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Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis all exhibited down-regulation of MANF (mesencephalic astrocyte-derived neurotrophic factor) and HSPA5 (heat shock 70-kDa protein 5) in the heart; this down-regulation was particularly notable in female mice. ICI myocarditis was amplified by heart-specific genetic deletion of mouse Manf and was attenuated by administration of recombinant MANF protein, suggesting a causal role. Ironically, both MANF and HSPA5 were transcriptionally induced by liganded estrogen receptor β and inhibited by androgen receptor. However, ICI treatment reduced serum estradiol concentration to a greater extent in female compared to male mice. Treatment with an estrogen receptor β-specific agonist and androgen depletion therapy attenuated ICI-associated cardiac effects. Together, our data suggest that ICI treatment inhibits estradiol-dependent expression of MANF/HSPA5 in the heart, curtailing the cardiomyocyte response to immune injury. This endocrine-cardiac-immune pathway offers new insights into the mechanisms of sex differences in cardiac disease and may offer treatment strategies for ICI myocarditis.

A large body of research on disability stigma conducted among young school children and adults in non-educational settings shows that individuals with non-visible disabilities experience more negative stigma compared to individuals with visible disabilities. However, there is a noticeable lack of research on disability stigma within higher education. The main purpose of the current research was to study how college students perceive their peers who have a disability and how these perceptions differ depending on the type of disability. Participants completed measures that assessed their perceptions of sociability, academic ability, and academic performance of students who have one of three disability types: physical (visible), cognitive (non-visible), and psychiatric (non-visible). For the given disability type, they also rated their expectations of classroom behaviors, deservingness of academic accommodations, and ability to deal with the disability. The results showed that students with visible disabilities compared to students with non-visible disabilities were perceived as being more sociable and academically capable, but they also were perceived as displaying more disruptive classroom behaviors. Differences between the two types of non-visible disabilities also were observed. Our study reveals a need for further research on perceptions of disability and how these perceptions impact students within higher education.

Initial evaluations generalise to new contexts, whereas counter-attitudinal evaluations are context-specific. Counter-attitudinal information may not change evaluations in new contexts because perceivers fail to retrieve counter-attitudinal cue-evaluation associations from memory outside the counter-attitudinal learning context. The current work examines whether an additional, counter-attitudinal retrieval cue can enhance the generalizability of counter-attitudinal evaluations. In four experiments, participants learned positive information about a target person, Bob, in one context, and then learned negative information about Bob in a different context. While learning the negative information, participants wore a wristband as a retrieval cue for counter-attitudinal Bob-negative associations. Participants then made speeded as well as deliberate evaluations of Bob while wearing or not wearing the wristband. Internal meta-analysis failed to find a reliable effect of the counter-attitudinal retrieval cue on speeded or deliberate evaluations, whereas the context cues influenced speeded and deliberate evaluations. Counter to predictions, counter-attitudinal retrieval cues did not disrupt the generalisation of first-learned evaluations or the context-specificity of second-learned evaluations (Experiments 2-4), but the counter-attitudinal retrieval cue did influence evaluations in the absence of context cues (Experiment 1). The current work provides initial evidence that additional counter-attitudinal retrieval cues fail to disrupt the renewal and generalizability of first-learned evaluations.

LSG1 is a conserved GTPase involved in ribosome assembly. It is required for the eviction of the nuclear export adapter NMD3 from the pre-60S subunit in the cytoplasm. In human cells, LSG1 has also been shown to interact with vesicle-associated membrane protein-associated proteins (VAPs) that are found primarily on the endoplasmic reticulum. VAPs interact with a large host of proteins which contain FFAT motifs (two phenylalanines (FF) in an acidic tract) and are involved in many cellular functions including membrane traffic and regulation of lipid transport. Here, we show that human LSG1 binds to VAPs via a noncanonical FFAT-like motif. Deletion of this motif specifically disrupts the localization of LSG1 to the ER, without perturbing LSG1-dependent recycling of NMD3 in cells or modulation of LSG1 GTPase activity in vitro. [ABSTRACT FROM AUTHOR]

Crowding is widely regarded as one of the most important risk factors in designing portfolio strategies. In this article, the authors analyze stock crowding using network analysis of fund holdings, which is used to compute crowding scores for stocks. These scores are used to construct costless long–short portfolios, computed in a distribution-free (model-free) way and without using any numerical optimization, with desirable properties of hedge portfolios. More specifically, these long–short portfolios provide protection for both small and large market price fluctuations because of their negative correlation with the market and positive convexity as a function of market returns. By adding their long–short portfolio to a baseline portfolio such as a traditional 60/40 portfolio, the authors show that their method provides an alternative way to hedge portfolio risk including tail risk, which does not require costly option-based strategies or complex numerical optimization. The total cost of such hedging amounts to the total cost of rebalancing the hedge portfolio. [ABSTRACT FROM AUTHOR]

In this chapter, we describe how a simple attentional mechanism can account for a wide variety of phenomena in social perception. According to Attention Theory (Kruschke, 1996, 2003), people preferentially attend to differentiating information in order to maximize category learning. When learning multiple social categories, people attend to all features that characterize the first-learned category but shift their attention to features that uniquely distinguish a later-learned category from the first. As a result, they form a stronger impression of the later-learned social category. First, we review research on attentional processes in stereotype formation and group categorization. We show how Attention Theory can account for both category accentuation and illusory correlation in the formation of majority and minority group stereotypes. We then explain how attention shifting influences face perception and racial categorization. Second, we describe attentional processes as they relate to context-based impression formation and the influence of individual- and group-based expectancies on context-based impressions. Last, we discuss implications for impression change.

The current research examined how people form context-based trait impressions and why some of these impressions are stronger than others. This research drew from principles of attention theory (Kruschke, 1996, 2001) in order to account for the processes underlying impression formation in context. According to attention theory, the traits expressed by an individual target person in a rarely occurring context should be more strongly associated with that context than the traits expressed in a commonly occurring context are associated with the common context. That is, people form stronger impressions of others' behavior in rare compared to common contexts. Four experiments provide support for these predictions. The current study is one of the first to examine the cognitive mechanisms by which perceivers form trait impressions of individuals across different contexts and to explain why some of these impressions are stronger than others. Implications of the nature of these impression formation processes are discussed.

Introduction:Almost half of veterans (44.6%) seen in the U.S. Department of Veterans Affairs outpatient setting are diagnosed with hypertension (HTN). Because of the widespread nature of HTN, use of virtual visits has the potential to improve blood pressure (BP) management. This evaluation assessed the effectiveness of video blood pressure visits (VBPVs) in the management of HTN in veterans enrolled in Veterans Health Administration primary care. Methods:The program was implemented within the existing veteran-centered medical home. VBPVs are scheduled where the nurse observes veterans taking their BP and provides teaching or counseling. A national training curriculum was delivered to local nurse champions through Microsoft Teams. We analyzed improvement in BP over a 2-year period. We also captured actions taken by nurses during the VBPV by searching the electronic notes. Ratings of training and comments were summarized using feedback forms completed after training. Results:In total, 81,476 veterans participated in VBPVs over 2 years. Of those, 44,682 veterans had an existing ICD-10 code related to HTN. Of the 18,078 veterans who had a pre- and post-VBPV BP, the average change to systolic measurement was −10.6 mm Hg (range −82 to 78). Average change to diastolic measurement was −4.61 mm Hg (range −59 to 55). Most interventions addressed medication management (77%). Nurses' evaluations of the program were positive. Conclusions:Video visits provide reliable and convenient veteran-centered care. Such visits enable care when unanticipated interruptions occur such as the coronavirus disease 2019 pandemic. In addition to medication management, nurse-led interventions such as counseling on lifestyle changes can be effective in HTN management. [ABSTRACT FROM AUTHOR]

The article presents the discussion on seeking medical care. Topics include experiencing outstanding support or relief from the feelings and getting a graphic and detailed recollection of an event from the personal health memory bank; and leaning toward impressions from a scary radiology scan, painful lab draws and even shadowy images of routine childhood vaccinations and visits.

For many years, bonds have provided investors in a traditional 60/40 asset mix with a positive carry hedge to equity market volatility and drawdowns. However, with interest rates at historic lows and an evolving inflation backdrop that could impact the negative correlation of stocks and bonds, multi-asset class investors are searching for additional tools to mitigate risk. One novel tool involves creating a long-short portfolio of uncrowded assets. In particular, crowding in stocks held by asset managers has a significant impact on stock performance. Crowded assets and strategies result in outperformance during trending markets but exhibit significant drawdowns and failures of diversification during spikes in volatility. Crowded stocks are expected to deliver negatively skewed market-adjusted returns and higher forward volatility once the market players give up on crowded trades. Conversely, uncrowded assets have the potential for positive skewness and long vol-like behavior. This article computes a stock-level crowding measure based on active bets by mutual and hedge funds. We construct a long-short equity portfolio based on a combination of a pure holdings-based crowding measure that is long volatility, has minimal equity beta, is not persistently correlated with common risk factors (style), and has a negative correlation to the most crowded stocks. We show how this long-short equity portfolio can be combined with a traditional 60/40 portfolio in order to provide better structural diversification. [ABSTRACT FROM AUTHOR]

Intrinsic rate constants were determined for proton transfer from monoketones to a family of amine bases. Specifically, the reaction of secondary alicyclic amines with 2-acetyl-1-methylpyridinium ion was examined. The intrinsic rate constants obtained were found to be lower than for any sterically unhindered carbon acids except for nitroalkanes. The results suggest the presence of a strong pi-acceptor character of the CO group and strong salvation in the enolate ion.

Background recognition of the multifactorial causes of delirium represents a clinical challenge. Objectives to develop and show proof of principle of a diagnostic support tool (DST) for identification of causes of delirium. Methods stage 1—development of the aetiology in delirium-diagnostic support tool (AiD-DST); stage 2—validation of the AiD-DST against reference standard diagnosis, based on clinical assessment from two independent consultant geriatricians. Results a series of eight steps AiD-DST were formulated by an expert group to identify possible causes of delirium. Forty inpatients admitted to a general medical unit with a consultant physician/geriatrician diagnosis of delirium were recruited, consented and reviewed against the AiD-DST. Mean age was 85.1 (standard deviation 7.9) years and 26 (65%) of participants were female. Participants had multiple chronic co-morbidities [median Charlson Comorbidity Index 7; interquartile range (IQR 6–9)] and median number of medications was 8 (IQR 6–11.75). Median number of causes of delirium detected on AiD-DST was 3 (IQR 3–4) versus 5 (IQR 3–6) using the reference standard diagnosis, with sensitivity of 88.8% (95% confidence interval, 81.6–93.9%) and specificity of 71.8% (63–79.5%). Conclusions the aetiology in delirium DST shows promise in the identification of cause(s) in delirium. [ABSTRACT FROM AUTHOR]

The article discusses that the Coronavirus disease 2019 (COVID-19) is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged out of Wuhan, China in late 2019. It mentions that the Public health efforts are oriented toward mitigation and limiting the rate of spread to prevent overextension of available health care resources such as ventilators by recommending wearing a mask, washing hands often, and practicing social distancing.

Case Presentation: A 54-year-old man presented with a 6-month history of progressive dyspnea occurring at rest and with minimal exertion. His medical history was notable for hypertension, non-insulin-dependent diabetes, coronary artery disease, and factor V Leiden heterozygosity. His social history was notable for a 43-pack-year smoking history but was otherwise unremarkable. [ABSTRACT FROM AUTHOR]

A large body of research on disability stigma conducted among young school children and adults in non-educational settings shows that individuals with non-visible disabilities experience more negative stigma compared to individuals with visible disabilities. However, there is a noticeable lack of research on disability stigma within higher education. The main purpose of the current research was to study how college students perceive their peers who have a disability and how these perceptions differ depending on the type of disability. Participants completed measures that assessed their perceptions of sociability, academic ability, and academic performance of students who have one of three disability types: physical (visible), cognitive (non-visible), and psychiatric (non-visible). For the given disability type, they also rated their expectations of classroom behaviors, deservingness of academic accommodations, and ability to deal with the disability. The results showed that students with visible disabilities compared to students with non-visible disabilities were perceived as being more sociable and academically capable, but they also were perceived as displaying more disruptive classroom behaviors. Differences between the two types of non-visible disabilities also were observed. Our study reveals a need for further research on perceptions of disability and how these perceptions impact students within higher education. [ABSTRACT FROM AUTHOR]

The older adult population continues to steadily increase. Largely attributed to longer life spans and aging of the Baby Boomer generation, continued growth of this population is expected to affect a multitude of challenging public health concerns. Specifically, falls in older adults are prevalent but overlooked concerns. Health care providers are well-positioned to provide valuable interventions in this aspect. An interdisciplinary, team-based approach of health care providers is required to maximize falls prevention through patient-centered and collaborative care. The current article highlights the implications of inappropriate medication use and the need to improve care coordination to tackle this public health issue affecting older adults. [ABSTRACT FROM AUTHOR]

Opioid drug overdose is currently the leading cause of death in the United States. An estimated 91 Americans die from opioid overdoses every day. Opioids are a class of drugs that interact with opioid receptors in the body and brain; they are often used to treat pain. This webliography examines the three classes of opioids – prescription opioids, synthetic opioids like fentanyl, and heroin; reasons for the increased usage of opioids; and resources available to the public. The resources include ways to keep current on opioid-related legislation such as Good Samaritan Laws, information on medical guidelines and community support or treatment, and literature to halt the opioid epidemic. [ABSTRACT FROM PUBLISHER]

By using sacrificial ZnO nanorods, a self non-uniform electric field was established to yield the aqueous growth of h111i oriented, single-crystalline (Zn,Sn)-doped Pd nanodendrites on TiO[sub 2] nanotubes for synthesizing three-dimensional hydrophobic heterostructures. Structural analyses revealed that primary dendrite arms grew along a h111i direction group; symmetric branches were built on the basal plane of the arms but sprouted in another [111] direction, similar to a twin structure. Sequential growth processes different from a diffusion-limited aggregation model were suggested, including the dissolution of ZnO nanorods for forming a self non-uniform electric field, the protruding of primary arms towards a Zn[sup 2+] concentrated zone, and then the development of branches through a cation depletion zone. A strong surface enhanced Raman scattering and high photocatalytic activity, owing to the strong surface plasmon resonance on the large-surface symmetric structures and the inhibited recombination of photogenerated electron-hole pairs, suggested the high potential of the heterostructures for applications in self-cleaning photocatalysts and nano-optoelectronic devices. [ABSTRACT FROM AUTHOR]

Canonical Wnt (cWnt) signaling through β-catenin regulates osteoblast proliferation and differentiation to enhance bone formation. We previously reported that osteogenic action of β-catenin is dependent on BMP signaling. Here, we further examined interactions between cWnt and BMP in bone. In osteoprogenitors stimulated with BMP2, β-catenin localizes to the nucleus, physically interacts with Smad4, and is recruited to DNA-binding transcription complexes containing Smad4, R-Smad1/5 and TCF4. Furthermore, Tcf/Lef-dependent transcription, Ccnd1 expression and proliferation all increase when Smad4, 1 or 5 levels are low, whereas TCF/Lef activities decrease when Smad4 expression is high. The ability of Smad4 to antagonize transcription of Ccnd1 is dependent on DNA-binding activity but Smad4-dependent transcription is not required. In mice, conditional deletion of Smad4 in osterix+ cells increases mitosis of cells on trabecular bone surfaces as well as in primary osteoblast cultures from adult bone marrow and neonatal calvaria. By contrast, ablation of Smad4 delays differentiation and matrix mineralization by primary osteoblasts in response to Wnt3a, indicating that loss of Smad4 perturbs the balance between proliferation and differentiation in osteoprogenitors. We propose that Smad4 and Tcf/Lef transcription complexes compete for β-catenin, thus restraining cWnt-dependent proliferative signals while favoring the matrix synthesizing activity of osteoblasts. [ABSTRACT FROM AUTHOR]

To examine interactions between bone morphogenic protein (BMP) and canonical Wnt signaling during skeletal growth, we ablated Smad4, a key component of the TGF-β-BMP pathway, in Osx1+ cells in mice. We show that loss of Smad4 causes stunted growth, spontaneous fractures and a combination of features seen in osteogenesis imperfecta, cleidocranial dysplasia and Wnt-deficiency syndromes. Bones of Smad4 mutant mice exhibited markers of fully differentiated osteoblasts but lacked multiple collagen-processing enzymes, including lysyl oxidase (Lox), a BMP2-responsive gene regulated by Smad4 and Runx2. Accordingly, the collagen matrix in Smad4 mutants was disorganized, but also hypomineralized. Primary osteoblasts from these mutants did not mineralize in vitro in the presence of BMP2 or Wnt3a, and Smad4 mutant mice failed to accrue new bone following systemic inhibition of the Dickkopf homolog Dkk1. Consistent with impaired biological responses to canonical Wnt, ablation of Smad4 causes cleavage of β-catenin and depletion of the low density lipoprotein receptor Lrp5, subsequent to increased caspase-3 activity and apoptosis. In summary, Smad4 regulates maturation of skeletal collagen and osteoblast survival, and is required for matrix-forming responses to both BMP2 and canonical Wnt. [ABSTRACT FROM AUTHOR]

Early detection of cervical cancer is critical for a favorable prognosis. Standard cytological detection methods, such as Pap smear, are highly subjective and HPV detection is not a reliable marker for predicting the malignancy potential of cervical lesions. As a result, there is a demand for a diagnostic assay capable of sensitive and specific detection of cervical cancer. In this preclinical exploratory study, qRT-PCR and western blotting were used to assess expression levels of CIP2A and p16^{INK4a} in cervical tissue samples (n_{normal adjacent} = 23, n_{tumor} = 29). CIP2A was abundantly expressed in cervical cancer cell lines and was not expressed in normal epithelial cells. CIP2A mRNA levels were higher in cervical tumor tissues in comparison to the level of CIP2A mRNA in normal adjacent tissue from cervical cancer patients. CIP2A protein was specifically expressed in cervical tumor tissues at different cancer grades and stages, and was not observed in normal adjacent tissue. Elevated CIP2A mRNA levels in cervical tissues had a sensitivity of 80% and specificity of 91% and CIP2A protein expression detection had a sensitivity of 83% and specificity of 100%, similar to that of p16^{INK4a}, with no correlation of CIP2A expression with HPV infection, age, race, or other patient characteristics. However the number of samples analyzed in this preliminary study is limited and a large prospective cohort study is necessary to further evaluate CIP2A as a biomarker for cervical cancer. [ABSTRACT FROM AUTHOR]