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Autistic children often require support in various competencies during early childhood. Parents and practitioners must collaborate for optimal child outcomes. Previous research indicates that parent-mediated learning supports children's social communication, encourages parent-practitioner collaboration, and fosters parental feelings of support. However, there are limited studies on parent experiences with this intervention approach. The present study explored parent experiences with a new telehealth parent-mediated learning intervention designed to support children's turn taking. Thematic analysis of 10 transcribed intervention sessions revealed the benefits of a mutual parent-practitioner relationship, parental feelings of support, and parent intervention acceptability. These findings are consistent with other studies on the parent-mediated learning approach and have implications for future practices in early intervention. Further research with multiple parents may provide additional insight into this intervention model's acceptability and supportive nature.

Abstract Production of cultivated meat requires defined medium formulations for the robust differentiation of myogenic cells into mature skeletal muscle fibres in vitro. Although these formulations can drive myogenic differentiation levels comparable to serum-starvation-based protocols, the resulting cultures are often heterogeneous, with a significant proportion of cells not participating in myofusion, limiting maturation of the muscle. To address this problem, we employed RNA sequencing to analyse heterogeneity in differentiating bovine satellite cells at single-nucleus resolution, identifying distinct cellular subpopulations including proliferative cells that fail to exit the cell cycle and quiescent ‘reserve cells’ that do not commit to myogenic differentiation. Our findings indicate that the MEK/ERK, NOTCH, and RXR pathways are active during the initial stages of myogenic cell fate determination, and by targeting these pathways, we can promote cell cycle exit while reducing reserve cell formation. This optimised medium formulation consistently yields fusion indices close to 100% in 2D culture. Furthermore, we demonstrate that these conditions enhance myotube formation and actomyosin accumulation in 3D bovine skeletal muscle constructs, providing proof of principle for the generation of highly differentiated cultivated muscle with excellent mimicry to traditional muscle.

Abstract Grassland landscapes are important ecosystems in East Africa, providing habitat and grazing grounds for wildlife and livestock and supporting pastoralism, an essential part of the agricultural sector. Since future grassland availability directly affects the future mobility needs of pastoralists and wildlife, we aim to model changes in the distribution of key grassland species under climate change. Here we combine a global and regional climate model with a machine learning-based species distribution model to understand the impact of regional climate change on different key grass species. The application of a dynamical downscaling step allows us to capture the fine-scale effects of the region’s complex climate, its variability and future changes. We show that the co-occurrence of the analysed grass species is reduced in large parts of eastern Africa, and particularly in the Turkana region, under the high-emission RCP8.5 scenario for the last 30 years of the 21st century. Our results suggest that future climate change will alter the natural resource base, with potentially negative impacts on pastoralism and wildlife in East Africa.

Abstract Postoperative fluid overload (FO) after cardiac surgery is common and affects recovery. Predicting FO could help optimize fluid management. This post-hoc analysis of the HERACLES randomized controlled trial evaluated the predictive value of MR-proADM for FO post-cardiac surgery. MR-proADM levels were measured at four different timepoints in 33 patients undergoing elective cardiac surgery. Patients were divided into FO (> 5% weight gain) and no-FO at ICU discharge. The primary outcome was the predictive power of MR-proADM at ICU admission for FO at discharge. Secondary outcomes included the predictive value of MR-proADM for FO on day 6 post-surgery and changes over time. The association between MR-proADM and FO at ICU discharge or day 6 post-surgery was not significant (crude odds ratio (cOR): 4.3 (95% CI 0.5–40.9, p = 0.201) and cOR 1.1 (95% CI 0.04–28.3, p = 0.954)). MR-proADM levels over time did not differ significantly between patients with and without FO at ICU discharge (p = 0.803). MR-proADM at ICU admission was not associated with fluid overload at ICU discharge in patients undergoing elective cardiac surgery. MR-proADM levels over time were not significantly different between groups, although elevated levels were observed in patients with FO.

Brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is increasingly used for frontline treatment of stage III/IV classical Hodgkin lymphoma (cHL). Peripheral neuropathy (PN) was the most common and treatment-limiting side effect seen in clinical trials but has not been studied in a nontrial setting, in which clinicians may have different strategies for managing it. We conducted a multisite retrospective study to characterize PN in patients who received BV + AVD for newly diagnosed cHL. One hundred fifty-three patients from 10 US institutions were eligible. Thirty-four patients (22%) had at least 1 ineligibility criteria for ECHELON-1, including stage, performance status, and comorbidities. PN was reported by 80% of patients during treatment; 39% experienced grade (G) 1, 31% G2, and 10% G3. In total, BV was modified in 44% of patients because of PN leading to BV discontinuation in 23%, dose reduction in 17%, and temporary hold in 4%. With a median follow-up of 24 months, PN resolution was documented in 36% and improvement in 33% at the last follow-up. Two-year progression-free survival (PFS) for the advanced-stage patients was 82.7% (95% confidence interval [CI], 0.76-0.90) and overall survival was 97.4% (95% CI, 0.94-1.00). Patients who discontinued BV because of PN did not have inferior PFS. In the nontrial setting, BV + AVD was associated with a high incidence of PN. In our cohort, which includes patients who would not have been eligible for the pivotal ECHELON-1 trial, BV discontinuation rates were higher than previously reported, but 2-year outcomes remain comparable.

Abstract Background Grapevine Pinot gris virus (GPGV) infects grapevines worldwide and causes symptoms such as chlorotic mottling and deformations on leaves, stunted shoots and short panicles, or none of these symptoms if it appears as latent infection. So far, the consequences of GPGV infections for winegrowers are difficult to assess since important information such as plant performance at different GPGV infection levels and symptom expression are not fully clarified. Methods In order to investigate the course of GPGV spread, annual visual evaluations and ELISA tests were conducted over 3–4 consecutive years in four GPGV-infected vineyards in southern Germany: GEM, HEC, NIM, and REI. The program PATCHY was used to analyze spatial disease patterns. Sanger sequencing was used to determine virus isolates in vines at different GPGV infection levels, to test their respective influence on symptom expression. Yield and GrapeScan (FTIR) analyses were conducted to test the impact of different GPGV infection levels and isolates on fruit quantity and quality. Results GPGV infections significantly increased in all four vineyards (GEM 22–32%, HEC 50–99%, NIM 83–90%, REI 56–76%) with significant spreading patterns across and along rows. Specific symptom progression patterns were not observed. According to our results, the virus isolate has an influence on whether symptoms develop during a GPGV infection. While yield analyses revealed that yield losses only occur in symptomatic vines and range from 13 to 96% depending on the severity of symptoms, latent infections have no impact on grape production. No relevant effects of GPGV infections on must quality were observed. Conclusions Secondary spread of GPGV was observed in all vineyards monitored, indicating vector-borne transmission that is likely to be accelerated by human viticultural management. GPGV should be further monitored to prevent the accumulation of detrimental symptomatic isolates. The results of this study can be used to assess the risk of GPGV to viticulture and should be considered when developing management strategies against the virus.

Abstract Background Overdose deaths continue to rise within the United States, despite effective treatments such as buprenorphine and methadone for opioid use disorder (OUD). Mobile medical units with the ability to dispense buprenorphine have been developed to engage patients and eliminate barriers to accessing OUD treatment. This study reports survey responses of patients of a mobile medical unit dispensing buprenorphine in areas of Chicago, IL with high overdose rates. Methods All patients who were dispensed buprenorphine via the mobile medical unit were invited to participate in a 7-item anonymous survey between May 24, 2023, and August 25, 2023. The survey included 5-point satisfaction scale, multiple-choice, and open-ended questions. Outcomes included satisfaction with buprenorphine dispensing from the mobile medical unit, satisfaction with filling buprenorphine at a pharmacy in the past, barriers experienced at pharmacies when filling buprenorphine, and whether the client would have started treatment that day if the mobile medical unit had not been present. Satisfaction scale and multiple-choice question responses were assessed using descriptive statistics. Wilcoxon signed-rank test was used to compare median satisfaction levels between receiving buprenorphine from the mobile medical unit versus filling a buprenorphine prescription at a community pharmacy. Open-ended questions were analyzed qualitatively using inductive thematic analysis. Results 106 unique patients were dispensed buprenorphine from the mobile unit during the study period. Of these patients, 54 (51%) completed the survey. Respondents reported high satisfaction with the buprenorphine dispensing process as a part of a mobile medical unit. Of those who had previously filled buprenorphine at a pharmacy, 83% reported at least one barrier, with delays in prescription dispensing from a community pharmacy, lack of transportation to/from the pharmacy, and opioid withdrawal symptoms being the most common barriers. 87% reported they would not have started buprenorphine that same day if the mobile medical unit had not been present. Nearly half of survey participants reported having taken buprenorphine that was not prescribed to them. Qualitative analysis of open-ended survey responses noted the importance of convenient accessibility, comprehensive care, and a non-judgmental environment. Conclusions Mobile medical units that dispense buprenorphine are an innovative model to reach patients with OUD who have significant treatment access barriers. This study found that patients who experienced barriers to accessing buprenorphine from a pharmacy were highly satisfied with the mobile medical unit’s buprenorphine dispensing process. Programs seeking to develop mobile buprenorphine dispensing programs should consider patient priorities of accessibility, comprehensive care, and welcoming, non-judgmental environments.

Abstract The human methyltransferase and transcriptional coactivator MLL4 and its paralog MLL3 are frequently mutated in cancer. MLL4 and MLL3 monomethylate histone H3K4 and contain a set of uncharacterized PHD fingers. Here, we report a novel function of the PHD2 and PHD3 (PHD2/3) fingers of MLL4 and MLL3 that bind to ASXL2, a component of the Polycomb repressive H2AK119 deubiquitinase (PR-DUB) complex. The structure of MLL4 PHD2/3 in complex with the MLL-binding helix (MBH) of ASXL2 and mutational analyses reveal the molecular mechanism which is conserved in homologous ASXL1 and ASXL3. The native interaction of the Trithorax MLL3/4 complexes with the PR-DUB complex in vivo depends solely on MBH of ASXL1/2, coupling the two histone modifying activities. ChIP-seq analysis in embryonic stem cells demonstrates that MBH of ASXL1/2 is required for the deubiquitinase BAP1 recruitment to MLL4-bound active enhancers. Our findings suggest an ASXL1/2-dependent functional link between the MLL3/4 and PR-DUB complexes.

This phenomenological study explored the perceptions of support first-generation women students enrolled in college have. Eleven first-generation women students who were enrolled in undergraduate and graduate programs across the United States completed one-on-one interviews. The participants explained the support they felt from family, friends, and members of their institutions, as well as areas where further support could be given. Key themes emerged, such as the role of mentorship, the need for financial assistance, the role of family, the roles of intersectional factors such as race and motherhood, and the offering of support during a crisis, particularly the COVID-19 pandemic.

ABSTRACT Understanding the distribution and habitat use of endangered species is essential for conservation efforts. Environmental DNA (eDNA) analysis has become a more common approach to defining species habitat occupancy through identification of residual DNA in water samples and has potential to detect populations that are in low abundance or use habitats over a large geographical range. Here, we optimized an eDNA protocol to detect the presence of the endangered white sturgeon (Acipenser transmontanus). We implemented lab‐based experiments to understand the sensitivity and persistence of white sturgeon eDNA and then applied these methods to habitats with known white sturgeon abundances categorized as high, low, or not present. Using quantitative PCR (qPCR) and a modified StrAci1N‐flap primer set, white sturgeon eDNA was detected in water collected from tanks holding white sturgeon down to a dilution of 10,000× (estimated eDNA concentration of 0.00035 μg/L—0.00176 μg/L). Following the removal of white sturgeon from the tanks, the eDNA signal decreased with time but could be detected for up to 7 days. In the field, all sites with high abundances of white sturgeon returned positive eDNA detections. We did not detect white sturgeon eDNA at sites with low abundance or in areas where they were not expected to be present. Results from this work further advance our interpretation of eDNA from wild populations and provide a noninvasive method to advance recovery efforts by identifying species presence in areas of suspected use or to guide additional inventory efforts.

The monoclonal antibody rituximab improves clinical outcome in the treatment of CD20-positive lymphomatous neoplasms, and it is an established drug for treatment of these cancers. Successful mRNA COVID-19 (SARS-CoV-2) vaccination is extremely important for lymphoma patients because they tend to be elderly with comorbidities which leaves them at increased risk of poor outcomes once infected by Coronavirus. Anti-CD20 therapies such as rituximab, deplete B-cell populations and can affect vaccine efficacy. Therefore, a knowledge of the effect of COVID-19 vaccination in this group is critical. We followed a cohort of 28 patients with CD20-positive lymphomatous malignancies treated with rituximab that started prior to their course of COVID-19 vaccination, including boosters. We assayed for vaccine “take” in the humoral (IgG and IgA) and cellular compartment. Here, we show that short-term and long-term development of IgG and IgA antibodies directed toward COVID-19 spike protein are reduced in these patients compared to healthy controls. Conversely, the robustness and breath of underlying T-cell response is equal to healthy controls. This response is not limited to specific parts of the spike protein but spans the spike region, including response to the conserved Receptor Binding Domain (RBD). Our data informs on rational vaccine design and bodes well for future vaccination strategies that require strong induction of T-cell responses in these patients.

To manage Earth in the Anthropocene, new tools, new institutions, and new forms of international cooperation will be required. Earth Virtualization Engines is proposed as an international federation of centers of excellence to empower all people to respond to the immense and urgent challenges posed by climate change.

Abstract Background Fluid accumulation (FA) is known to be associated with acute kidney injury (AKI) during intensive care unit (ICU) stay but data on mid-term renal outcome is scarce. The aim of this study was to investigate the association between FA at ICU day 3 and major adverse kidney events in the first 30 days after ICU admission (MAKE30). Methods Retrospective, single-center cohort study including adult ICU patients with sufficient data to compute FA and MAKE30. We defined FA as a positive cumulative fluid balance greater than 5% of bodyweight. The association between FA and MAKE30, including its sub-components, as well as the serum creatinine trajectories during ICU stay were examined. In addition, we performed a sensitivity analysis for the stage of AKI and the presence of chronic kidney disease (CKD). Results Out of 13,326 included patients, 1,100 (8.3%) met the FA definition. FA at ICU day 3 was significantly associated with MAKE30 (adjusted odds ratio [aOR] 1.96; 95% confidence interval [CI] 1.67–2.30; p

Abstract Background RNA helicases are emerging as key factors regulating host-virus interactions. The DEAD-box ATP-dependent RNA helicase DDX5, which plays an important role in many aspects of cellular RNA biology, was also found to either promote or inhibit viral replication upon infection with several RNA viruses. Here, our aim is to examine the impact of DDX5 on Sindbis virus (SINV) infection. Methods We analysed the interaction between DDX5 and the viral RNA using imaging and RNA-immunoprecipitation approaches. The interactome of DDX5 in mock- and SINV-infected cells was determined by mass spectrometry. We validated the interaction between DDX17 and the viral capsid by co- immunoprecipitation in the presence or absence of an RNase treatment. We determined the subcellular localization of DDX5, its cofactor DDX17 and the viral capsid protein by co-immunofluorescence. Finally, we investigated the impact of DDX5 depletion and overexpression on SINV infection at the viral protein, RNA and infectious particle accumulation level. The contribution of DDX17 was also tested by knockdown experiments. Results In this study we demonstrate that DDX5 interacts with the SINV RNA during infection. Furthermore, the proteomic analysis of the DDX5 interactome in mock and SINV-infected HCT116 cells identified new cellular and viral partners and confirmed the interaction between DDX5 and DDX17. Both DDX5 and DDX17 re-localize from the nucleus to the cytoplasm upon SINV infection and interact with the viral capsid protein. We also show that DDX5 depletion negatively impacts the viral replication cycle, while its overexpression has a pro-viral effect. Finally, we observed that DDX17 depletion reduces SINV infection, an effect which is even more pronounced in a DDX5-depleted background, suggesting a synergistic pro-viral effect of the DDX5 and DDX17 proteins on SINV. Conclusions These results not only shed light on DDX5 as a novel and important host factor to the SINV life cycle, but also expand our understanding of the roles played by DDX5 and DDX17 as regulators of viral infections.

Intercropping of legume and cereal crop species shows potential to reduce root disease pressures by changing root-associated microbiomes and improving nitrogen (N) use via soil N-dependent fixation of atmospheric N2 by symbiotic rhizobia. A two-year field study was conducted to evaluate the effect of pea–barley association on crop performance and on the root fungal community. Five pea cultivars (Alvesta, Karpate, Mytic, Respect, and Vitra) were grown either in pure stands or mixed with one variety of barley (Atrika). We measured crop grain yield and root rot incidence and analyzed root fungal communities. In mixed stands, total grain yield was more stable compared with that in each pure stand, but pea root disease incidence was higher except for cultivars Vitra and Karpate. The effect of cropping system on fungal alpha diversity depended on the cultivar, with Vitra showing higher Shannon diversity and Alvesta showing lower richness in mixed compared with pure stands. All four operational taxonomic units (OTUs) belonging to the Didymellaceae family were positively associated with pea root rot, and another disease-associated OTU in pea, Neoascochyta exitialis, was found to be also part of the barley core microbiome. Eleven of twelve OTUs belonging to the Glomeraceae family were associated with healthy roots and abundant in cultivar Vitra. This study shows how the phenotype and fungal microbiome of different pea cultivars respond distinctly to intercropping. Furthermore, the identification of disease- and health-associated taxa in the pea root fungal community refines the characterization of different cultivar candidates for intercropping. [Graphic: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Summary: Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0–90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio. Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).

As an essential process for the maintenance of cellular homeostasis and function, autophagy is responsible for the lysosome-mediated degradation of damaged proteins and organelles; therefore, dysregulation of autophagy in humans can lead to a variety of diseases. The link between impaired autophagy and disease highlights the need to investigate possible interventions to address dysregulations. One possible intervention is hyperthermia, which is described in this protocol. To investigate these interventions, a method for absolute quantification of autophagosomal compartments is required that allows comparison of autophagosomal activity under different conditions. Existing methods such as western blotting and immunohistochemistry for analysing the location and relative abundance of intracellular proteins associated with autophagy, or transmission electron microscopy (TEM), which are either very time-consuming, expensive, or both, are less suitable for this purpose. The method described in this protocol allows the absolute quantification of autophagosomes per cell in human fibroblasts using the CYTO-ID® Autophagy Detection Kit after heat therapy compared to a control. The Cyto-ID® assay is based on the use of a specific dye that selectively stains autophagic compartments, combined with an additional Hoechst 33342 dye for nuclear staining. The subsequent recognition of these stained compartments by the Cytation Imager enables the software to determine the number of autophagosomes per nucleus in living cells. Additionally, this absolute quantification uses an image-based method, and the protocol is easy to use and not time-consuming. Furthermore, the method is not only suitable for heat therapy but can also be adapted to any other desired therapy or substance.

Summary: The development of vaccines and therapeutics that are broadly effective against known and emergent coronaviruses is an urgent priority. We screened the circulating B cell repertoires of COVID-19 survivors and vaccinees to isolate over 9,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific monoclonal antibodies (mAbs), providing an expansive view of the SARS-CoV-2-specific Ab repertoire. Among the recovered antibodies was TXG-0078, an N-terminal domain (NTD)-specific neutralizing mAb that recognizes diverse alpha- and beta-coronaviruses. TXG-0078 achieves its exceptional binding breadth while utilizing the same VH1-24 variable gene signature and heavy-chain-dominant binding pattern seen in other NTD-supersite-specific neutralizing Abs with much narrower specificity. We also report CC24.2, a pan-sarbecovirus neutralizing antibody that targets a unique receptor-binding domain (RBD) epitope and shows similar neutralization potency against all tested SARS-CoV-2 variants, including BQ.1.1 and XBB.1.5. A cocktail of TXG-0078 and CC24.2 shows protection in vivo, suggesting their potential use in variant-resistant therapeutic Ab cocktails and as templates for pan-coronavirus vaccine design.