IRF8-driven reprogramming of the immune microenvironment enhances anti-tumor adaptive immunity and reduces immunosuppression in murine glioblastoma.

BACKGROUND: Glioblastoma (GBM) has a highly immunosuppressive tumor immune microenvironment (TIME), largely mediated by myeloid-derived suppressor cells (MDSCs). Here, we utilized a retroviral replicating vector (RRV) to deliver Interferon Regulatory Factor 8 (IRF8), a master regulator of type 1 conventional dendritic cell (cDC1) development, in a syngeneic murine GBM model. We hypothesized that RRV-mediated delivery of IRF8 could "reprogram" intratumoral MDSCs into antigen-presenting cells (APCs) and thereby restore T-cell responses. METHODS: Effects of RRV-IRF8 on survival and tumor growth kinetics were examined in the SB28 murine GBM model. Immunophenotype was analyzed by flow cytometry and gene expression assays. We assayed functional immunosuppression and antigen presentation by ex vivo T-cell-myeloid co-culture. RESULTS: Intratumoral injection of RRV-IRF8 in mice bearing intracerebral SB28 glioma significantly suppressed the tumor growth and prolonged survival. RRV-IRF8 treated tumors exhibited significant enrichment of cDC1s and CD8+ T-cells. Additionally, myeloid cells derived from RRV-IRF8 tumors showed decreased expression of the immunosuppressive markers Arg1 and IDO1 and demonstrated reduced suppression of naïve T-cell proliferation in ex vivo co-culture, compared to controls. Furthermore, DCs from RRV-IRF8 tumors showed increased antigen presentation compared to those from control tumors. In vivo treatment with azidothymidine (AZT), a viral replication inhibitor, showed that IRF8 transduction in both tumor and non-tumor cells is necessary for survival benefit, associated with a reprogrammed, cDC1- and CD8 T-cell-enriched TIME. CONCLUSIONS: Our results indicate that reprogramming of glioma-infiltrating myeloid cells by in vivo expression of IRF8 may reduce immunosuppression and enhance antigen presentation, achieving improved tumor control.

IRF8-driven reprogramming of the immune microenvironment enhances anti-tumor adaptive immunity and reduces immunosuppression in murine glioblastoma.

Background: Glioblastoma (GBM) has a highly immunosuppressive tumor immune microenvironment (TIME), largely mediated by myeloid-derived suppressor cells (MDSCs). Here, we utilized a retroviral replicating vector (RRV) to deliver Interferon Regulatory Factor 8 (IRF8), a master regulator of type 1 conventional dendritic cell (cDC1) development, in a syngeneic murine GBM model. We hypothesized that RRV-mediated delivery of IRF8 could "reprogram" intratumoral MDSCs into antigen-presenting cells (APCs) and thereby restore T-cell responses. Methods: Effects of RRV-IRF8 on survival and tumor growth kinetics were examined in the SB28 murine GBM model. Immunophenotype was analyzed by flow cytometry and gene expression assays. We assayed functional immunosuppression and antigen presentation by ex vivo T-cell-myeloid co-culture. Results: Mice with RRV-IRF8 pre-transduced intracerebral tumors had significantly longer survival and slower tumor growth compared to controls. RRV-IRF8 treated tumors exhibited significant enrichment of cDC1s and CD8+ T-cells. Additionally, myeloid cells derived from RRV-IRF8 tumors showed decreased expression of the immunosuppressive markers Arg1 and IDO1 and demonstrated reduced suppression of naïve T-cell proliferation in ex vivo co-culture, compared to controls. Furthermore, DCs from RRV-IRF8 tumors showed increased antigen presentation compared to those from control tumors. In vivo treatment with azidothymidine (AZT), a viral replication inhibitor, showed that IRF8 transduction in both tumor and non-tumor cells is necessary for survival benefit, associated with a reprogrammed, cDC1- and CD8 T-cell-enriched TIME. Conclusions: Our results indicate that reprogramming of glioma-infiltrating myeloid cells by in vivo expression of IRF8 may reduce immunosuppression and enhance antigen presentation, achieving improved tumor control.

Crop cover and nutrient levels mediate the effects of land management type on aquatic invertebrate richness in prairie potholes.

Aquatic invertebrates provide important ecosystem services, including decomposition and nutrient cycling, and provide nutrition for birds, fish, amphibians, and bats. Thus, the effects of agricultural land management practices on aquatic invertebrates are relevant to farmers, wildlife biologists, and policymakers. Here, we used data on aquatic invertebrates (159 taxa, 73 to species, 75 to genus/family) collected in 40 wetlands in the Canadian prairies to test for direct and indirect relationships among land management types (perennial cover, organic, minimum tillage, conventional), landscape structure (cropland and wetland cover within the surrounding landscape), and water quality (total nutrient levels, turbidity) on species richness of invertebrates using structural equation modelling. Additionally, we assessed variation in community composition within and among wetlands in different land use management types using a direct gradient analysis and variance partitioning. The direct effects of land management type were not supported but we found strong supportive evidence that effects of land management on richness were significantly mediated through cropland cover, nutrient levels, and turbidity. After controlling for these indirect effects, aquatic invertebrate richness decreased along a gradient from the lowest to the highest farming intensity, i.e., richness decreased from perennial cover sites to organic to minimum tillage to conventional sites. Support was also found for negative effects of nutrient levels and turbidity on richness. We did not find significant support for differences in gamma diversity or a simple test (homogeneity of multivariate dispersions) of differences in turnover among land management types; however, land management had a significant effect in distance-based redundancy analysis. Taken together, these results suggest that focusing conservation efforts on reducing cropland erosion and nutrient inputs to wetlands and creating more permanent cover may be effective strategies for conserving richness of aquatic invertebrates in agricultural landscapes in this region.

On the Belatedness of Psychoanalytic Clinical Writing.

The belatedness of analytic writing and its effects on analytic processes are explored through the concepts of nachträglichkeit and thirdness. The temporal gap between being with and writing about functions as a meaningful pause filled with opportunities for investigating unconscious pathways to the analyst's countertransference. The significance of analytic narration in affecting specific psychoanalytic developments is explored. The theoretical framework utilizes the concept of après coup, which brings to light new meanings in an afterwardness of time. Aspects of analytical writing dynamics are discussed as equivalent to those of nachträglichkeit. Analysts also deploy thirdness in constructing presentations of clinical material. This could be an intrapsychic third or an external figure representing an internal introjected third. A clinical vignette demonstrates the enhanced understanding achieved by writing. It specifically assisted in exploring the analyst's enactment relating to change in the setting, the background for which was a move to online analysis. This evoked infantile anxieties and painful confusions about loss. Historically, the patient had to navigate a path through miasmic ambiguities between reality and phantasy, truths and lies. A conclusion is reached, arguing that analytic processes extend beyond the duration of sessions, and that the processes of clinical writing can provide a significant contribution.

Examining the Family-Centeredness of Speech-Language Pathologists Working With Children Who Use Augmentative and Alternative Communication.

PURPOSE: Family-professional partnerships are important for youth learning to use aided augmentative and alternative communication (AAC). This study examined the family-oriented beliefs and practices of speech-language pathologists (SLPs) working with preschool and school-aged children learning to use aided AAC (aged 3-21 years), specifically during the COVID-19 pandemic. METHOD: Participants were 25 SLPs who participated in an individual semistructured interview. Qualitative analysis was used to identify and describe groups of SLPs based on commonalities and differences in their beliefs and practices working with families. The characteristics of SLPs in each group was also explored descriptively (e.g., race/ethnicity, work setting, caseload). RESULTS: SLPs clustered into three groups based on their beliefs and practices: (a) professionally centered, (b) family-allied, and (c) family-focused. SLPs varied across these groups in how they planned services, offered training/coaching, communicated, shared resources, offered emotional support, and adapted to and with different families. CONCLUSIONS: Findings indicate the need to support greater family-centeredness in AAC services by building on the strengths of SLPs in the field. Promoting strong family-professional partnerships could in turn improve outcomes for students who use AAC. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25044125.

Associations between patient-reported functional disability and measures of physical ability in juvenile fibromyalgia.

ABSTRACT: Juvenile fibromyalgia (JFM) is a chronic condition characterized by symptoms of pain and fatigue and is associated with sedentary behavior and functional disability. Adults with fibromyalgia exhibit deficits in physical fitness as evidenced by lower aerobic capacity and physical endurance, but it is unknown whether these impairments are apparent in adolescents with JFM. Furthermore, the extent to which functional disability and pain interference relate to measures of physical fitness has not been investigated in a pediatric pain population. During a baseline assessment for a clinical trial, 321 adolescents with juvenile fibromyalgia (M age = 15.14, 85.2% female) completed measures of pain intensity, fatigue, JFM symptom severity, functional disability, and pain interference. They also completed 2 validated fitness tasks: (1) the Harvard step test, which assesses aerobic fitness, and (2) the 6-minute walk test, a simple submaximal test of endurance. We examined associations among self-report measures and fitness assessments using bivariate correlations. We then employed hierarchical regression analyses to determine the unique contributions of physical fitness assessments to self-reported functional disability and pain interference. Results indicated that youth with JFM exhibited deficits in aerobic capacity and physical endurance. However, physical fitness explained negligible variance in functional disability and pain interference beyond that accounted for by pain, fatigue, and JFM symptom severity. Scores on available functional disability measures may reflect perceived difficulties in coping with symptoms during physical tasks rather than actual physical capability. Rigorous and sensitive assessments of physical fitness and endurance are needed to determine whether rehabilitation interventions for pediatric pain improve physical functioning.

Augmentative and Alternative Communication Services During the COVID-19 Pandemic: Contextual Determinants of the Parent-Speech-Language Pathologist Partnership.

PURPOSE: The COVID-19 pandemic caused significant changes for family-professional interactions. Many services shifted to telepractice, with new opportunities for parents and speech-language pathologists (SLPs) to partner for service delivery. Parent-coached models of augmentative and alternative communication (AAC) intervention provide positive outcomes for children; however, SLPs have reported difficulty building strong partnerships with families. The shift to telepractice during the COVID-19 pandemic provided a unique context to examine factors influencing parent-SLP partnerships, particularly for parents with children who use aided AAC. METHOD: Twenty-five parents and 25 SLPs who engaged in services with children and youth from 3 to 21 years of age who used aided AAC during the initial stages of the COVID-19 pandemic in June 2020 participated. Semistructured interviews were conducted individually with parents and SLPs to understand perspectives on whether the change in service delivery facilitated or hindered family-oriented practice. Inductive qualitative analysis was used to analyze information about the factors impacting parent-SLP partnerships. RESULTS: The parent-SLP partnership was influenced by setting and systemic determinants, and intrinsic determinants to the parent and the SLP that included their history and rapport, beliefs about partnering, and knowledge and skills. These determinants served as barriers or facilitators to their partnership. CONCLUSIONS: It is essential to consider the relationship, expectations, and knowledge and skills that SLPs and parents bring to the partnership, along with extrinsic structural factors that can impact this partnership. Positive rapport, valued partnership, and an openness to sharing knowledge through teaming and collaboration provided for positive parent-SLP partnerships.

Direct and indirect effects of agricultural land cover on avian biodiversity in eastern Canada.

Agriculture is one of the largest threats to global biodiversity. However, most studies have focused only on the direct effects of agriculture on biodiversity, and few have addressed the indirect effects, potentially over or under-estimating the overall impacts of agriculture on biodiversity. The indirect effect is the response not to the agricultural cover types or operations per se, but instead, to the way that agriculture influences the extent and configuration of different types of natural land cover in the landscape. We used structural equation modelling (SEM) to evaluate the direct, indirect, and total effects of agriculture on species richness of three bird guilds: forest birds, shrub-edge birds, and open country birds. We found that forest bird richness was driven by the negative indirect effect of cropland via forest loss. Shrub-edge and open country bird richness increased with the amount of agriculture land covers; however, importantly, we found negative indirect effects of agriculture on both guilds via a reduction in more natural land covers. This latter result highlights how we would have over-estimated the positive effects of agriculture on shrub-edge and open country bird richness had we not measured both direct and indirect effects (i.e., the total effect size is less than the direct effect size). Overall, our results suggest that a bird-friendly agricultural landscape in our region would have forest that is configured to maximize forest edge, and a high proportion of perennial forage within the agricultural portion of the landscape. Supplementary Information: The online version contains supplementary material available at 10.1007/s10531-023-02559-1.

Field Resistance to Rose Rosette Disease as Determined by Multi-Year Evaluations in Tennessee and Delaware.

Rose rosette disease (RRD) caused by the rose rosette emaravirus (RRV) and transmitted by the eriophyid mite Phyllocoptes fructiphilus (Pf), both native to North America, has caused significant damage to roses over the last several decades. As cultural and chemical control of this disease is difficult and expensive, a field trial was established to systematically screen rose germplasm for potential sources of resistance. One hundred and eight rose accessions representing the diversity of rose germplasm were planted in Tennessee and Delaware, managed to encourage disease development, and evaluated for symptom development and viral presence for three years. All major commercial rose cultivars were susceptible to this viral disease to varying levels. The rose accessions with no or few symptoms were species accessions from the sections Cinnamomeae, Carolinae, Bracteatae, and Systylae or hybrids with these. Among these, some were asymptomatic; they displayed no symptoms but were infected by the virus. Their potential depends on their ability to serve as a source of viruses. The next step is to understand the mechanism of resistance and genetic control of the various sources of resistance identified.