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This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals. Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed. The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex. We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed “SNAREopathies.”

With the increase of virtual education due to COVID-19, there is an increased need for quality professional development for virtual educators. To keep up with the changes in educational technology and the best practices of virtual learning, professional development is needed. This qualitative study explored various professional development activities for virtual education during COVID-19 experienced by middle school teachers. This study utilized Siemen’s (2004) connectivism theory as the conceptual framework. The three research questions focused on types of professional development, what was learned from the professional development, and what worked well for educators during the professional development experiences. Data was collected from seventeen middle school educators from a large suburban school district in a metropolitan area through one-on-one semi-structured interviews and document analysis. The data was analyzed and coded to find themes. Comparisons were made between the findings of this study and the literature available to assist interpretation. The themes from this study relate to and extend best practices for professional development for virtual education. The results will impact designers of professional development for virtual education, virtual educators, and students as well as blended learning and 1:1 educators and learners.

Patients at risk for hereditary breast and ovarian cancer (HBOC) traditionally participate in individual cancer genetic counseling sessions to be educated about cancer genetics concepts, their personal cancer risks and genetic testing. With expanding technology and increased public awareness of HBOC, referrals to cancer genetic counseling services have grown. The current number of practicing genetic counselors struggles to meet the demands of increased referrals, so new service delivery models need to be explored. The purpose of this study is to assess the utility of group genetic counseling for HBOC by evaluating the perspectives of patients that received group genetic counseling versus perspectives of those that received individual genetic counseling. We aimed to determine patient satisfaction and comfort level while also assessing the time efficiency and patient receptiveness to group sessions. Sixty-eight individuals with a new diagnosis of breast cancer participated, were randomly assigned to group genetic counseling (n=30) or individual genetic counseling (n=38) and gave perspectives on their genetic counseling session. Results demonstrate that each study cohort reported high satisfaction with their genetic counseling session. Participants in the group genetic counseling cohort were less likely to be overwhelmed by information given in their appointments (p=0.01). Comfort levels were similar between the two study groups and a majority of participants reported high comfort levels after their appointment. A majority of participants in the individual genetic counseling stated that they would not be willing to participate in group genetic counseling had they been given the choice and cited privacy and comfort as the main reasoning. Additionally, our study found that group genetic counseling led to a significant savings in genetic counselor time (p=0.0008). This study demonstrates that group genetic counseling shows promise by reducing the genetic counselor time per patient, which allows for the ability to see more patients, while providing similar satisfaction and benefits to patients as individual genetic counseling models.

A Correction to this paper has been published: https://doi.org/10.1038/s41436-020-01090-w

Safety culture has been shown to influence the accident and injury rate in the workplace, with more positive safety cultures leading to lower rates of accidents and injuries. Given this relationship, identifying methods to improve a company's safety culture is of special interest to both ergonomists and safety professionals. In this study, we explore the use of safety posters to influence perceived safety culture. A virtual environment was developed to simulate a warehouse environment with varying levels of signage. A within-subjects design was used (n=40), with signage varying across four levels (no signage, safety signs, safety posters, both safety signs and safety posters). Participants completed surveys after each scenario, with questions measuring priority of safety, safety awareness, personal perception of safety, perception of co worker safety, and safety culture. Results showed a statistically significant difference for each measure, based on varying levels of signage. The presence of safety posters significantly increased participant ratings of safety culture. This study presents evidence that incorporating safety posters in the workplace is a low-cost and low-effort mechanism to positively influence safety culture.

Triple-negative breast cancer (TNBC) lacks targeted therapies, leaving cytotoxic chemotherapy as the current standard treatment. However, chemotherapy resistance remains a major clinical challenge. Increased insulin-like growth factor 1 signaling can potently blunt chemotherapy response, and lysosomal processes including the nutrient scavenging pathway autophagy can enable cancer cells to evade chemotherapy-mediated cell death. Thus, we tested whether inhibition of insulin receptor/insulin-like growth factor 1 receptor with the drug BMS-754807 and/or lysosomal disruption with hydroxychloroquine (HCQ) could sensitize TNBC cells to the chemotherapy drug carboplatin. Using in vitro studies in multiple TNBC cell lines, in concert with in vivo studies employing a murine syngeneic orthotopic transplant model of TNBC, we show that BMS-754807 and HCQ each sensitized TNBC cells and tumors to carboplatin and reveal that exogenous metabolic modulators may work synergistically with carboplatin as indicated by Bliss analysis. Additionally, we demonstrate the lack of overt in vivo toxicity with our combination regimens and, therefore, propose that metabolic targeting of TNBC may be a safe and effective strategy to increase sensitivity to chemotherapy. Thus, we conclude that the use of exogenous metabolic modulators, such as BMS-754807 or HCQ, in combination with chemotherapy warrants additional study as a strategy to improve therapeutic responses in women with TNBC.

Despite the robust healing capacity of the liver, regenerative failure underlies numerous hepatic diseases, including the JAG1 haploinsufficient disorder, Alagille syndrome (ALGS). Cholestasis due to intrahepatic duct (IHD) paucity resolves in certain ALGS cases but fails in most with no clear mechanisms or therapeutic interventions. We find that modulating jag1b and jag2b allele dosage is sufficient to stratify these distinct outcomes, which can be either exacerbated or rescued with genetic manipulation of Notch signaling, demonstrating that perturbations of Jag/Notch signaling may be causal for the spectrum of ALGS liver severities. Although regenerating IHD cells proliferate, they remain clustered in mutants that fail to recover due to a blunted elevation of Notch signaling in the distal-most IHD cells. Increased Notch signaling is required for regenerating IHD cells to branch and segregate into the peripheral region of the growing liver, where biliary paucity is commonly observed in ALGS. Mosaic loss- and-gain-offunction analysis reveals Sox9b to be a key Notch transcriptional effector required cell autonomously to regulate these cellular dynamics during IHD regeneration. Treatment with a small-molecule putative Notch agonist stimulates Sox9 expression in ALGS patient fibroblasts and enhances hepatic sox9b expression, rescues IHD paucity and cholestasis, and increases survival in zebrafish mutants, thereby providing a proof-of-concept therapeutic avenue for this disorder.

Background: In 2021, a large petroleum leak contaminated a water source that supplied drinking water to military and civilians in Oahu, Hawaii. Methods: We conducted an Assessment of Chemical Exposures (ACE) survey and supplemented that information with complementary data sources: (1) poison center caller records; (2) emergency department visit data; and (3) a key informant questionnaire. Results: Among 2,289 survey participants, 86% reported ≥1 new or worsening symptom, 75% of which lasted ≥30 days, and 37% sought medical care. Most (n = 1,653, 72%) reported new mental health symptoms. Among equally observable symptoms across age groups, proportions of children ≤2 years experiencing vomiting, runny nose, skin rashes, and coughing (33, 46, 56, and 35%, respectively) were higher than other age groups. Poison center calls increased the first 2 weeks after the contamination, while emergency department visits increased in early December 2021. Key informant interviews revealed themes of lack of support, mental health symptoms, and long-term health impact concerns. Discussion: This event led to widespread exposure to petroleum products and negatively affected thousands of people. Follow-up health surveys or interventions should give special consideration to longer-term physical and mental health, especially children due to their unique sensitivity to environmental exposures.

We report for the first time an anticancer benefit of tirzepatide-a dual glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonist-in a model of obesity and breast cancer in female mice. Long-term tirzepatide treatment induced weight loss, mitigated obesity-driven changes in circulating metabolic hormone levels, and suppressed orthotopic E0771 mammary tumor growth. Relative to tirzepatide, chronic calorie restriction, an established anticancer intervention in preclinical models, promoted even greater weight loss, systemic hormonal regulation, and tumor suppression. We conclude that tirzepatide represents a promising pharmacologic approach for mitigating the procancer effects of obesity. Moreover, strategies promoting greater weight loss than achieved with tirzepatide alone may augment the anticancer benefits of tirzepatide.

Obesity, an established risk and progression factor for at least 13 cancer types, is highly prevalent globally, and effective strategies to mitigate the burden of obesity-related cancer are urgently needed. We investigated whether tirzepatide, a widely used incretin-mimetic drug that induces substantial weight loss, offers anticancer benefits. Across 3 tumor models, we demonstrate that chronic tirzepatide treatment reverses diet-induced increases in body weight and fat mass, systemic metabolic perturbations, and tumor growth. We also showed that the anticancer activity of tirzepatide does not involve direct effects on the neoplastic cells used, which lack incretin receptor expression. The anticancer actions of tirzepatide require the reversal of both the metabolic dysregulation and hyporesponsiveness of CD8+ tumor infiltrating lymphocytes evident in obesity. Our findings establish tirzepatide as a promising compound for intercepting obesity-related cancers.