Socio-behavioral factors related to PrEP non-adherence among gay male PrEP users living in California and New York: A behavioral theory informed approach.

One effective preventative measure to reduce the number of new HIV infections is through the uptake of daily oral HIV pre-exposure prophylaxis (PrEP). Although previous clinical trials have proven the effectiveness of on-demand PrEP uptake, daily PrEP uptake is the most popular prevention method among PrEP users and is still recommended by most healthcare professionals and organizations. Informed by the integrative model of behavioral prediction, the current study examined the socio-behavioral factors associated with PrEP non-adherence. The present study conducted a cross-sectional survey of 210 gay male daily PrEP users living in California and New York. The results showed more than two-thirds of the sample indicated that they had skipped taking PrEP within the last 30 days, averaging around four to five missed doses. General attitudes toward desirable and undesirable outcomes, perceived behavioral control, and social-level barriers were associated with daily PrEP uptake non-adherence. The findings highlight providers' role in PrEP adherence and the importance of habit-forming, which can be enhanced by cost-effective strategies and technological innovations.

Effects of fact-checking social media vaccine misinformation on attitudes toward vaccines.

Social media vaccine misinformation can negatively influence vaccine attitudes. It is urgent to develop communication approaches to reduce the misinformation's impact. This study aimed to test the effects of fact-checking labels for misinformation on attitudes toward vaccines. An online survey experiment with 1198 participants recruited from a U.S. national sample was conducted in 2018. Participants were randomly assigned to six conditions: misinformation control, or fact-checking label conditions attributed to algorithms, news media, health institutions, research universities, or fact-checking organizations. We analyzed differences in vaccine attitudes between the fact-checking label and control conditions. Further, we compared perceived expertise and trustworthiness of the five categories of fact-checking sources. Fact-checking labels attached to misinformation posts made vaccine attitudes more positive compared to the misinformation control condition (P = .003, Cohen's d= 0.21). Conspiracy ideation moderated the effect of the labels on vaccine attitudes (P = .02). Universities and health institutions were rated significantly higher on source expertise than other sources. Mediation analyses showed labels attributed to universities and health institutions indirectly resulted in more positive attitudes than other sources through perceived expertise. Exposure to fact-checking labels on misinformation can generate more positive attitudes toward vaccines in comparison to exposure to misinformation. Incorporating labels from trusted universities and health institutions on social media platforms is a promising direction for addressing the vaccine misinformation problem. This points to the necessity for closer collaboration between public health and research institutions and social media companies to join efforts in addressing the current misinformation threat.

Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction.

MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we report that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy manifested by a loss of cardiac contractility, abnormal mitochondria ultrastructure, and defective mitochondrial respiration. Strikingly, genetic ablation of both proapoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, while the overt consequences of Mcl-1 loss were obviated by combining with the loss of Bax and Bak, mitochondria from the Mcl-1-, Bax-, and Bak-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration. Together, these data indicate that merely blocking cell death is insufficient to completely overcome the need for MCL-1 function in cardiomyocytes and suggest that in cardiac muscle, MCL-1 also facilitates normal mitochondrial function. These findings are important, as specific MCL-1-inhibiting therapeutics are being proposed to treat cancer cells and may result in unexpected cardiac toxicity.

Dietary modulation of the microbiome affects autoinflammatory disease.

The incidences of chronic inflammatory disorders have increased considerably over the past three decades. Recent shifts in dietary consumption may have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2(cmo) mice, which express a homozygous Leu98Pro missense mutation in the Pombe Cdc15 homology family protein PSTPIP2 (proline-serine-threonine phosphatase interacting protein 2), spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis in humans. Recent reports demonstrated a crucial role for interleukin-1ß (IL-1ß) in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2(cmo) mice from inflammatory bone disease. Thus, the upstream mechanisms controlling IL-1ß production in Pstpip2(cmo) mice remain to be identified. In addition, the environmental factors driving IL-1ß-dependent inflammatory bone erosion are unknown. Here we show that the intestinal microbiota of diseased Pstpip2(cmo) mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2(cmo) mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced pro-IL-1ß expression in distant neutrophils. Furthermore, pro-IL-1ß expression was also decreased in Pstpip2(cmo) mice treated with antibiotics, and in wild-type mice that were kept under germ-free conditions. We further demonstrate that combined deletion of caspases 1 and 8 was required for protection against IL-1ß-dependent inflammatory bone disease, whereas the deletion of either caspase alone or of elastase or neutrophil proteinase 3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a crucial factor regulating inflammasome- and caspase-8-mediated maturation of IL-1ß and osteomyelitis in Pstpip2(cmo) mice.

Acquisition of Cholangiocarcinoma Traits during Advanced Hepatocellular Carcinoma Development in Mice.

Past studies have identified hepatic tumors with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) characteristics that have a more aggressive behavior and a poorer prognosis than classic HCC. Whether this pathologic heterogeneity is due to a cell of origin of bipotent liver progenitors or the plasticity of cellular constituents comprising these tumors remains debated. In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis by orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC and displayed a striking acquisition of CC-related pathologic and molecular features, which was absent in the primary HCC tumors. Our study directly demonstrates the pathologic evolution of HCC during advanced tumor development, providing the first evidence that tumors with mixed HCC and CC features, or at least a subset of these tumors, represent a more advanced developmental stage of HCC. Finally, liver cancer organoid-generated high-grade tumors exhibited significantly increased extracellular vesicle secretion, suggesting that identifying tumor-specific extracellular vesicle proteins in plasma may be a promising tool for liver cancer detection.

Opposition to Nonprescription Naloxone Access: Measurement and Psychosocial Predictors.

Background: Access of naloxone has been increased in recent years, yet opposition to unrestricted availability persists. Objectives: To validate a measure of opposition to the policy of nonprescription naloxone and foster a better understanding of the characteristics of individuals who oppose such a policy. Methods: Respondents from a crowdsource platform (N = 621) responded to an instrument developed to assess opposition to nonprescription naloxone. Construct validity was assessed by examining the relationship of the opposition scale with measures of social distance, belief in a just world, right wing authoritarianism, social dominance orientation (SDO), perceptions of the degree of threat to the nation presented by opioid users, past exposure to opioid misuse, and conservative political ideology. Results: A 9-item measure of opposition emerged (α=.96). Opposition to nonprescription naloxone was generally associated with construct validation variables as expected. In a regression analysis that adjusted for demographic characteristics, opposition was most strongly related to authoritarianism, the perception that opioid users present a threat to our nation, the belief that we live in a just world, social dominance orientation, greater perceived social distance between self and opioid users, and past experiences with users. Opposition scores differentiated those who supported versus opposed specific policies regarding naloxone access and were particularly high among Republicans. Most respondents did not oppose policies on nonprescription naloxone access. Conclusions/Importance: The instrument developed provides a reliable and valid tool that enables future investigations into understanding and overcoming the psychological, social, and political foundations of opposition to expanded naloxone access.

Critical role for inflammasome-independent IL-1ß production in osteomyelitis.

The immune system plays an important role in the pathophysiology of many acute and chronic bone disorders, but the specific inflammatory networks that regulate individual bone disorders remain to be elucidated. Here, we characterized the osteoimmunological underpinnings of osteolytic bone disease in Pstpip2(cmo) mice. These mice carry a homozygous L98P missense mutation in the Pombe Cdc15 homology family phosphatase PSTPIP2 that is responsible for the development of a persistent autoinflammatory disease resembling chronic recurrent multifocal osteomyelitis in humans. We found that improper regulation of IL-1ß production resulted in secondary induction of inflammatory cytokines, inflammatory cell infiltration in the bone, and unremitting bone inflammation. Aberrant Il1ß expression precedes the development of osteolytic damage in young Pstpip2(cmo) mice, and genetic deletion of Il1r and Il1ß, but not Il1α, rescued osteolytic bone disease in mutant mice. Intriguingly, caspase-1 and nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 activation in the inflammasome complex were dispensable for Pstpip2(cmo)-mediated bone disease. Thus, our findings establish a critical role for inflammasome-independent production of IL-1ß in osteolytic bone disease and identify PSTPIP2 as a negative regulator of caspase-1-autonomous IL-1ß production.

A perivascular niche for brain tumor stem cells.

Cancers are believed to arise from cancer stem cells (CSCs), but it is not known if these cells remain dependent upon the niche microenvironments that regulate normal stem cells. We show that endothelial cells interact closely with self-renewing brain tumor cells and secrete factors that maintain these cells in a stem cell-like state. Increasing the number of endothelial cells or blood vessels in orthotopic brain tumor xenografts expanded the fraction of self-renewing cells and accelerated the initiation and growth of tumors. Conversely, depletion of blood vessels from xenografts ablated self-renewing cells from tumors and arrested tumor growth. We propose that brain CSCs are maintained within vascular niches that are important targets for therapeutic approaches.

Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia.

The introduction of cultured p185(BCR-ABL)-expressing (p185+) Arf (-/-) pre-B cells into healthy syngeneic mice induces aggressive acute lymphoblastic leukemia (ALL) that genetically and phenotypically mimics the human disease. We adapted this high-throughput Philadelphia chromosome-positive (Ph(+)) ALL animal model for in vivo luminescent imaging to investigate disease progression, targeted therapeutic response, and ALL relapse in living mice. Mice bearing high leukemic burdens (simulating human Ph(+) ALL at diagnosis) entered remission on maximally intensive, twice-daily dasatinib therapy, but invariably relapsed with disseminated and/or central nervous system disease. Although relapse was frequently accompanied by the eventual appearance of leukemic clones harboring BCR-ABL kinase domain (KD) mutations that confer drug resistance, their clonal emergence required prolonged dasatinib exposure. KD P-loop mutations predominated in mice receiving less intensive therapy, whereas high-dose treatment selected for T315I "gatekeeper" mutations resistant to all 3 Food and Drug Administration-approved BCR-ABL kinase inhibitors. The addition of dexamethasone and/or L-asparaginase to reduced-intensity dasatinib therapy improved long-term survival of the majority of mice that received all 3 drugs. Although non-tumor-cell-autonomous mechanisms can prevent full eradication of dasatinib-refractory ALL in this clinically relevant model, the emergence of resistance to BCR-ABL kinase inhibitors can be effectively circumvented by the addition of "conventional" chemotherapeutic agents with alternate antileukemic mechanisms of action.

Radial glia cells are candidate stem cells of ependymoma.

Tumors of the same histologic type often comprise clinically and molecularly distinct subgroups; however, the etiology of these subgroups is unknown. Here, we report that histologically identical, but genetically distinct, ependymomas exhibit patterns of gene expression that recapitulate those of radial glia cells in the corresponding region of the central nervous system. Cancer stem cells isolated from ependymomas displayed a radial glia phenotype and formed tumors when orthotopically transplanted in mice. These findings identify restricted populations of radial glia cells as candidate stem cells of the different subgroups of ependymoma, and they support a general hypothesis that subgroups of the same histologic tumor type are generated by different populations of progenitor cells in the tissues of origin.

Preclinical dose-finding study with a liver-tropic, recombinant AAV-2/8 vector in the mouse model of galactosialidosis.

Galactosialidosis (GS) is a lysosomal storage disease linked to deficiency of the protective protein/cathepsin A (PPCA). Similarly to GS patients, Ppca-null mice develop a systemic disease of the reticuloendothelial system, affecting most visceral organs and the nervous system. Symptoms include severe nephropathy, visceromegaly, infertility, progressive ataxia, and shortened life span. Here, we have conducted a preclinical, dose-finding study on a large cohort of GS mice injected intravenously at 1 month of age with increasing doses of a GMP-grade rAAV2/8 vector, expressing PPCA under the control of a liver-specific promoter. Treated mice, monitored for 16 weeks post-treatment, had normal physical appearance and behavior without discernable side effects. Despite the restricted expression of the transgene in the liver, immunohistochemical and biochemical analyses of other systemic organs, serum, and urine showed a dose-dependent, widespread correction of the disease phenotype, suggestive of a protein-mediated mechanism of cross-correction. A notable finding was that rAAV-treated GS mice showed high expression of PPCA in the reproductive organs, which resulted in reversal of their infertility. Together these results support the use of this rAAV-PPCA vector as a viable and safe method of gene delivery for the treatment of systemic disease in non-neuropathic GS patients.

Bypassing misinformation without confrontation improves policy support as much as correcting it.

Curbing the negative impact of misinformation is typically assumed to require correcting misconceptions. Conceivably, however, bypassing the misinformation through alternate beliefs of opposite implications may reduce the attitudinal impact of the misinformation. Three experiments, one preregistered with a sample representative of the United States population, examined the impact of (a) directly correcting prior misinformation offered in support of restricting Genetically Modified (GM) foods (i.e., the correction strategy) and (b) discussing information in support of GM foods (i.e., the bypassing strategy), compared to a misinformation-only control condition. Findings consistently revealed that bolstering beliefs with opposite implications is just as effective at reducing opposition to GM foods as is correcting misinformation about GM foods. Thus, bypassing should be added to our arsenal of methods to curb the impact of misinformation.

A comparison of three methods to determine the subject matter in textual data.

This study compares three different methods commonly employed for the determination and interpretation of the subject matter of large corpuses of textual data. The methods reviewed are: (1) topic modeling, (2) community or group detection, and (3) cluster analysis of semantic networks. Two different datasets related to health topics were gathered from Twitter posts to compare the methods. The first dataset includes 16,138 original tweets concerning HIV pre-exposure prophylaxis (PrEP) from April 3, 2019 to April 3, 2020. The second dataset is comprised of 12,613 tweets about childhood vaccination from July 1, 2018 to October 15, 2018. Our findings suggest that the separate "topics" suggested by semantic networks (community detection) and/or cluster analysis (Ward's method) are more clearly identified than the topic modeling results. Topic modeling produced more subjects, but these tended to overlap. This study offers a better understanding of how results may vary based on method to determine subject matter chosen.

State policies increase vaccination by shaping social norms.

In a survey and four preregistered experiments, we examined if implementing a vaccine-promoting policy is likely to encourage vaccination by shaping the norms of a society. By combining state-level policy data with a longitudinal survey, we found that vaccine-supportive policies and laws are associated with more positive social norms. To establish a causal effect, we conducted four preregistered experiments to gauge the impact of policies, including the government recommendation for children to receive the COVID-19 vaccine and changes in funding for immunization programs. We find that vaccine-supportive policies strengthen the intention to receive an additional recommended COVID-19 booster shot and the intention to vaccinate children against COVID-19. We also find that these effects are mediated by the promotion of social norms supportive of vaccination. In this context, communicating about laws and policies in favor of vaccination may create a culture of vaccination and increase vaccination coverage.

Comparison of public discussions of gene editing on social media between the United States and China.

The world's first gene-edited babies event has stirred controversy on social media over the use of gene editing technology. Understanding public discussions about this controversy will provide important insights about opinions of science and facilitate informed policy decisions. This study compares public discussion topics about gene editing on Twitter and Weibo, as wel asthe evolution of these topics over four months. Latent Dirichlet allocation (LDA) was used to generate topics for 11,244 Weibo posts and 57,525 tweets from September 25, 2018, to January 25, 2019. Results showed a difference between the topics on Twitter versus Weibo: there were more nuanced discussions on Twitter, and the discussed topics between platforms focused on different areas. Temporal analysis showed that most discussions took place around gene-edited events. Based on our findings, suggestions were provided for policymakers and science communication practitioners to develop more effective communication strategies toward audiences in China and the U.S.

Inflammasome-independent role of apoptosis-associated speck-like protein containing a CARD (ASC) in T cell priming is critical for collagen-induced arthritis.

Rheumatoid arthritis is an autoimmune disease with 1% prevalence in the industrialized world. The contributions of the inflammasome components Nlrp3, ASC, and caspase-1 in the pathogenesis of collagen-induced arthritis have not been characterized. Here, we show that ASC(-/-) mice were protected from arthritis, whereas Nlrp3(-/-) and caspase-1(-/-) mice were susceptible to collagen-induced arthritis. Unlike Nlrp3(-/-) and caspase-1(-/-) mice, the production of collagen-specific antibodies was abolished in ASC(-/-) mice. This was due to a significantly reduced antigen-specific activation of lymphocytes by ASC(-/-) dendritic cells. Antigen-induced proliferation of purified ASC(-/-) T cells was restored upon incubation with wild type dendritic cells, but not when cultured with ASC(-/-) dendritic cells. Moreover, direct T cell receptor ligation with CD3 and CD28 antibodies induced a potent proliferation of ASC(-/-) T cells, indicating that ASC is specifically required in dendritic cells for antigen-induced T cell activation. Therefore, ASC fulfills a hitherto unrecognized inflammasome-independent role in dendritic cells that is crucial for T cell priming and the induction of antigen-specific cellular and humoral immunity and the onset of collagen-induced arthritis.

Understanding Human Papillomavirus Vaccine Promotions and Hesitancy in Northern California Through Examining Public Facebook Pages and Groups.

Human papillomavirus (HPV) vaccination coverage among adolescents is lower in rural regions and remains under the 80% coverage goal by Healthy People 2030. Through both sentiment analysis and topic modeling, this research examines how local health agencies and groups in nine Northern California counties promote HPV vaccines through Facebook and how target populations react to promotion posts in comments that elucidate their sentiments and hesitancy toward HPV vaccination. In January 2021, we identified 2,105 public Facebook pages and 1,065 groups related to health within the counties and collected a total of 212 posts and 505 comments related to the HPV vaccine. The posts were published between 2010 and 2021, with the majority (83%) published after 2017. There were large variations of Facebook activities across counties. We categorized four counties with HPV vaccination initiation rates below 40% as low-coverage counties and five counties with rates above 40% as high-coverage counties. In general, low-coverage counties had fewer Facebook activities in comparison to high coverage. Results showed that, on average, comments about the HPV vaccine exhibited more positive emotion, more negative emotion, and more anger than the posts. Overall, thematic topics that emerged from posts centered around awareness and screening of HPV and cervical cancer, STI testing services, information sources, and calls to action for health services. However, comment topics did not correspond to posts and were mostly related to vaccine hesitancy, discussing vaccine risks, safety concerns, and distrust in vaccine science, citing misinformation. When comparing high- versus low-coverage counties, posts expressed similar sentiments; however, comments within high-coverage counties expressed more anger than in low-coverage counties. Comments from both high- and low-coverage counties expressed concerns with vaccine safety, risks, and injury. It is important to note that commenters exchanged information sources and tried to address misinformation themselves. Our results suggest that the promotion of HPV vaccines from public Facebook pages and groups is limited in frequency and content diversity. This illustrates problems with generalized social media vaccination promotion without community tailoring and addressing specific hesitancy concerns. Public health agencies should listen to the thoughts of targeted audiences reflected through comments and design relevant messages to address these concerns for HPV vaccination promotion.

Genetic alterations in mouse medulloblastomas and generation of tumors de novo from primary cerebellar granule neuron precursors.

Mice lacking p53 and one or two alleles of the cyclin D-dependent kinase inhibitor p18(Ink4c) are prone to medulloblastoma development. The tumor frequency is increased by exposing postnatal animals to ionizing radiation at a time when their cerebella are developing. In irradiated mice engineered to express a floxed p53 allele and a Nestin-Cre transgene, tumor development can be restricted to the brain. Analysis of these animals indicated that inactivation of one or both Ink4c alleles did not affect the time of medulloblastoma onset but increased tumor invasiveness. All such tumors exhibited complete loss of function of the Patched 1 (Ptc1) gene encoding the receptor for sonic hedgehog, and many exhibited other recurrent genetic alterations, including trisomy of chromosome 6, amplification of N-Myc, modest increases in copy number of the Ccnd1 gene encoding cyclin D1, and other complex chromosomal rearrangements. In contrast, medulloblastomas arising in Ptc1(+/-) mice lacking one or both Ink4c alleles retained p53 function and exhibited only limited genomic instability. Nonetheless, complete inactivation of the wild-type Ptc1 allele was a universal event, and trisomy of chromosome 6 was again frequent. The enforced expression of N-Myc or cyclin D1 in primary cerebellar granule neuron precursors isolated from Ink4c(-/-), p53(-/-) mice enabled the cells to initiate medulloblastomas when injected back into the brains of immunocompromised recipient animals. These "engineered" tumors exhibited gene expression profiles indistinguishable from those of medulloblastomas that arose spontaneously. These results underscore the functional interplay between a network of specific genes that recurrently contribute to medulloblastoma formation.

Combinatorial screening using orthotopic patient derived xenograft-expanded early phase cultures of osteosarcoma identify novel therapeutic drug combinations.

Lead discovery in osteosarcoma has been hampered by the lack of new agents, limited representative clinical samples and paucity of accurate preclinical models. We developed orthotopic patient-derived xenografts (PDXs) that recapitulated the molecular, cellular and histologic features of primary tumors, and screened PDX-expanded short-term cultures and commercial cell lines of osteosarcoma against focused drug libraries. Osteosarcoma cells were most sensitive to HDAC, proteasome, and combination PI3K/MEK and PI3K/mTOR inhibitors, and least sensitive to PARP, RAF, ERK and MEK inhibitors. Correspondingly, PI3K signaling pathway genes were up-regulated in metastatic tumors compared to primary tumors. In combinatorial screens, as a class, HDAC inhibitors showed additive effects when combined with standard-of-care agents gemcitabine and doxorubicin. This lead discovery strategy afforded a means to perform high-throughput drug screens of tumor cells that accurately recapitulated those from original human tumors, and identified classes of novel and repurposed drugs with activity against osteosarcoma.

Continuous delivery of IFN-beta promotes sustained maturation of intratumoral vasculature.

IFNs have pleiotropic antitumor mechanisms of action. The purpose of this study was to further investigate the effects of IFN-beta on the vasculature of human xenografts in immunodeficient mice. We found that continuous, systemic IFN-beta delivery, established with liver-targeted adeno-associated virus vectors, led to sustained morphologic and functional changes of the tumor vasculature that were consistent with vessel maturation. These changes included increased smooth muscle cell coverage of tumor vessels, improved intratumoral blood flow, and decreased vessel permeability, tumor interstitial pressure, and intratumoral hypoxia. Although these changes in the tumor vasculature resulted in more efficient tumor perfusion, further tumor growth was restricted, as the mature vasculature seemed to be unable to expand to support further tumor growth. In addition, maturation of the intratumoral vasculature resulted in increased intratumoral penetration of systemically administered chemotherapy. Finally, molecular analysis revealed increased expression by treated tumors of angiopoietin-1, a cytokine known to promote vessel stabilization. Induction of angiopoietin-1 expression in response to IFN-beta was broadly observed in different tumor lines but not in those with defects in IFN signaling. In addition, IFN-beta-mediated vascular changes were prevented when angiopoietin signaling was blocked with a decoy receptor. Thus, we have identified an alternative approach for achieving sustained vascular remodeling-continuous delivery of IFN-beta. In addition to restricting tumor growth by inhibiting further angiogenesis, maturation of the tumor vasculature also improved the efficiency of delivery of adjuvant therapy. These results have significant implications for the planning of combination anticancer therapy.