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Background & aimsThere are limited data regarding fibrosis progression in biopsy-proven nonalcoholic fatty liver disease (NAFLD) in people with type 2 diabetes mellitus (T2DM) compared with people without T2DM. We assessed the time to fibrosis progression in people with T2DM compared with people without T2DM in a large, multicenter, study of people with NAFLD who had paired liver biopsies.MethodsThis study included 447 adult participants (64% were female) with NAFLD who had paired liver biopsies more than 1 year apart. Liver histology was systematically assessed by a central pathology committee blinded to clinical data. The primary outcome was the cumulative incidence of a ≥1-stage increase in fibrosis in participants with T2DM compared with participants without T2DM.ResultsThe mean (SD) age and body mass index (calculated as weight in kilograms divided by the square of the height in meters) were 50.9 (11.5) years and 34.7 (6.3), respectively. The median time between biopsies was 3.3 years (interquartile range, 1.8-6.1 years). Participants with T2DM had a significantly higher cumulative incidence of fibrosis progression at 4 years (24% vs 20%), 8 years (60% vs 50%), and 12 years (93% vs 76%) (P = .005). Using a multivariable Cox proportional hazards model adjusted for multiple confounders, T2DM remained an independent predictor of fibrosis progression (adjusted hazard ratio, 1.69; 95% CI, 1.17-2.43; P = .005). The cumulative incidence of fibrosis regression by ≥1 stage was similar in participants with T2DM compared with participants without T2DM (P = .24).ConclusionsIn this large, multicenter cohort study of well-characterized participants with NAFLD and paired liver biopsies, we found that fibrosis progressed faster in participants with T2DM compared with participants without T2DM. These data have important implications for clinical practice and trial design.

Maintaining adolescents' engagement with STEM (science, technology, engineering, and math) in and out of school may help ensure that adolescents are prepared to enter the STEM workforce. This study aims to extend prior work by documenting internal and external factors that matter for both STEM class engagement as well as engagement with STEM outside of school through STEM activism. Participants included ninth and tenth grade students (N = 852) from ethnically diverse public schools in the Southeastern United States, approximately evenly divided by gender. Findings from regression analyses revealed that girls and participants who perceive educational barriers to STEM were less engaged in STEM classes, whereas those who reported learning about more male scientists in class, and those who reported higher levels of belonging, STEM growth mindset, and STEM motivation were more engaged in STEM classes. Those who reported higher critical motivation, critical action, belonging, and STEM motivation were more engaged in STEM activism outside of school. Findings suggest that STEM teachers and out-of-school program developers may learn new ways to engage students from each other. Further, findings highlight some factors that may promote engagement in STEM both in and out of schools such as belonging and STEM motivation.

Background & aimsType 2 diabetes (T2D) is a growing problem in children. Children with NAFLD are at potentially high risk for developing T2D; however, the incidence of T2D in this population is unknown. This study aimed to determine the incidence of T2D in children with NAFLD and identify associated risk factors.MethodsChildren with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network were followed longitudinally. Incidence of T2D was determined by using clinical history and fasting laboratory values. Cumulative incidence curves were developed for time to T2D. A Cox regression multivariable model was constructed using best subsets Akaike's Information Criteria selection.ResultsThis study included 892 children with NAFLD and with a mean age of 12.8 years (2.7) followed for 3.8 years (2.3) with a total 3234 person-years at risk. The incidence rate of T2D was 3000 new cases per 100,000 person-years at risk. At baseline, 63 children had T2D, and during follow-up, an additional 97 children developed incident T2D, resulting in a period prevalence of 16.8%. Incident T2D was significantly higher in females versus males (hazard ratio [HR], 1.8 [1.0-2.8]), associated with BMI z-score (HR, 1.8 [1.0-3.0]), and more severe liver histology including steatosis grade (HR, 1.3 [1.0-1.7]), and fibrosis stage (HR, 1.3 [1.0-1.5]).ConclusionsChildren with NAFLD are at high risk for existing and incident T2D. In addition to known risk factors for T2D (female and BMI z-score), severity of liver histology at the time of NAFLD diagnosis was independently associated with T2D development. Targeted strategies to prevent T2D in children with NAFLD are needed.

Racially minoritized groups are underrepresented in science, technology, engineering, and math (STEM) degree programs and careers, warranting the need to examine students' racialized experiences in K-12 settings that may influence their STEM persistence. In particular, the current study explored adolescent perceptions of school racial climate (SRC) as a potential contributor to pre-college racial disparities in STEM. We used latent class analysis to group adolescents based on their SRC perceptions and explored group differences in their interest in a STEM career and their belonging, psychological needs satisfaction, and engagement in STEM courses. Adolescent participants (N = 412, 50.2% female, 36.9% male, 12.9% other/not reported, M[subscript] age = 15.72 years, standard deviation = 1.24) attending five high schools in the Southeastern United States, were grouped into five classes based on their perceptions of SRC: Critical SRC (CritSRC), Average SRC, Average with Stereotyping, Positive SRC (PosSRC), and Positive with Stereotyping. Latent class membership differed by race, age, and learning environment. Results revealed that students with more positive perceptions of SRC reported greater belonging, engagement, and needs satisfaction in their STEM courses and more interest in a STEM career compared to students with CritSRC perceptions. Findings also indicated that White students were more likely than Black students to perceive a PosSRC. Recommendations for areas of future research and policy implications are discussed.

Women and ethnic minoritized individuals are underrepresented in science, technology, engineering, and mathematics (STEM) domains in postsecondary education and in the workforce. The aim of the current study was to examine whether adolescents' perceptions of inclusivity, belonging, and discrimination in high school STEM classes are related to their STEM class engagement in and outside of school. In this study, ethnically diverse 9th-12th grade high school students from low-income public schools in the United States (N = 523, M[subscript age] = 15.72, SD = 1.24, 49.4% female) completed measures of classroom inclusivity, perceived teacher discrimination, belonging, STEM classroom engagement, and STEM activism orientation. Path analyses revealed direct effects of inclusion and perceived discrimination on STEM activism orientation. Further, findings demonstrated direct effects of inclusion on belonging and on belonging and both STEM classroom engagement and STEM activism orientation. Finally, findings revealed a significant indirect effect of inclusion on STEM classroom engagement through belonging.

The Mississippi IDeA Networks of Biomedical Research Excellence (INBRE) supported by the National Institute of General Medical Sciences (Grant P20GM103476) launched the new Mississippi INBRE Outreach Scholars (MIOS) summer research program in 2019. The program was designed to offer students community outreach and research experiences related to the study of behavioral and health disparities life sciences. The program was adapted in early 2020 to offer the program in a fully online format in the summer of 2020. This article details the program adaptations and discusses program evaluation data related to scholars' perceptions of program benefits and expectations and their confidence in research-related skills. The program evaluation was a mixed-method approach that included a qualitative postprogram survey and a pre-post quantitative survey. Scholars identified technical and communication skill building and resilience as areas of personal growth. Overall, the program met scholars' expectations for the program and significantly improved their confidence on 8 of the 19 (with confidence interval estimated differences from 0.3 to 2.56, where a difference of 1 is an improvement across 1 anchor on a Likert-type scale) various research-related tasks/skills after completion of the program. The analyses presented demonstrated that a combined qualitative and quantitative analysis approach is useful for examining the extent to which programs such as Mississippi INBRE are meeting goals of providing a rich research experience in health disparities for a diverse student body. Future longitudinal data may be examined to explore the long-term impact of MIOS on career preparation and choices and graduate education.

The mechanistic target of rapamycin (mTOR) is a kinase whose activity is elevated in hematological malignancies. mTOR-complex-1 (mTORC1) phosphorylates numerous substrates to promote cell proliferation and survival. Eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) are mTORC1 substrates with an integral role in oncogenic protein translation. Current pharmacological approaches to inhibit mTORC1 activity and 4E-BP phosphorylation have drawbacks. Recently we described a series of bi-steric compounds that are potent and selective inhibitors of mTORC1, inhibiting 4E-BP phosphorylation at lower concentrations than mTOR kinase inhibitors (TOR-KIs). Here we report the activity of the mTORC1-selective bi-steric inhibitor, RMC-4627, in BCR-ABL-driven models of B-cell acute lymphoblastic leukemia (B-ALL). RMC-4627 exhibited potent and selective inhibition of 4E-BP1 phosphorylation in B-ALL cell lines without inhibiting mTOR-complex-2 (mTORC2) activity. RMC-4627 suppressed cell cycle progression, reduced survival, and enhanced dasatinib cytotoxicity. Compared to a TOR-KI compound, RMC-4627 was more potent, and its effects on cell viability were sustained after washout in vitro. Notably, a once-weekly, well tolerated dose reduced leukemic burden in a B-ALL xenograft model and enhanced the activity of dasatinib. These preclinical studies suggest that intermittent dosing of a bi-steric mTORC1-selective inhibitor has therapeutic potential as a component of leukemia regimens, and further study is warranted.

Shp1, encoded by the gene Ptpn6, is a protein tyrosine phosphatase that transduces inhibitory signals downstream of immunoreceptors in many immune cell types. Blocking Shp1 activity represents an exciting potential immunotherapeutic strategy for the treatment of cancer, as Shp1 inhibition would be predicted to unleash both innate and adaptive immunity against tumor cells. Antibodies blocking the interaction between CD47 on tumor cells and SIRPα on macrophages enhance macrophage phagocytosis, show efficacy in preclinical tumor models, and are being evaluated in the clinic. Here we found that Shp1 bound to phosphorylated peptide sequences derived from SIRPα and transduced the anti-phagocytic signal, as Shp1 loss in mouse bone marrow-derived macrophages increased phagocytosis of tumor cells in vitro. We also generated a novel mouse model to evaluate the impact of global, inducible Ptpn6 deletion on anti-tumor immunity. We found that inducible Shp1 loss drove an inflammatory disease in mice that was phenotypically similar to that seen when Ptpn6 is knocked out from birth. This indicates that acute perturbation of Shp1 in vivo could drive hyperactivation of immune cells, which could be therapeutically beneficial, though at the risk of potential toxicity. In this model, we found that Shp1 loss led to robust anti-tumor immunity against two immune-rich syngeneic tumor models that are moderately inflamed though not responsive to checkpoint inhibitors, MC38 and E0771. Shp1 loss did not promote anti-tumor activity in the non-inflamed B16F10 model. The observed activity in MC38 and E0771 tumors was likely due to effects of both innate and adaptive immune cells. Following Shp1 deletion, we observed increases in intratumoral myeloid cells in both models, which was more striking in E0771 tumors. E0771 tumors also contained an increased ratio of effector to regulatory T cells following Shp1 loss. This was not observed for MC38 tumors, though we did find increased levels of IFNγ, a cytokine produced by effector T cells, in these tumors. Overall, our preclinical data suggested that targeting Shp1 may be an attractive therapeutic strategy for boosting the immune response to cancer via a mechanism involving both innate and adaptive leukocytes.

A significantly higher proportion of patients with nonalcoholic steatohepatitis (NASH) who received obeticholic acid (OCA) had histological improvement relative to placebo in the FLINT (farnesoid X nuclear receptor ligand obeticholic acid for noncirrhotic, NASH treatment) trial. However, genetic predictors of response to OCA are unknown. We conducted a genome-wide association study (GWAS) in FLINT participants to identify variants associated with NASH resolution and fibrosis improvement. Genotyping was performed using the Omni2.5 content GWAS chip. To avoid false positives introduced by population stratification, we focused our GWAS on white participants. Six regions on chromosomes 1, 4, 6, 7, 15, and 17 had multiple single nucleotide polymorphisms (SNPs) with suggestive association (P

Background & aimsNoninvasive methods are needed to determine disease stage in patients with nonalcoholic fatty liver disease (NAFLD). We evaluated the diagnostic performance of several widely available fibrosis models for the assessment of hepatic fibrosis in patients with NAFLD.MethodsWe performed a retrospective analysis of data from individuals enrolled in the NIDDK NASH Clinical Research Network, from 2004 through 2018. Using biopsy as the reference standard, we determined the diagnostic performance of the aspartate aminotransferase (AST):platelet ratio (APRI), FIB-4, ratio of AST:alanine aminotransferase (ALT) and the NAFLD fibrosis score (NFS) in a cross-sectional study of 1904 subjects. The ability of these models to detect changes in fibrosis stage was assessed in a longitudinal data set of 292 subjects with 2 biopsies and accompanying laboratory data. Outcomes were detection of fibrosis of any stage (stages 0-4), detection of moderate fibrosis (stages 0-1 vs 2-4), and detection of advanced fibrosis (stages 0-2 vs 3-4). Diagnostic performance was evaluated using the C-statistic, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) analyses.ResultsIn the cross-sectional study, FIB-4 and NFS outperformed other non-invasive models for detecting advanced fibrosis; the C-statistics were 0.80 for FIB-4 and 0.78 for NFS. In the longitudinal study, 216 patients had non-advanced fibrosis at baseline and 35 patients progressed to advanced fibrosis after median follow up of 2.6 years. After we adjusted for fibrosis stage and model score at initial biopsy, change in APRI, FIB-4, and NFS were significantly associated with change in fibrosis. A unit change in APRI, FIB-4, or NFS was associated with changes in fibrosis stage of 0.33 (95% CI, 0.20-0.45; P < .001), 0.26 (95% CI, 0.15-0.37; P < .001), and 0.19 (95% CI, 0.07-0.31; P = .002), respectively. The cross-validated C-statistic for detecting progression to advanced fibrosis for APRI was 0.82 (95% CI, 0.74-0.89), for FIB-4 was 0.81 (95% CI, 0.73-0.81), and for NFS was 0.80 (95% CI, 0.71-0.88).ConclusionsIn a combined analysis of data from 2 large studies, we found that FIB-4, APRI, and NFS can detect advanced fibrosis and fibrosis progression in patients with NAFLD.

Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.

The purpose of this article is to make policy recommendations based on the authors' experiences with, and research about, reflective, differentiated, and teacher-generated music teacher professional development (PD). By doing so, we argue for a bottom-up process that capitalizes on our music teacher and music teacher educator expertise along with the research literature in music teacher PD. We explore music teachers' PD needs considering four career stages to explain how knowledge generated at each level informs our understanding of differentiated PD. From preservice music teachers and music teacher candidates, to in-service and veteran teachers, our discussion explores meaningful and effective ways to engage in deep, reflective thinking about the music teaching and learning process. Accordingly, we provide specific policy recommendations for music teachers at each career stage so that they might take greater ownership of their own learning, growth, and development through local, reflective, self-initiated, and differentiated PD opportunities.

The purpose of this intrinsic case study was to clarify the roles of a music educator and music therapist in a North American public school district. This case was unique because some of the students with special needs received both music instruction and music therapy services, yet there was little collaboration between the two disciplines. In an effort to learn more about each music discipline and to add to the knowledge base of the connections between music education and music therapy I posed four research questions: (1) What were the goals of the music teacher and music therapist for the students in their classrooms? (2) What were the perceptions of the music teacher regarding music therapy services in an educational setting? (3) What were the perceptions of the music therapist regarding student experiences in the music classroom? (4) In what ways did the music therapist and music educator collaborate, or not, to improve outcomes for students with special needs? I found the goals of the educator and therapist in music were unique yet complementary, and clarification of these goals is needed to assist educators who work with students with special needs.

Abstract Background Malaria is a leading global cause of preventable morbidity and mortality, especially in sub-Saharan Africa, despite recent advances in treatment and prevention technologies. Scale-up and wide distribution of long-lasting insecticide-treated nets (LLINs) could rapidly decrease malarial disease in endemic areas, if used properly and continuously. Studies have shown that effective use of LLINs depends, in part, upon understanding causal factors associated with malaria. This study examined malaria beliefs, attitudes, and practices toward LLINs assessed during a large-scale integrated prevention campaign (IPC) in rural Kenya. Methods Qualitative interviews were conducted with 34 IPC participants who received LLINs as part of a comprehensive prevention package of goods and services. One month after distribution, interviewers asked these individuals about their attitudes and beliefs regarding malaria, and about their use of LLINs. Results Virtually all participants noted that mosquitoes were involved in causing malaria, though a substantial proportion of participants (47 percent) also mentioned an incorrect cause in addition to mosquitoes. For example, participants commonly noted that the weather (rain, cold) or consumption of bad food and water caused malaria. Regardless, most participants used the LLINs they were given and most mentioned positive benefits from their use, namely reductions in malarial illness and in the costs associated with its diagnosis and treatment. Conclusions Attitudes toward LLINs were positive in this rural community in Western Kenya, and respondents noted benefits with LLIN use. With improved understanding and clarification of the direct (mosquitoes) and indirect (e.g., standing water) causes of malaria, it is likely that LLIN use can be sustained, offering effective household-level protection against malaria.