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BackgroundInflammation plays a key role in the pathophysiology of coronary heart disease (CHD) and its acute manifestation, acute coronary syndrome (ACS). Aging is associated with a decline of the immune system, a process known as immunosenescence. This is characterized by an increase in highly proinflammatory T cells that are involved in CHD progression, plaque destabilization, and myocardial ischemia–reperfusion injury. Telomere dysfunction has been implicated in immunosenescence of T lymphocytes. Telomerase is the enzyme responsible for maintaining telomeres during cell divisions. It has a protective effect on cells under oxidative stress and helps regulate flow-mediated dilation in microvasculature. ObjectiveThe TACTIC (Telomerase ACTivator to reverse Immunosenescence in Acute Coronary Syndrome) trial will investigate whether a telomerase activator, TA-65MD, can reduce the proportion of senescent T cells in patients with ACS with confirmed CHD. It will also assess the effect of TA-65MD on decreasing telomere shortening, reducing oxidative stress, and improving endothelial function. MethodsThe study was designed as a single-center, randomized, double-blind, parallel-group, placebo-controlled phase II trial. Recruitment started in January 2019. A total of 90 patients, aged 65 years or older, with treated ACS who have had CHD confirmed by angiography will be enrolled. They will be randomized to one of two groups: TA-65MD oral therapy (8 mg twice daily) or placebo taken for 12 months. The primary outcome is the effect on immunosenescence determined by a decrease in the proportion of CD8+ TEMRA (T effector memory cells re-expressing CD45RA [CD45 expressing exon A]) cells at 12 months. Secondary outcomes include leukocyte telomere length, endothelial function, cardiac function as measured by echocardiography and NT-proBNP (N-terminal fragment of the prohormone brain-type natriuretic peptide), systemic inflammation, oxidative stress, and telomerase activity. ResultsThe study received National Health Service (NHS) ethics approval on August 9, 2018; Medicines and Healthcare products Regulatory Agency approval on October 19, 2018; and NHS Health Research Authority approval on October 22, 2018. The trial began recruiting participants in January 2019 and completed recruitment in March 2020; the trial is due to report results in 2021. ConclusionsThis pilot trial in older patients with CHD will explore outcomes not previously investigated outside in vitro or preclinical models. The robust design ensures that bias has been minimized. Should the results indicate reduced frequency of immunosenescent CD8+ T cells as well as improvements in telomere length and endothelial function, we will plan a larger, multicenter trial in patients to determine if TA-65MD is beneficial in the treatment of CHD in elderly patients. Trial RegistrationISRCTN Registry ISRCTN16613292; http://www.isrctn.com/ISRCTN16613292 and European Union Drug Regulating Authorities Clinical Trials Database (EudraCT), European Union Clinical Trials Register 2017-002876-26; https://tinyurl.com/y4m2so8g International Registered Report Identifier (IRRID)DERR1-10.2196/19456

In the original publication [...].

Ionizing radiation (IR) can reprogram proteasome structure and function in cells and tissues. In this article, we show that IR can promote immunoproteasome synthesis with important implications for Ag processing and presentation and tumor immunity. Irradiation of a murine fibrosarcoma (FSA) induced dose-dependent de novo biosynthesis of the immunoproteasome subunits LMP7, LMP2, and Mecl-1, in concert with other changes in the Ag-presentation machinery (APM) essential for CD8+ T cell-mediated immunity, including enhanced expression of MHC class I (MHC-I), β2-microglobulin, transporters associated with Ag processing molecules, and their key transcriptional activator NOD-like receptor family CARD domain containing 5. In contrast, in another less immunogenic, murine fibrosarcoma (NFSA), LMP7 transcripts and expression of components of the immunoproteasome and the APM were muted after IR, which affected MHC-I expression and CD8+ T lymphocyte infiltration into NFSA tumors in vivo. Introduction of LMP7 into NFSA largely corrected these deficiencies, enhancing MHC-I expression and in vivo tumor immunogenicity. The immune adaptation in response to IR mirrored many aspects of the response to IFN-γ in coordinating the transcriptional MHC-I program, albeit with notable differences. Further investigations showed divergent upstream pathways in that, unlike IFN-γ, IR failed to activate STAT-1 in either FSA or NFSA cells while heavily relying on NF-κB activation. The IR-induced shift toward immunoproteasome production within a tumor indicates that proteasomal reprogramming is part of an integrated and dynamic tumor-host response that is specific to the stressor and the tumor and therefore is of clinical relevance for radiation oncology.

BackgroundInternet-based assessment has the potential to assist with the diagnosis of mental health disorders and overcome the barriers associated with traditional services (eg, cost, stigma, distance). Further to existing online screening programs available, there is an opportunity to deliver more comprehensive and accurate diagnostic tools to supplement the assessment and treatment of mental health disorders. ObjectiveThe aim was to evaluate the diagnostic criterion validity and test-retest reliability of the electronic Psychological Assessment System (e-PASS), an online, self-report, multidisorder, clinical assessment and referral system. MethodsParticipants were 616 adults residing in Australia, recruited online, and representing prospective e-PASS users. Following e-PASS completion, 158 participants underwent a telephone-administered structured clinical interview and 39 participants repeated the e-PASS within 25 days of initial completion. ResultsWith structured clinical interview results serving as the gold standard, diagnostic agreement with the e-PASS varied considerably from fair (eg, generalized anxiety disorder: κ=.37) to strong (eg, panic disorder: κ=.62). Although the e-PASS’ sensitivity also varied (0.43-0.86) the specificity was generally high (0.68-1.00). The e-PASS sensitivity generally improved when reducing the e-PASS threshold to a subclinical result. Test-retest reliability ranged from moderate (eg, specific phobia: κ=.54) to substantial (eg, bulimia nervosa: κ=.87). ConclusionsThe e-PASS produces reliable diagnostic results and performs generally well in excluding mental disorders, although at the expense of sensitivity. For screening purposes, the e-PASS subclinical result generally appears better than a clinical result as a diagnostic indicator. Further development and evaluation is needed to support the use of online diagnostic assessment programs for mental disorders. Trial RegistrationAustralian and New Zealand Clinical Trials Registry ACTRN121611000704998; http://www.anzctr.org.au/trial_view.aspx?ID=336143 (Archived by WebCite at http://www.webcitation.org/618r3wvOG).

BackgroundInterferon-gamma (IFNγ) exerts potent growth inhibitory effects on a wide range of cancer cells through unknown signaling pathways. We pursued complementary screening approaches to characterize the growth inhibition pathway.MethodsWe performed chemical genomics and whole genome targeting CRISPR/Cas9 screens using patient-derived melanoma lines to uncover essential nodes in the IFNγ-mediated growth inhibition pathway. We used transcriptomic profiling to identify cell death pathways activated upon IFNγ exposure. Live imaging experiments coupled with apoptosis assays confirmed the involvement of these pathways in IFNγ-mediated cell death.ResultsWe show that IFNγ signaling activated ERK. Blocking ERK activation rescued IFNγ-mediated apoptosis in 17 of 23 (~ 74%) cell lines representing BRAF, NRAS, NF1 mutant, and triple wild type subtypes of cutaneous melanoma. ERK signaling induced a stress response, ultimately leading to apoptosis through the activity of DR5 and NOXA proteins.ConclusionsOur results provide a new understanding of the IFNγ growth inhibition pathway, which will be crucial in defining mechanisms of immunotherapy response and resistance.

BackgroundThe development of e-mental health interventions to treat or prevent mental illness and to enhance wellbeing has risen rapidly over the past decade. This development assists the public in sidestepping some of the obstacles that are often encountered when trying to access traditional face-to-face mental health care services. ObjectiveThe objective of our study was to investigate the posttreatment effectiveness of five fully automated self-help cognitive behavior e-therapy programs for generalized anxiety disorder (GAD), panic disorder with or without agoraphobia (PD/A), obsessive–compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and social anxiety disorder (SAD) offered to the international public via Anxiety Online, an open-access full-service virtual psychology clinic for anxiety disorders. MethodsWe used a naturalistic participant choice, quasi-experimental design to evaluate each of the five Anxiety Online fully automated self-help e-therapy programs. Participants were required to have at least subclinical levels of one of the anxiety disorders to be offered the associated disorder-specific fully automated self-help e-therapy program. These programs are offered free of charge via Anxiety Online. ResultsA total of 225 people self-selected one of the five e-therapy programs (GAD, n = 88; SAD, n = 50; PD/A, n = 40; PTSD, n = 30; OCD, n = 17) and completed their 12-week posttreatment assessment. Significant improvements were found on 21/25 measures across the five fully automated self-help programs. At postassessment we observed significant reductions on all five anxiety disorder clinical disorder severity ratings (Cohen d range 0.72–1.22), increased confidence in managing one’s own mental health care (Cohen d range 0.70–1.17), and decreases in the total number of clinical diagnoses (except for the PD/A program, where a positive trend was found) (Cohen d range 0.45–1.08). In addition, we found significant improvements in quality of life for the GAD, OCD, PTSD, and SAD e-therapy programs (Cohen d range 0.11–0.96) and significant reductions relating to general psychological distress levels for the GAD, PD/A, and PTSD e-therapy programs (Cohen d range 0.23–1.16). Overall, treatment satisfaction was good across all five e-therapy programs, and posttreatment assessment completers reported using their e-therapy program an average of 395.60 (SD 272.2) minutes over the 12-week treatment period. ConclusionsOverall, all five fully automated self-help e-therapy programs appear to be delivering promising high-quality outcomes; however, the results require replication. Trial RegistrationAustralian and New Zealand Clinical Trials Registry ACTRN121611000704998; http://www.anzctr.org.au/trial_view.aspx?ID=336143 (Archived by WebCite at http://www.webcitation.org/618r3wvOG)

Background Mental illness is an escalating concern worldwide. The management of disorders such as anxiety and depression largely falls to family doctors or general practitioners (GPs). However, GPs are often too time constrained and may lack the necessary training to adequately manage the needs of such patients. Evidence-based Internet interventions represent a potentially valuable resource to reduce the burden of care and the cost of managing mental health disorders within primary care settings and, at the same time, improve patient outcomes. Objective The present study sought to extend the efficacy of a therapist-assisted Internet treatment program for panic disorder, Panic Online, by determining whether comparable outcomes could be achieved and maintained when Panic Online was supported by either GPs or psychologists. Methods Via a natural groups design, 96 people with a primary diagnosis of panic disorder (with or without agoraphobia) completed the Panic Online program over 12 weeks with the therapeutic assistance of their GP (n = 53), who had received specialist training in cognitive behavioral therapy, or a clinical psychologist (n = 43). Participants completed a clinical diagnostic telephone interview, conducted by a psychologist, and a set of online questionnaires to assess panic-related symptoms at three time periods (pretreatment, posttreatment, and 6 month follow-up). Results Both treatments led to clinically significant improvements on measures of panic and panic-related symptomatology from pretreatment to posttreatment. Both groups were shown to significantly improve over time. Improvements for both groups were maintained at follow-up; however, the groups did differ significantly on two quality of life domains: physical (F1,82 = 9.13, P = .00) and environmental (F1,82 = 4.41, P = .04). The attrition rate was significantly higher among those being treated by their GP (χ21 = 4.40, P = .02, N = 96). Conclusions This study provides evidence that Internet-based interventions are an effective adjunct to existing mental health care systems. Consequently, this may facilitate and enhance the delivery of evidence-based mental health treatments to increasingly large segments of the population via primary care systems and through suitably trained health professionals.

Effective marine science teaching starts with well-written, measurable learning objectives that define outcomes for learners, inform instruction, and guide assessment. Yet, there are few resources to help marine science educators write effective learning objectives. To address this need, we created an evidence-based Marine Science Learning Objectives Tool (MS-LOT) to help marine educators evaluate their learning objectives. MS-LOT considers two critical aspects of learning objectives in marine science education: focus and assessment. As a case study, University of Georgia (UGA) Marine Extension and Georgia Sea Grant educators used MS-LOT to analyze their 207 learning objectives for 5th–12th grade educational programs. Findings revealed 1) gaps in content, science practices, and affective outcomes in instruction, 2) a focus on low-cognitive level outcomes, and 3) unmeasurable learning objectives. We respond to issues uncovered from the analysis and detail how MS-LOT will be useful for all marine educators, especially those working with K-12 learners.

A succession of interconnected environmental factors is believed to contribute substantially to the development of autism spectrum disorder (ASD). This exploratory study therefore aims to identify potential risk factors for ASD that are associated with pregnancy, birth and infant feeding. Demographic and health-related data on children aged 3-13 years (N = 4306) was collected through an online survey completed by biological mothers. A fitted logistic regression model identified advanced maternal age, prenatal bleeding, pre-eclampsia, perinatal pethidine usage, foetal distress before birth and male sex of child as associated with an increased risk of ASD, whereas longer gestational duration demonstrated a protective effect. These findings highlight potential risk factors and predictor interrelationships which may contribute to overall ASD risk.

Recent studies have shown that lipoprotein(a) (Lp(a)) is an important risk factor for a plethora of different cardiovascular diseases. It has been proven that Lp(a) levels are genetically determined and correlate with risk of cardiovascular disease, independent of lifestyle factors. As of yet, treatment options to reduce Lp(a) levels are limited, but new research into Lp(a) reduction yields promising results. This review delves into Lp(a)'s biochemistry and mechanism of effect, the association between Lp(a) and cardiovascular diseases, and possible therapies to minimise cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background Advancements in machine learning (ML) have improved the accuracy of models that predict human immunodeficiency virus (HIV) incidence. These models have used electronic medical records and registries. We aim to broaden the application of these tools by using deidentified public health datasets for notifiable sexually transmitted infections (STIs) from a southern US county known for high HIV incidence. The goal is to assess the feasibility and accuracy of ML in predicting HIV incidence, which could inform and enhance public health interventions. Methods We analyzed 2 deidentified public health datasets from January 2010 to December 2021, focusing on notifiable STIs. Our process involved data processing and feature extraction, including sociodemographic factors, STI cases, and social vulnerability index (SVI) metrics. Various ML models were trained and evaluated for predicting HIV incidence using metrics such as accuracy, precision, recall, and F1 score. Results We included 85 224 individuals; 2027 (2.37%) were newly diagnosed with HIV during the study period. The ML models demonstrated high performance in predicting HIV incidence among males and females. Influential features for males included age at STI diagnosis, previous STI information, provider type, and SVI. For females, predictive features included age, ethnicity, previous STI information, overall SVI, and race. Conclusions The high accuracy of our ML models in predicting HIV incidence highlights the potential of using public health datasets for public health interventions such as tailored HIV testing and prevention. While these findings are promising, further research is needed to translate these models into practical public health applications. [ABSTRACT FROM AUTHOR]

Parents of children with autism spectrum disorder appear to experience high levels of psychological distress, yet little is known about the prevalence of psychological disorders in this population. The aim of this systematic review and meta-analysis was to estimate the proportion of these parents who experience clinically significant psychopathology. Articles reporting proportions of psychological disorders in a sample of parents of children with autism spectrum disorder were located. The initial search returned 25,988 articles. Thirty-one studies with a total sample of 9208 parents were included in the final review. The median meta-analytic proportions were 31% (95% confidence interval = [24%, 38%]) for depressive disorders, 33% (95% confidence interval = [20%, 48%]) for anxiety disorders, 10% (95% confidence interval = [1%, 41%]) for obsessive-compulsive disorder, 4% (95% confidence interval = [0%, 22%]) for personality disorders, 2% (95% confidence interval = [1%, 4%]) for alcohol and substance use disorders and 1% (95% confidence interval = [0%, 5%]) for schizophrenia spectrum disorders. Significant heterogeneity was detected in these categories. Further research is needed to gain more insight into variables that may moderate parental psychopathology. This review and meta-analysis is the first to provide prevalence estimates of psychological disorders in parents of children with autism spectrum disorder.

Triple Negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2. TNBC accounts for 15-20% of all breast cancer cases but accounts for over 50% of mortality. We propose that Estrogen receptor-beta (ERβ) and IGF2 play a significant role in the pathogenesis of TNBCs, and could be important targets for future therapy. Tissue microarrays (TMAs) from over 250 TNBC patients' were analyzed for ERβ and IGF2 expression by immunohistochemistry. Expression was correlated with clinical outcomes. In addition, TNBC cell lines Caucasians (CA): MB-231/BT549 and African Americans (AAs): MB-468/HCC70/HCC1806 were used to investigate the effect of hormonal and growth factor regulation on cell proliferation. TMAs from AAs had higher expression of ERβ and IGF2 expression when compared to CA. ERβ and IGF2 were found to be upregulated in our TNBC cell lines when compared to other cell types. TNBC cells treated with ERβ agonist displayed significant increase in cell proliferation and migration when compared to controls. AA tissue samples from TNBC patients had higher expression of ERβ. African-American breast cancer TNBC tissue samples from TNBC patients have higher expression of ERβ. In addition, TNBC cell lines were also found to express high levels of ERβ. IGF2 increased transcription of ERβ in TNBC cells. Understanding the mechanisms of IGF2/ERβ axis in TNBC tumors could provide an opportunity to target this aggressive subtype of breast cancer.

The aim of this study was to examine whether the extended bivalent fear of evaluation model (extended BFOE) of Social Anxiety Disorder (SAD) could be used to explain bladder and bowel incontinence anxiety (BBIA). It was hypothesised that the relationship between dysfunctional attitudes (DAs) and BBIA would be mediated by fear of negative evaluation (FNE), fear of positive evaluation (FPE), concerns of social reprisal (CSR), and disqualification of positive social outcomes (DPSO). Three-hundred-and-seventeen undergraduate students (76.7% female; mean age = 31.07 years) completed a cross-sectional online study. A structural equation model (SEM) supported the proposed model ([chi].sup.2p value = .131, CMIN/df = 1.560, CFI = .996, TLI = .990, RMSEA = .042, SRMR = .0245) with significant relationships found between DAs and FNE (p .001), DAs and FPE (p = .002), DAs and CSR (p = .007), FNE and CSR (p < .001), FNE and DPSO (p < .001), FPE and CSR (p < .001), FPE and DPSO (p < .001), CSR and DPSO (p < .001), BBIPSS bladder and bowel with incontinence anxiety (p < .001). These results suggest that DAs, FNE, and DPSO are important contributory factors in BBIA. Given that FNE was the strongest mediator in the model, clinicians may find it advantageous to target FNE in treatment of incontinence-anxiety., Author(s): Kenley L. J. Kuoch [sup.1] , Denny Meyer [sup.2] [sup.3] , David W. Austin [sup.4] , Simon R. Knowles [sup.1] [sup.5] [sup.6] [sup.7] [sup.8] Author Affiliations: (1) grid.1027.4, 0000 [...]

The current study aimed to explore the validity of a single, self-report measure for bladder and bowel anxieties (Bladder and Bowel Anxiety Grouping Item; BABAGI), using two appropriate scales entitled the Shy Bladder and Bowel Scale (SBBS) and the Bladder and Bowel Incontinence Phobia Severity Scale (BBIPSS). This study also aimed to examine the similarities and differences in dysfunctional attitudes (DAs), fear of negative and positive evaluation (FNE and FPE), concerns of social reprisal (CSR), and disqualification of positive social outcomes (DPSO) across individuals who self-identify as having paruresis/parcopresis, incontinence anxiety, or neither condition according to the BABAGI measure. Three-hundred-and-six undergraduate students (77.1% female; mean age = 31.18 years) completed a cross-sectional, online study. The results supported the hypothesis that by using the BABAGI, self-reported paruresis/parcopresis could be reliably identified by SBBS scores of above 6.75 and that self-reported incontinence anxiety could be reliably identified by BBIPSS scores above 15.21. The results also supported the hypothesis that individuals who self-identified as having paruresis/parcopresis or incontinence anxiety would score higher in socio-cognitive processes (DAs, FNE, FPE, CSR, DPSO) compared to individuals who self-identified as having neither condition. Given that the paruresis/parcopresis and incontinence anxiety groups do not significantly differ from each other with respect to socio-cognitive processes, this suggests that both sets of conditions share similar underlying psychosocial processes., Author(s): Kenley L. J. Kuoch [sup.1] , Denny Meyer [sup.2] [sup.3] , David W. Austin [sup.4] , Simon R. Knowles [sup.1] [sup.5] [sup.6] [sup.7] Author Affiliations: (1) grid.1027.4, 0000 0004 [...]

Paruresis has been recognized as a subtype of Social Anxiety Disorder (SAD). A well-established model of SAD is the extended bivalent fear of evaluation model (extended BFOE) which include socio-cognitive processes such as fear of negative and positive evaluation (FNE and FPE), concerns of social reprisal (CSR), and disqualification of positive social outcomes (DPSO). In addition to the extended BFOE, dysfunctional attitudes (DAs) have also been recognized to contribute towards social anxiety symptoms and distress. The aim of this study was to examine whether an extended BFOE model for SAD could be used to explain paruresis and parcopresis symptoms. Three-hundred-and-sixteen undergraduate students (76.6% female; mean age = 31.25 years) completed a cross-sectional online study. A structural equation model (SEM) indicated the data supported the proposed model very well ([chi].sup.2p value = .345, CMIN/df = 1.064, CFI = 1.00, TLI = .999, RMSEA = .014, SRMR = .0107) with significant direct relationships being found between DAs and FNE (p = .002), DAs and FPE (p = .002), FNE and CSR (p = .001), FPE and CSR (p = .001), CSR and paruresis score (p = .045), CSR and DAs (p = .006), FPE and paruresis score (p = .001), FPE and parcopresis score (p = .004), FNE and paruresis score (p = .004), and FNE and parcopresis score (p = .002). Although this research should be replicated, the current study provides evidence that DAs, FNE, FPE and CSR are important contributory factors in paruresis and parcopresis symptoms., Author(s): Kenley L. J. Kuoch [sup.1] , Denny Meyer [sup.2] [sup.3] , David W. Austin [sup.4] , Simon R. Knowles [sup.1] [sup.5] [sup.6] [sup.7] Author Affiliations: (1) grid.1027.4, 0000 0004 [...]

Triple-negative breast cancer (TNBC) occurs in 10-15% of all breast cancer patients, yet it accounts for about half of all breast cancer deaths. There is an urgent need to identify new antitumor targets to provide additional treatment options for patients afflicted with this aggressive disease. Preclinical evidence suggests a critical role for insulin-like growth factor-2 (IGF2) and androgen receptor (AR) in regulating TNBC progression. To advance this work, a panel of TNBC cell lines was investigated with all cell lines showing significant expression of IGF2. Treatment with IGF2 stimulated cell proliferation in vitro (p < 0.05). Importantly, combination treatments with IGF1R inhibitors BMS-754807 and NVP-AEW541 elicited significant inhibition of TNBC cell proliferation (p < 0.001). Based on Annexin-V binding assays, BMS-754807, NVP-AEW541 and enzalutamide induced TNBC cell death (p < 0.005). Additionally, combination of enzalutamide with BMS-754807 or NVP-AEW541 exerted significant reductions in TNBC proliferation even in cells with low AR expression (p < 0.001). Notably, NVP-AEW541 and BMS-754807 reduced AR levels in BT549 TNBC cells. These results provide evidence that IGF2 promotes TNBC cell viability and proliferation, while inhibition of IGF1R/IR and AR pathways contribute to blockade of TNBC proliferation and promotion of apoptosis in vitro.