Effective treatment of low-risk acute GVHD with itacitinib monotherapy.

The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those of 140 contemporaneous, matched control patients treated with SCSs. More patients responded to itacitinib within 7 days (81% vs 66%, P = .02), and response rates at day 28 were very high for both groups (89% vs 86%, P = .67), with few symptomatic flares (11% vs 12%, P = .88). Fewer itacitinib-treated patients developed a serious infection within 90 days (27% vs 42%, P = .04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, P = .02). No other grade ≥3 adverse events occurred in >10% of itacitinib-treated patients. There were no significant differences between groups at 1 year for nonrelapse mortality (4% vs 11%, P = .21), relapse (18% vs 21%, P = .64), chronic GVHD (28% vs 33%, P = .33), or survival (88% vs 80%, P = .11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD and deserves further investigation.

Implementation of a Program for Appendicitis MRI in a Pediatric Hospital.

MRI is increasingly used as an alternate to CT for the evaluation of suspected appendicitis in pediatric patients presenting to the emergency department (ED) with abdominal pain, when further imaging is needed after an initial ultrasound examination. The available literature shows a similar diagnostic performance of MRI and CT in this setting. At the authors' institution, to evaluate for appendicitis in children in the ED, MRI is performed using a rapid three-sequence free-breathing protocol without IV contrast media. Implementation of an MRI program for appendicitis in children involves multiple steps, including determination of imaging resource availability, collaboration with other services to develop imaging pathways, widespread educational efforts, and regular quality review. Such programs can face numerous practice-specific challenges, such as those involving scanner capacity, costs, and buy-in of impacted groups. Nonetheless, through careful consideration of these factors, MRI can be used to positively impact the care of children presenting to the ED with suspected appendicitis. This Clinical Perspective aims to provide guidance on the development of a program for appendicitis MRI in children, drawing on one institution's experience while highlighting the advantages of MRI and practical strategies for overcoming potential barriers.

Evaluating the usability of a co-designed power assisted exercise graphical user interface for people with stroke.

BACKGROUND: Digital advancement of power assisted exercise equipment will advance exercise prescription for people with stroke (PwS). This article reports on the remote usability evaluation of a co-designed graphical user interface (GUI) and denotes an example of how video-conference software can increase reach to participants in the testing of rehabilitation technologies. The aim of this study was to evaluate the usability of two sequential versions of the GUI. METHODS: We adopted a mixed methods approach. Ten professional user (PU) (2M/8F) and 10 expert user (EU) participants (2M/8F) were recruited. Data collection included a usability observation, a 'think aloud' walk through, task completion, task duration and user satisfaction as indicated by the Post Study System Usability Questionnaire (PSSUQ). Identification of usability issues informed the design of version 2 which included an additional submenu. Descriptive analysis was conducted upon usability issues and number of occurrences detected on both versions of the GUI. Inferential analysis enabled comparison of task duration and PSSUQ data between the PU and EU groups. RESULTS: Analysis of the 'think aloud' walkthrough data enabled identification of 22 usability issues on version 1 from a total of 100 usability occurrences. Task completion for all tasks was 100%. Eight usability issues were directly addressed in the development of version 2. Two recurrent and 24 new usability issues were detected in version 2 with a total of 86 usability occurrences. Paired two tailed T-tests on task duration data indicated a significant decrease amongst the EU group for task 1.1 on version 2 (P = 0.03). The mean PSSUQ scores for version 1 was 1.44 (EU group) and 1.63 (PU group) compared with 1.40 (EU group) and 1.41 (PU group) for version 2. CONCLUSIONS: The usability evaluation enabled identification of usability issues on version 1 of the GUI which were effectively addressed on the iteration of version 2. Testing of version 2 identified usability issues within the new submenu. Application of multiple usability evaluation methods was effective in identifying and addressing usability issues in the GUI to improve the experience of PAE for PwS. The use of video-conference software to conduct synchronous, remote usability testing is an effective alternative to face to face testing methods.

The Exeter Activity Unlimited statement on physical activity and exercise for cystic fibrosis: methodology and results of an international, multidisciplinary, evidence-driven expert consensus.

BACKGROUND: The roles of physical activity (PA) and exercise within the management of cystic fibrosis (CF) are recognised by their inclusion in numerous standards of care and treatment guidelines. However, information is brief, and both PA and exercise as multi-faceted behaviours require extensive stakeholder input when developing and promoting such guidelines. METHOD: On 30th June and 1st July 2021, 39 stakeholders from 11 countries, including researchers, healthcare professionals and patients participated in a virtual conference to agree an evidence-based and informed expert consensus about PA and exercise for people with CF. This consensus presents the agreement across six themes: (i) patient and system centred outcomes, (ii) health benefits, iii) measurement, (iv) prescription, (v) clinical considerations, and (vi) future directions. The consensus was achieved by a stepwise process, involving: (i) written evidence-based synopses; (ii) peer critique of synopses; (iii) oral presentation to consensus group and peer challenge of revised synopses; and (iv) anonymous voting on final proposed synopses for adoption to the consensus statement. RESULTS: The final consensus document includes 24 statements which surpassed the consensus threshold (>80% agreement) out of 30 proposed statements. CONCLUSION: This consensus can be used to support health promotion by relevant stakeholders for people with CF.

Current preparation status in AAC: perspectives of special education teachers in the United States.

Special education teachers are essential team members in the provision of services to students with complex communication needs. Professional competencies related to augmentative and alternative communication (AAC) practices have been outlined for special education teachers as part of their professional standards. Yet, it is unclear to what extent these professionals have knowledge and skills in this area. Given existing gaps in the literature, an anonymous, web-based survey was disseminated across the United States to gather information on special education teachers' self-reported knowledge and skills in AAC. A total of 1198 special education teachers from 46 states responded to the survey. Findings indicated that most special education teachers did not receive formal training in AAC during their teacher licensure preparation programs, resulting in low levels of self-reported knowledge and skills. Data also indicated that while influencing factors existed, special education teachers' knowledge and skills in AAC remained minimal. Implications and recommendations for stakeholders are discussed.

Shiga toxin sub-type 2a increases the efficiency of Escherichia coli O157 transmission between animals and restricts epithelial regeneration in bovine enteroids.

Specific Escherichia coli isolates lysogenised with prophages that express Shiga toxin (Stx) can be a threat to human health, with cattle being an important natural reservoir. In many countries the most severe pathology is associated with enterohaemorrhagic E. coli (EHEC) serogroups that express Stx subtype 2a. In the United Kingdom, phage type (PT) 21/28 O157 strains have emerged as the predominant cause of life-threatening EHEC infections and this phage type commonly encodes both Stx2a and Stx2c toxin types. PT21/28 is also epidemiologically linked to super-shedding (>103 cfu/g of faeces) which is significant for inter-animal transmission and human infection as demonstrated using modelling studies. We demonstrate that Stx2a is the main toxin produced by stx2a+/stx2c+ PT21/28 strains induced with mitomycin C and this is associated with more rapid induction of gene expression from the Stx2a-encoding prophage compared to that from the Stx2c-encoding prophage. Bacterial supernatants containing either Stx2a and/or Stx2c were demonstrated to restrict growth of bovine gastrointestinal organoids with no restriction when toxin production was not induced or prevented by mutation. Isogenic strains that differed in their capacity to produce Stx2a were selected for experimental oral colonisation of calves to assess the significance of Stx2a for both super-shedding and transmission between animals. Restoration of Stx2a expression in a PT21/28 background significantly increased animal-to-animal transmission and the number of sentinel animals that became super-shedders. We propose that while both Stx2a and Stx2c can restrict regeneration of the epithelium, it is the relatively rapid and higher levels of Stx2a induction, compared to Stx2c, that have contributed to the successful emergence of Stx2a+ E. coli isolates in cattle in the last 40 years. We propose a model in which Stx2a enhances E. coli O157 colonisation of in-contact animals by restricting regeneration and turnover of the colonised gastrointestinal epithelium.

Effects of Vaccine-Related Conspiracy Theories on Chinese Young Adults' Perceptions of the HPV Vaccine: An Experimental Study.

This online experiment used the Theory of Planned Behavior to examine the impact of exposure to conspiracy social media messages on Chinese young adults' perceptions of the HPV vaccine. Three major findings were identified. First, exposure to anti-vaccine conspiracy theories resulted in less favorable attitudes toward the HPV vaccine, less positive perceived norms regarding getting vaccinated, and weaker vaccination intentions. Second, people who were more knowledgeable about the HPV vaccine had more favorable attitudes, more positive norms, higher perceived behavioral control, and greater behavioral intentions. Finally, vaccine knowledge moderated the effect of exposure to anti-vaccine conspiracy theories. Our results suggest that, among Chinese young adult social media users, preexisting knowledge of the HPV vaccine may have a protective effect against exposure to online conspiracy theories.

MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD.

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3α) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS (P < .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, P = .004) and for Minnesota risk (0.72, P = .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies.

A high resolution atlas of gene expression in the domestic sheep (Ovis aries).

Sheep are a key source of meat, milk and fibre for the global livestock sector, and an important biomedical model. Global analysis of gene expression across multiple tissues has aided genome annotation and supported functional annotation of mammalian genes. We present a large-scale RNA-Seq dataset representing all the major organ systems from adult sheep and from several juvenile, neonatal and prenatal developmental time points. The Ovis aries reference genome (Oar v3.1) includes 27,504 genes (20,921 protein coding), of which 25,350 (19,921 protein coding) had detectable expression in at least one tissue in the sheep gene expression atlas dataset. Network-based cluster analysis of this dataset grouped genes according to their expression pattern. The principle of 'guilt by association' was used to infer the function of uncharacterised genes from their co-expression with genes of known function. We describe the overall transcriptional signatures present in the sheep gene expression atlas and assign those signatures, where possible, to specific cell populations or pathways. The findings are related to innate immunity by focusing on clusters with an immune signature, and to the advantages of cross-breeding by examining the patterns of genes exhibiting the greatest expression differences between purebred and crossbred animals. This high-resolution gene expression atlas for sheep is, to our knowledge, the largest transcriptomic dataset from any livestock species to date. It provides a resource to improve the annotation of the current reference genome for sheep, presenting a model transcriptome for ruminants and insight into gene, cell and tissue function at multiple developmental stages.

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis.

Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies.

How Journalists Characterize Health Inequalities and Redefine Solutions for Native American Audiences.

Many Native American communities experience severe health inequalities, including shorter average lifespan and higher rates of chronic illnesses. Journalism that serves Native Americans is a promising channel for heath communication, but only if scholars first understand the particular cultural contexts of indigenous communities. This research contributes to that goal by investigating how journalists serving Native American communities characterize health and the issues they identify with covering determinants of health. In in-depth interviews (N = 24), journalists contrasted how they cover health issues as embedded in cultural context with shallow, more negative coverage by non-Native media organizations. Interviews also revealed a tension between "medical" and "cultural" models of health, contributing to the oversaturation of certain issues, like diabetes, while other health topics are underrepresented. The journalists also expressed how social determinants and histories of oppression shape health inequalities, illuminating the roles of historical trauma and the destruction of indigenous health beliefs and behaviors. Failure to recognize these issues could stymie efforts to communicate about health issues facing Native American audiences.

Development of in vitro enteroids derived from bovine small intestinal crypts.

Cattle are an economically important domestic animal species. In vitro 2D cultures of intestinal epithelial cells or epithelial cell lines have been widely used to study cell function and host-pathogen interactions in the bovine intestine. However, these cultures lack the cellular diversity encountered in the intestinal epithelium, and the physiological relevance of monocultures of transformed cell lines is uncertain. Little is also known of the factors that influence cell differentiation and homeostasis in the bovine intestinal epithelium, and few cell-specific markers that can distinguish the different intestinal epithelial cell lineages have been reported. Here we describe a simple and reliable procedure to establish in vitro 3D enteroid, or "mini gut", cultures from bovine small intestinal (ileal) crypts. These enteroids contained a continuous central lumen lined with a single layer of polarized enterocytes, bound by tight junctions with abundant microvilli on their apical surfaces. Histological and transcriptional analyses suggested that the enteroids comprised a mixed population of intestinal epithelial cell lineages including intestinal stem cells, enterocytes, Paneth cells, goblet cells and enteroendocrine cells. We show that bovine enteroids can be successfully maintained long-term through multiple serial passages without observable changes to their growth characteristics, morphology or transcriptome. Furthermore, the bovine enteroids can be cryopreserved and viable cultures recovered from frozen stocks. Our data suggest that these 3D bovine enteroid cultures represent a novel, physiologically-relevant and tractable in vitro system in which epithelial cell differentiation and function, and host-pathogen interactions in the bovine small intestine can be studied.

A Csf1r-EGFP Transgene Provides a Novel Marker for Monocyte Subsets in Sheep.

Expression of Csf1r in adults is restricted to cells of the macrophage lineage. Transgenic reporters based upon the Csf1r locus require inclusion of the highly conserved Fms-intronic regulatory element for expression. We have created Csf1r-EGFP transgenic sheep via lentiviral transgenesis of a construct containing elements of the mouse Fms-intronic regulatory element and Csf1r promoter. Committed bone marrow macrophage precursors and blood monocytes express EGFP in these animals. Sheep monocytes were divided into three populations, similar to classical, intermediate, and nonclassical monocytes in humans, based upon CD14 and CD16 expression. All expressed EGFP, with increased levels in the nonclassical subset. Because Csf1r expression coincides with the earliest commitment to the macrophage lineage, Csf1r-EGFP bone marrow provides a tool for studying the earliest events in myelopoiesis using the sheep as a model.

Social Representation of Cyberbullying and Adolescent Suicide: A Mixed-Method Analysis of News Stories.

Cyberbullying has provoked public concern after well-publicized suicides of adolescents. This mixed-methods study investigates the social representation of these suicides. A content analysis of 184 U.S. newspaper articles on death by suicide associated with cyberbullying or aggression found that few articles adhered to guidelines suggested by the World Health Organization and the American Foundation for Suicide Prevention to protect against suicidal behavioral contagion. Few articles made reference to suicide or bullying prevention resources, and most suggested that the suicide had a single cause. Thematic analysis of a subset of articles found that individual deaths by suicide were used as cautionary tales to prompt attention to cyberbullying. This research suggests that newspaper coverage of these events veers from evidence-based guidelines and that more work is needed to determine how best to engage with journalists about the potential consequences of cyberbullying and suicide coverage.

International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium.

Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation.

Macrophage colony-stimulating factor (CSF1) controls monocyte production and maturation and the steady-state size of the liver in pigs.

Macrophage colony-stimulating factor (CSF1) is an essential growth and differentiation factor for cells of the macrophage lineage. To explore the role of CSF1 in steady-state control of monocyte production and differentiation and tissue repair, we previously developed a bioactive protein with a longer half-life in circulation by fusing pig CSF1 with the Fc region of pig IgG1a. CSF1-Fc administration to pigs expanded progenitor pools in the marrow and selectively increased monocyte numbers and their expression of the maturation marker CD163. There was a rapid increase in the size of the liver, and extensive proliferation of hepatocytes associated with increased macrophage infiltration. Despite the large influx of macrophages, there was no evidence of liver injury and no increase in circulating liver enzymes. Microarray expression profiling of livers identified increased expression of macrophage markers, i.e., cytokines such as TNF, IL1, and IL6 known to influence hepatocyte proliferation, alongside cell cycle genes. The analysis also revealed selective enrichment of genes associated with portal, as opposed to centrilobular regions, as seen in hepatic regeneration. Combined with earlier data from the mouse, this study supports the existence of a CSF1-dependent feedback loop, linking macrophages of the liver with bone marrow and blood monocytes, to mediate homeostatic control of the size of the liver. The results also provide evidence of safety and efficacy for possible clinical applications of CSF1-Fc.

Individual and social determinants of obesity in strategic health messages: Interaction with political ideology.

Antiobesity health communication campaigns often target individual behavior, but these ads might inflate the role of individual responsibility at the expense of other health determinants. In a 2 × 2 full-factorial, randomized, online experiment, 162 American adults viewed antiobesity advertisements that varied in emphasizing social or individual causation for obesity through text and images. Locus for attribution of responsibility for obesity causes and solutions was measured, as was how these responses were moderated by political ideology. Participants who viewed text emphasizing individual responsibility were less likely to agree that genetic factors caused obesity. Conservative participants who viewed images of overweight individuals were less likely than liberal participants to agree that social factors were responsible for causing obesity. In addition, among conservative participants who viewed images of fast food versus images of overweight individuals, agreement that the food industry bore some responsibility mediated support for policy solutions to obesity. These findings, among others, demonstrate that awareness of multilevel determinants of health outcomes can be a precursor of support for policy solutions to obesity among those not politically inclined to support antiobesity policy. In addition, stigmatizing images of overweight individuals in antiobesity campaigns might overemphasize the role of individual behavior in obesity at the expense of other factors.

Localized Health News Releases and Community Newspapers: A Method for Rural Health Promotion.

Newspaper health stories often originate with news releases from health organizations. Tailoring news releases to a particular mass media outlet increases the possibility that the release will result in a published story. This study describes a 2-year effort to promote coverage of health through dissemination of localized health news releases to newspapers. Each newspaper received stories tailored to that community. Localized elements of stories included local headlines and local data. Nearly half of newspapers in our study (48.2%) published at least one of our health news stories, and 541 health news stories were published as a result of the project. We also examined which types of newspapers were most likely to publish health news stories. Newspapers in rural versus suburban and urban areas were more likely to publish health news stories, as were midsized newspapers. In addition, rural newspapers were more likely than urban newspapers to publish stories about aging, specifically arthritis and heart disease. Our findings indicate that tailoring health news releases with local information and targeting releases to align with newspaper audience demographics could increase the quantity and quality of health-promoting information available to rural residents, who experience disparities in health care access and health outcomes.

Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach.

Ionizable lipid nanoparticles (LNPs) have gained attention as mRNA delivery platforms for vaccination against COVID-19 and for protein replacement therapies. LNPs enhance mRNA stability, circulation time, cellular uptake, and preferential delivery to specific tissues compared to mRNA with no carrier platform. However, LNPs are only in the beginning stages of development for safe and effective mRNA delivery to the placenta to treat placental dysfunction. Here, we develop LNPs that enable high levels of mRNA delivery to trophoblasts in vitro and to the placenta in vivo with no toxicity. We conducted a Design of Experiments to explore how LNP composition, including the type and molar ratio of each lipid component, drives trophoblast and placental delivery. Our data revealed that utilizing C12-200 as the ionizable lipid and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as the phospholipid in the LNP design yields high transfection efficiency in vitro. Analysis of lipid molar composition as a design parameter in LNPs displayed a strong correlation between apparent pKa and poly (ethylene) glycol (PEG) content, as a reduction in PEG molar amount increases apparent pKa. Further, we present one LNP platform that exhibits the highest delivery of placental growth factor mRNA to the placenta in pregnant mice, resulting in synthesis and secretion of a potentially therapeutic protein. Lastly, our high-performing LNPs have no toxicity to both the pregnant mice and fetuses. Our results demonstrate the feasibility of LNPs as a platform for mRNA delivery to the placenta, and our top LNP formulations may provide a therapeutic platform to treat diseases that originate from placental dysfunction during pregnancy.