Using Social Listening for Digital Public Health Surveillance of Human Papillomavirus Vaccine Misinformation Online: Exploratory Study.

Despite challenges related to the data quality, representativeness, and accuracy of artificial intelligence-driven tools, commercially available social listening platforms have many of the attributes needed to be used for digital public health surveillance of human papillomavirus vaccination misinformation in the online ecosystem.

Comparing synaptic proteomes across five mouse models for autism reveals converging molecular similarities including deficits in oxidative phosphorylation and Rho GTPase signaling.

Specific and effective treatments for autism spectrum disorder (ASD) are lacking due to a poor understanding of disease mechanisms. Here we test the idea that similarities between diverse ASD mouse models are caused by deficits in common molecular pathways at neuronal synapses. To do this, we leverage the availability of multiple genetic models of ASD that exhibit shared synaptic and behavioral deficits and use quantitative mass spectrometry with isobaric tandem mass tagging (TMT) to compare their hippocampal synaptic proteomes. Comparative analyses of mouse models for Fragile X syndrome (Fmr1 knockout), cortical dysplasia focal epilepsy syndrome (Cntnap2 knockout), PTEN hamartoma tumor syndrome (Pten haploinsufficiency), ANKS1B syndrome (Anks1b haploinsufficiency), and idiopathic autism (BTBR+) revealed several common altered cellular and molecular pathways at the synapse, including changes in oxidative phosphorylation, and Rho family small GTPase signaling. Functional validation of one of these aberrant pathways, Rac1 signaling, confirms that the ANKS1B model displays altered Rac1 activity counter to that observed in other models, as predicted by the bioinformatic analyses. Overall similarity analyses reveal clusters of synaptic profiles, which may form the basis for molecular subtypes that explain genetic heterogeneity in ASD despite a common clinical diagnosis. Our results suggest that ASD-linked susceptibility genes ultimately converge on common signaling pathways regulating synaptic function and propose that these points of convergence are key to understanding the pathogenesis of this disorder.

State of Gender-Based Microaggressions Among Surgeons and Development of Simulation Workshops for Addressing Microaggressions for Surgical Trainees and Students.

BACKGROUND: Microaggressions are statements or actions taken in a discriminatory manner. Microaggressions can be subtle or explicit, intentional or unintentional, but regardless of the type of microaggressions, it is important to identify and address them, as they are linked to physician burnout and add to levels of depression, anxiety, and stress. In this study, we evaluated the prevalence, quality, and impacts of gender-based microaggressions on surgeons and surgical trainees using simulation-based education. Further, we plan to iteratively develop more simulation sessions based on the findings of this study. METHODS: We used simulation-based education to develop and implement microaggression scenarios. Those scenarios were performed by standardized patients (trained actors) who demonstrated the different microaggression situations previously seen at the workplace and wards. Published tools to address gender-based microaggressions were outlined in preparation (prebrief) for a discussion of recorded simulations. A debrief of developing potential resolutions as learners and future allies and how similar microaggressions may have been perpetuated in our own careers followed each scenario. Additionally, an 11-item survey was developed based on validated surveys of sexist and Microaggressions Experience and Stress Scale and disseminated through email listservs and social media links. Data collection occurred from November to December 2022. RESULTS: When surveyed after the workshop, 100% of participants (n = 6) said that they would recommend this session to follow colleagues, and 100% completely agreed the content of the simulation was relevant to their future practice. Further, 100% of participants agreed or completely agreed that their ability to perform these tasks (addressing microaggressions) has improved after this course. Most respondents to the disseminated survey (n = 147) were vascular surgeons (95/147; 64.6%) and identified as White (93/147; 63.3%), and as women (142/147; 96.6%). Most were identified as targets of gender-based microaggressions (128/147; 87.1%) and or silent witnesses to such microaggressions (87/147; 59.2%). However, there were reports of having a perpetrator of a microaggression (2/147; 1.4%), a nonsilent witness (3/147; 2.0%), or having no target, witness, or perpetrator (3/147; 2.0%). Of the quality of microaggressions, the most common impacts were when the targeted individual attempted to hide their emotions to not appear too emotional (described in the literature as "leaving gender at the door") (32/147; 21.8%), were told that women no longer experience discrimination (25/147; 17.0%), and were asked when one would have children (24/147; 16.3%). The most stressful types of microaggressions were ones in which male peers were the only ones receiving recognition for work (55/147; 37.4%), targets were told women no longer experience discrimination (49/147; 33.3%), and in which men spoke about women in degrading terms regarding their gender or on topics related to their gender (35/147; 23.8%). Qualitative responses to the survey included comments remarking on the relevancy and prevalence of gender-based microaggressions, reasons for silence, the personal and professional impacts (e.g., pay equity) of microaggressions and gender bias, and future areas of work to address bias in medicine. CONCLUSIONS: Given the prevalence of microaggressions seen in surgery, especially among vascular surgeons, future steps include discussion of how techniques can be developed and applied to other types of microaggressions (e.g., due to race/ethnicity, sexuality, disability, religion), implementation of future workshops that address intersectionality in scenarios and potentially virtual sessions to increase accessibility to these types of training options for learners at other institutions.

Addressing Lung Cancer Health Disparities in West Virginia: An Academic-Industry Collaboration Model.

Lung cancer screening is underused nationwide, particularly in rural areas where incidence and mortality rates are high, suggesting the need for innovative methods to reach underserved populations. Partners from national, state, and community positions can combine the service and science needed to save lives with mobile lung cancer screening.

Evaluation of change in emergency care knowledge and skills among front-line healthcare providers in Ukraine with the Basic Emergency Care course: a pretest/post-test study.

OBJECTIVE: Evaluate the change in participant emergency care knowledge and skill confidence after implementation of the WHO-International Committee of the Red Cross (ICRC) Basic Emergency Care (BEC) course. DESIGN: Pretest/post-test quasi-experimental study. SETTING: Mechnikov Hospital in Dnipro, Ukraine. PARTICIPANTS: Seventy-nine participants engaged in the course, of whom 50 (63.3%) completed all assessment tools. The course was open to healthcare providers of any level who assess and treat emergency conditions as part of their practice. The most common participant profession was resident physician (24%), followed by health educator (18%) and prehospital provider (14%). INTERVENTIONS: The 5-day WHO-ICRC BEC course. PRIMARY AND SECONDARY OUTCOME MEASURES: Change in pre-course and post-course knowledge and skill confidence assessments. Open-ended written feedback was collected upon course completion and analysed for common themes. RESULTS: Participant knowledge assessment scores improved from 19 (IQR 15-20) to 22 (IQR 19-23) on a 25-point scale (p<0.001). Participant skill confidence self-assessment scores improved from 2.5 (IQR 2.1-2.8) to 2.9 (IQR 2.5-3.3) on a 4-point scale (p<0.001). The most common positive feedback themes were high-quality teaching and useful skill sessions. The most common constructive feedback themes were translation challenges and request for additional skill session time. CONCLUSIONS: This first implementation of the WHO-ICRC BEC course for front-line healthcare providers in Ukraine was successful and well received by participants. This is also the first report of a BEC implementation outside of Africa and suggests that the course is also effective in the European context, particularly in humanitarian crisis and conflict settings. Future research should evaluate long-term knowledge retention and the impact on patient outcomes. Further iterations should emphasise local language translation and consider expanding clinical skills sessions.

Targeting farnesylation as a novel therapeutic approach in HRAS-mutant rhabdomyosarcoma.

Activating RAS mutations are found in a subset of fusion-negative rhabdomyosarcoma (RMS), and therapeutic strategies to directly target RAS in these tumors have been investigated, without clinical success to date. A potential strategy to inhibit oncogenic RAS activity is the disruption of RAS prenylation, an obligate step for RAS membrane localization and effector pathway signaling, through inhibition of farnesyltransferase (FTase). Of the major RAS family members, HRAS is uniquely dependent on FTase for prenylation, whereas NRAS and KRAS can utilize geranylgeranyl transferase as a bypass prenylation mechanism. Tumors driven by oncogenic HRAS may therefore be uniquely sensitive to FTase inhibition. To investigate the mutation-specific effects of FTase inhibition in RMS we utilized tipifarnib, a potent and selective FTase inhibitor, in in vitro and in vivo models of RMS genomically characterized for RAS mutation status. Tipifarnib reduced HRAS processing, and plasma membrane localization leading to decreased GTP-bound HRAS and decreased signaling through RAS effector pathways. In HRAS-mutant cell lines, tipifarnib reduced two-dimensional and three-dimensional cell growth, and in vivo treatment with tipifarnib resulted in tumor growth inhibition exclusively in HRAS-mutant RMS xenografts. Our data suggest that small molecule inhibition of FTase is active in HRAS-driven RMS and may represent an effective therapeutic strategy for a genomically-defined subset of patients with RMS.

Pten haploinsufficiency causes desynchronized growth of brain areas involved in sensory processing.

How changes in brain scaling relate to altered behavior is an important question in neurodevelopmental disorder research. Mice with germline Pten haploinsufficiency (Pten +/-) closely mirror the abnormal brain scaling and behavioral deficits seen in humans with macrocephaly/autism syndrome, which is caused by PTEN mutations. We explored whether deviation from normal patterns of growth can predict behavioral abnormalities. Brain regions associated with sensory processing (e.g., pons and inferior colliculus) had the biggest deviations from expected volume. While Pten +/- mice showed little or no abnormal behavior on most assays, both sexes showed sensory deficits, including impaired sensorimotor gating and hyporeactivity to high-intensity stimuli. Developmental analysis of this phenotype showed sexual dimorphism for hyporeactivity. Mapping behavioral phenotypes of Pten +/- mice onto relevant brain regions suggested abnormal behavior is likely when associated with relatively enlarged brain regions, while unchanged or relatively decreased brain regions have little predictive value.

Environmental Enrichment Rescues Social Behavioral Deficits and Synaptic Abnormalities in Pten Haploinsufficient Mice.

Pten germline haploinsufficient (Pten+/-) mice, which model macrocephaly/autism syndrome, show social and repetitive behavior deficits, early brain overgrowth, and cortical-subcortical hyperconnectivity. Previous work indicated that altered neuronal connectivity may be a substrate for behavioral deficits. We hypothesized that exposing Pten+/- mice to environmental enrichment after brain overgrowth has occurred may facilitate adaptation to abnormal "hard-wired" connectivity through enhancing synaptic plasticity. Thus, we reared Pten+/- mice and their wild-type littermates from weaning under either standard (4-5 mice per standard-sized cage, containing only bedding and nestlet) or enriched (9-10 mice per large-sized cage, containing objects for exploration and a running wheel, plus bedding and nestlet) conditions. Adult mice were tested on social and non-social assays in which Pten+/- mice display deficits. Environmental enrichment rescued sex-specific deficits in social behavior in Pten+/- mice and partially rescued increased repetitive behavior in Pten+/- males. We found that Pten+/- mice show increased excitatory and decreased inhibitory pre-synaptic proteins; this phenotype was also rescued by environmental enrichment. Together, our results indicate that environmental enrichment can rescue social behavioral deficits in Pten+/- mice, possibly through normalizing the excitatory synaptic protein abundance.

The Lived Experience of a Newly Diagnosed Older Person With HIV in Ukraine.

Low- and middle-income countries are home to 80% of older people with HIV (OPWH). Ukrainian OPWH experience higher mortality and decreased antiretroviral therapy (ART) initiation than younger patients, but there is little data examining OPWH's perspectives around new diagnosis and impact on care. In this study, we examined accounts of 30 newly diagnosed OPWH in Ukraine, exploring challenges faced in the peri-diagnosis period. Themes emerged representing the longitudinal coping process: OPWH (1) viewed themselves as low risk before diagnosis; (2) experienced HIV diagnosis as a traumatic event challenging their self-image; (3) used disclosure to seek support among a small circle of family, friends, or health care providers; (4) avoided disclosure to outsiders including primary care providers for fears of stigma and breaches in confidentiality; (5) viewed age as an asset; and (6) used HIV diagnosis as starting point for growth. These findings highlight the need for age-specific programming to increase HIV knowledge and coping, increase screening, and improve long-term planning.

Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAFV600E-Mutant Human Glioma.

PURPOSE: Selective RAF-targeted therapy is effective in some patients with BRAFV600E-mutated glioma, though emergent and adaptive resistance occurs through ill-defined mechanisms. EXPERIMENTAL DESIGN: Paired pre-/post- RAF inhibitor (RAFi)-treated glioma samples (N = 15) were obtained and queried for treatment-emergent genomic alterations using DNA and RNA sequencing (RNA-seq). Functional validation of putative resistance mechanisms was performed using established and patient-derived BRAFV600E-mutant glioma cell lines. RESULTS: Analysis of 15 tissue sample pairs identified 13 alterations conferring putative resistance were identified among nine paired samples (including mutations involving ERRFI1, BAP1, ANKHD1, and MAP2K1). We performed functional validation of mechanisms of resistance, including loss of NF1, PTEN, or CBL, in BRAFV600E-mutant glioma lines, and demonstrate they are capable of conferring resistance in vitro. Knockdown of CBL resulted in increased EGFR expression and phosphorylation, a possible mechanism for maintaining ERK signaling within the cell. Combination therapy with a MEKi or EGFR inhibitor was able to overcome resistance to BRAFi, in NF1 knockdown and CBL knockdown, respectively. Restoration of wild-type PTEN in B76 cells (PTEN-/-) restored sensitivity to BRAFi. We identified and validated CRAF upregulation as a mechanism of resistance in one resistant sample. RNA-seq analysis identified two emergent expression patterns in resistant samples, consistent with expression patterns of known glioma subtypes. CONCLUSIONS: Resistance mechanisms to BRAFi in glioma are varied and may predict effective precision combinations of targeted therapy, highlighting the importance of a personalized approach.

SmartPhrase: Development of an Electronic Health Record System to Promote Chemotherapy and Immunotherapy Safety.

A collaborative interprofessional team of healthcare providers from a regional comprehensive community cancer program established standardized chemotherapy and immunotherapy preadministration documentation in the electronic health record. This quality improvement project facilitated adherence to administration considerations defined within Oncology Nursing Society chemotherapy and immunotherapy guidelines and established organizational accreditation goals. The goal was to foster safe and seamless patient-centered care.

Combination MEK and mTOR inhibitor therapy is active in models of glioblastoma.

BACKGROUND: RAS effector signaling pathways such as PI3K/mTOR and ERK are frequently dysregulated in glioblastoma. While small molecule targeted therapies against these pathways have appeared promising in preclinical studies, they have been disappointing in clinical trials due to toxicity and de novo and adaptive resistance. To identify predictors of glioblastoma sensitivity to dual pathway inhibition with mTORC1/2 and MEK inhibitors, we tested these agents, alone and in combination, in a cohort of genomically characterized glioblastoma cell lines. METHODS: Seven genomically characterized, patient-derived glioblastoma neurosphere cell lines were evaluated for their sensitivity to the dual mTORC1/2 kinase inhibitor sapanisertib (MLN0128, TAK-228) alone or in combination with the MEK1/2 inhibitor trametinib (GSK1120212), using assessment of proliferation and evaluation of the downstream signaling consequences of these inhibitors. RESULTS: Sapanisertib inhibited cell growth in neurosphere lines, but induced apoptosis only in a subset of lines, and did not completely inhibit downstream mTOR signaling via ribosomal protein S6 (RPS6). Growth sensitivity to MEK inhibitor monotherapy was observed in a subset of lines defined by loss of NF1, was predicted by an ERK-dependent expression signature, and was associated with effective phospho-RPS6 inhibition. In these lines, combined MEK/mTOR treatment further inhibited growth and induced apoptosis. Combined MEK and mTOR inhibition also led to modest antiproliferative effects in lines with intact NF1 and insensitivity to MEK inhibitor monotherapy. CONCLUSIONS: These data demonstrate that combined MEK/mTOR inhibition is synergistic in glioblastoma cell lines and may be more potent in NF1-deficient glioblastoma.

Combined Inhibition of SHP2 and MEK Is Effective in Models of NF1-Deficient Malignant Peripheral Nerve Sheath Tumors.

Loss of the RAS GTPase-activating protein (RAS-GAP) NF1 drives aberrant activation of RAS/MEK/ERK signaling and other effector pathways in the majority of malignant peripheral nerve sheath tumors (MPNST). These dysregulated pathways represent potential targets for therapeutic intervention. However, studies of novel single agents including MEK inhibitors (MEKi) have demonstrated limited efficacy both preclinically and clinically, with little advancement in overall patient survival. By interrogation of kinome activity through an unbiased screen and targeted evaluation of the signaling response to MEK inhibition, we have identified global activation of upstream receptor tyrosine kinases (RTK) that converges on activation of RAS as a mechanism to limit sensitivity to MEK inhibition. As no direct inhibitors of pan-RAS were available, an inhibitor of the protein tyrosine phosphatase SHP2, a critical mediator of RAS signal transduction downstream of multiple RTK, represented an alternate strategy. The combination of MEKi plus SHP099 was superior to MEKi alone in models of NF1-MPNST, including those with acquired resistance to MEKi. Our findings have immediate translational implications and may inform future clinical trials for patients with MPNST harboring alterations in NF1. SIGNIFICANCE: Combined inhibition of MEK and SHP2 is effective in models of NF1-MPNST, both those naïve to and those resistant to MEKi, as well as in the MPNST precursor lesion plexiform neurofibroma.

Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations.

Mutations that inactivate negative translation regulators cause autism spectrum disorders (ASD), which predominantly affect males and exhibit social interaction and communication deficits and repetitive behaviors. However, the cells that cause ASD through elevated protein synthesis resulting from these mutations remain unknown. Here we employ conditional overexpression of translation initiation factor eIF4E to increase protein synthesis in specific brain cells. We show that exaggerated translation in microglia, but not neurons or astrocytes, leads to autism-like behaviors in male mice. Although microglial eIF4E overexpression elevates translation in both sexes, it only increases microglial density and size in males, accompanied by microglial shift from homeostatic to a functional state with enhanced phagocytic capacity but reduced motility and synapse engulfment. Consequently, cortical neurons in the mice have higher synapse density, neuroligins, and excitation-to-inhibition ratio compared to control mice. We propose that functional perturbation of male microglia is an important cause for sex-biased ASD.

Identifying Needs for Advancing the Profession and Workforce in Environmental Health.

An ever-changing landscape for environmental health (EH) requires in-depth assessment and analysis of the current challenges and emerging issues faced by EH professionals. The Understanding the Needs, Challenges, Opportunities, Vision, and Emerging Roles in Environmental Health initiative addressed this need.After receiving responses from more than 1700 practitioners, during an in-person workshop, focus groups identified and described priority problems and supplied context on addressing the significant challenges facing EH professionals with state health agencies and local health departments. The focus groups developed specific problem statements detailing the EH profession and workforce's prevailing challenges and needs according to 6 themes, including effective leadership, workforce development, equipment and technology, information systems and data, garnering support, and partnerships and collaboration.We describe the identified priority problems and needs and provide recommendations for ensuring a strong and robust EH profession and workforce ready to address tomorrow's challenges.

Connecting Genotype with Behavioral Phenotype in Mouse Models of Autism Associated with PTEN Mutations.

A subset of individuals with autism spectrum disorder (ASD) and macrocephaly carry mutations in the gene PTEN. Animal models, particularly mice, have been helpful in establishing a causal role for Pten mutations in autism-relevant behavioral deficits. These models are a useful tool for investigating neurobiological mechanisms of these behavioral phenotypes and developing potential therapeutic interventions. Here we provide an overview of various genetic mouse models that have been used to characterize behavioral phenotypes caused by perturbation of Pten We discuss convergent and divergent phenotypes across models with the aim of highlighting a set of behavioral domains that are sensitive to the effects of Pten mutation and that may provide useful readouts for translational and basic neuroscience research.

Pten haploinsufficiency disrupts scaling across brain areas during development in mice.

Haploinsufficiency for PTEN is a cause of autism spectrum disorder and brain overgrowth; however, it is not known if PTEN mutations disrupt scaling across brain areas during development. To address this question, we used magnetic resonance imaging to analyze brains of male Pten haploinsufficient (Pten+/-) mice and wild-type littermates during early postnatal development and adulthood. Adult Pten+/- mice display a consistent pattern of abnormal scaling across brain areas, with white matter (WM) areas being particularly affected. This regional and WM enlargement recapitulates structural abnormalities found in individuals with PTEN haploinsufficiency and autism. Early postnatal Pten+/- mice do not display the same pattern, instead exhibiting greater variability across mice and brain regions than controls. This suggests that Pten haploinsufficiency may desynchronize growth across brain regions during early development before stabilizing by maturity. Pten+/- cortical cultures display increased proliferation of glial cell populations, indicating a potential substrate of WM enlargement, and provide a platform for testing candidate therapeutics. Pten haploinsufficiency dysregulates coordinated growth across brain regions during development. This results in abnormally scaled brain areas and associated behavioral deficits, potentially explaining the relationship between PTEN mutations and neurodevelopmental disorders.

Rare BRAF mutations in pancreatic neuroendocrine tumors may predict response to RAF and MEK inhibition.

The clinical significance of BRAF alterations in well-differentiated (WD) metastatic pancreatic neuroendocrine tumor (panNET) is unknown, but BRAF-mutated panNET could represent a subset characterized by an identifiable and clinically actionable driver. Following the identification of two patients with WD metastatic panNET whose tumors harbored BRAF mutations, we queried the MSK-IMPACT series of 80 patients with WD metastatic panNET for additional mutations in BRAF, and in other genes involved in RAS/ RTK/ PI3K signaling pathways. BRAF mutations were identified in six samples (7.5%): two tumors harbored V600E mutations, one tumor each expressed K601E, T599K, and T310I mutations, and one tumor expressed both G596D and E451K BRAF. Few additional actionable driver alterations were identified. To determine the ERK activating capability of four BRAF mutations not previously characterized, mutant constructs were tested in model systems. Biochemical characterization of BRAF mutations revealed both high and low activity mutants. Engineered cells expressing BRAF K601E and V600E were used for in vitro drug testing of RAF and MEK inhibitors currently in clinical use. BRAF K601E demonstrated reduced sensitivity to dabrafenib compared to BRAF V600E, but the combination of RAF plus MEK inhibition was effective in cells expressing this mutation. Herein, we describe the clinical course of a patient with BRAF K601E and a patient with BRAF V600E WD metastatic panNET, and the identification of four mutations in BRAF not previously characterized. The combined clinical and biochemical data support a potential role for RAF and MEK inhibitors, or a combination of these, in a selected panNET population.

Divergence in perceptions of diabetes control among patients with type 2 diabetes mellitus treated with basal insulin and health care professionals: results from the US Perceptions of Control (POC-US) study.

Background: Approximately 60% of the patients with type 2 diabetes mellitus (T2DM) on basal insulin have an HbA1c ≥7%. This analysis of the US Perceptions of Control (POC-US) study aimed to understand US patient and health care professional (HCP) views of diabetes "control," which may play a role in whether patients reduce their HbA1c or achieve HbA1c <7%. Methods: A cross-sectional, Web-based survey of 500 US HCPs (primary care physicians, endocrinologists, nurse practitioners/physician assistants) and 618 US adults with T2DM using basal insulin was conducted to assess perceptions, attitudes, and behaviors associated with T2DM management. The survey was developed from previous research examples and qualitative exploratory research and was pretested. Patients self-reported their most recent HbA1c level and confirmed this value with their HCP, if necessary. Results: Patients and HCPs differed on some definitions of "in control." HbA1c value was used most often by both populations, but more frequently by HCPs (91% vs 69%). Patients also often used behavioral criteria (eg, adherence to lifestyle changes and/or treatment regimens), and HCPs often used clinical criteria (eg, hypoglycemia). Most HCPs focused on the last 3 months to define control (67% vs 34% patients; P<0.05), whereas patients more frequently reported focusing on "the current moment" or "the past week." Patients were more likely to agree that controlling their condition is "completely the patients' responsibility" (patients, 67%; HCPs, 34%; P<0.05); HCPs were more likely to agree that they have "a responsibility to actively contribute to the control of their patients' T2DM" (90% vs 60%; P<0.05). Conclusion: US patients with T2DM have differing views from HCPs on key aspects of diabetes control and management and are less likely to consider HbA1c value as a criterion for determining control. Recognizing and addressing these differences may improve patient-HCP communication and may potentially improve patient outcomes.