized pilot feasibility trial were to explore (1) feasibility and acceptability of videoconference-delivered SMART-3RP, (2) feasibility and acceptability of remote blood pressure monitoring, and (3) changes in health anxiety, mindfulness, and resiliency. Methods: Participants (N ​= ​12 adults with CHD; Mean age ​= ​41.2 years, SD ​= ​13.8, 100% white, and 75% female) were 1:1 randomized into a pilot from July 2020 to September 2020. Participants completed surveys at baseline, three-month, and six-month follow-up; recorded their blood pressure via a digital health platform four times per week for eight weeks post-randomization (n ​= ​32 total recordings); and completed individual exit interviews. Results: 91% (29/32) of patients screened were eligible; of those, 41% (12/29) enrolled. 83% were retained at three-month follow-up (10/12) and 90% of those (9/10) were retained at six months. Average adherence to blood pressure monitoring was 70% (22/32 recordings completed; SD ​= ​31.9). Effect sizes from baseline to three months suggested greater improvement in the immediate group compared to the waitlist group for health anxiety (Cohen's r ​= ​−.59), mindfulness (r ​= ​−0.44), and resiliency (r ​= ​−0.49). Exit interviews revealed positive experiences with the intervention, benefits of mindfulness skills for coping with anxiety, and suggestions for improvement including further targeting ACHD-specific needs. Conclusions: These findings support the feasibility of conducting a randomized controlled efficacy trial of SMART-3RP for ACHD, and the acceptability and potential utility of SMART-3RP for emotional health in ACHD.

The COVID-19 pandemic has highlighted genetic vaccination as a powerful and cost-effective tool to counteract infectious diseases. Invasive fungal infections (IFI) remain a major challenge among immune compromised patients, particularly those undergoing allogeneic hematopoietic bone marrow transplantation (HSCT) or solid organ transplant (SOT) both presenting high morbidity and mortality rates. Candidiasis and Aspergillosis are the major fungal infections among these patients and the failure of current antifungal therapies call for new therapeutic aids. Vaccination represents a valid alternative, and proof of concept of the efficacy of this approach has been provided at clinical level. This review will analyze current understanding of antifungal immunology, with a particular focus on genetic vaccination as a suitable strategy to counteract these diseases.

Background: The Relaxation Sensitivity Index (RSI) measures relaxation-related fears developed and validated in western samples. The RSI captures three facets of fear regarding relaxation: physical, cognitive, and social concerns. This study aimed to translate and identify the factor structure of the Chinese version of the RSI.Methods: In a preliminary study, 26 items were generated mainly by translation and modified from the original RSI. In Study 1, factor analysis and internal consistency reliability analysis were conducted on separated half samples of 597 Chinese college students. In Study 2, test-retest reliability, convergent, and predictive criterion validity were examined based on 465 Chinese college students.Results: Fourteen items were selected based on the factor loading and item prevalence in the preliminary study. Factor analysis based on Study 1 identified three factors: Social appealing, Social performance, and Physical concerns. In general, the RSI demonstrated good internal consistency (αs = 0.750–0.860), convergent validity and predictive criterion validity, while the test-retest reliability is relatively low (rs = 0.525–0.685). Notably, less related to the other two factors, Social performance concerns may be a unique factor solely predicting social anxiety (p

Objective Parents of children with learning/attentional disabilities (LAD) and autism spectrum disorder (ASD) are at elevated risk for chronic stress. Types of stress and treatment needs differ between these parent groups. We adapted our evidence-based mind–body intervention (SMART-3RP) for parents of children with LAD and ASD, delivered via videoconferencing. Preliminary results from our two wait-list randomized pilot trials suggest the programs were feasible and efficacious. To gain an in-depth understanding of acceptability, the purpose of this secondary analysis from the RCTs is to (1) explore feedback regarding the virtual SMART-3RP and (2) compare feedback across LAD and ASD parents. Methods Participants were randomized to immediate or delayed SMART-3RP (separate groups for LAD and ASD) and completed a feedback questionnaire post-intervention ( N = 33 LAD, N = 37 ASD; 93% female, 93% white, Mage = 45.52, SD = 6.50). Results Participants reported the intervention had the right number of sessions (69%), session duration (83%), and amount of structure (83%). They felt comfortable during sessions (89%) and found mind–body skills helpful (89%). There were no significant differences between parent groups other than a trend for more ASD parents reporting sessions were too long (22% ASD vs. 6% LAD, X 2 = 5.67, p =0.06). Qualitative themes were similar across parents and included that video delivery had some technical challenges but enabled participation; group support and mind–body skills were helpful; and further SMART-3RP sessions or therapy is needed. Conclusion LAD and ASD parents found a synchronous video-based mind–body resiliency program acceptable. Technology limitations notwithstanding, online delivery was very satisfactory and overcame obstacles to participation.