Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.

DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. Cases were identified clinically. Available records, including magnetic resonance imaging and electroencephalography, were reviewed. Genetic testing was performed by whole exome and whole-genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement and severe neutropenia were also observed in one or more patients. Five of the children died in infancy or childhood; the other four are currently aged between 5 months and 6 years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene.

Understanding the unique and common perspectives of partners engaged in knowledge mobilization activities within pediatric pain management: a mixed methods study.

BACKGROUND: Knowledge mobilization (KM) is essential to close the longstanding evidence to practice gap in pediatric pain management. Engaging various partners (i.e., those with expertise in a given topic area) in KM is best practice; however, little is known about how different partners engage and collaborate on KM activities. This mixed-methods study aimed to understand what different KM partner groups (i.e., health professionals, researchers, and patient/caregiver partners) perceive as supporting KM activities within pediatric pain management. METHODS: This study used a convergent mixed-methods design. Ten partners from each of the three groups participated in interviews informed by the Consolidated Framework for Implementation Research, where they discussed what impacted KM activities within pediatric pain. Participants then rated and ranked select factors discussed in the interview. Transcripts were analyzed within each group using reflexive thematic analysis. Group-specific themes were then triangulated to identify convergence and divergence among groups. A matrix analysis was then conducted to generate meta-themes to describe overarching concepts. Quantitative data were analyzed using descriptive statistics. RESULTS: Unique themes were developed within each partner group and further analysis generated four meta-themes: (1) team dynamics; (2) role of leadership; (3) policy influence; (4) social influence. There was full agreement among groups on the meaning of team dynamics. While there was partial agreement on the role of leadership, groups differed on who they described as taking on leadership positions. There was also partial agreement on policy influence, where health professionals and researchers described different institutions as being responsible for providing funding support. Finally, there was partial agreement on social influence, where the role of networks was seen as serving distinct purposes to support KM. Quantitative analyses indicated that partner groups shared similar priorities (e.g., team relationships, communication quality) when it came to supporting KM in pediatric pain. CONCLUSIONS: While partners share many needs in common, there is also nuance in how they wish to be engaged in KM activities as well as the contexts in which they work. Strategies must be introduced to address these nuances to promote effective engagement in KM to increase the impact of evidence in pediatric pain.

A Review of Radiation-Induced Vascular Injury and Clinical Impact.

ABSTRACT: The number of cancer survivors continues to increase because of advances in therapeutic modalities. Along with surgery and chemotherapy, radiotherapy is a commonly used treatment modality in roughly half of all cancer patients. It is particularly helpful in the oncologic treatment of patients with breast, head and neck, and prostate malignancies. Unfortunately, among patients receiving radiation therapy, long-term sequalae are often unavoidable, and there is accumulating clinical evidence suggesting significant radiation-related damage to the vascular endothelium. Ionizing radiation has been known to cause obliterative fibrosis and increased wall thickness in irradiated blood vessels. Clinically, these vascular changes induced by ionizing radiation can pose unique surgical challenges when operating in radiated fields. Here, we review the relevant literature on radiation-induced vascular damage focusing on mechanisms and signaling pathways involved and highlight microsurgical anastomotic outcomes after radiotherapy. In addition, we briefly comment on potential therapeutic strategies, which may have the ability to mitigate radiation injury to the vascular endothelium.

Export of Diverse and Bioactive Small Proteins through a Type I Secretion System.

Small proteins perform a diverse array of functions, from microbial competition, to endocrine signaling, to building biomaterials. Microbial systems that can produce recombinant small proteins enable discovery of new effectors, exploration of sequence activity relationships, and have the potential for in vivo delivery. However, we lack simple systems for controlling small-protein secretion from Gram-negative bacteria. Microcins are small-protein antibiotics secreted by Gram-negative bacteria that inhibit the growth of neighboring microbes. They are exported from the cytosol to the environment in a one-step process through a specific class of type I secretion systems (T1SSs). However, relatively little is known about substrate requirements for small proteins exported through microcin T1SSs. Here, we investigate the prototypic microcin V T1SS from Escherichia coli and show that it can export a remarkably wide range of natural and synthetic small proteins. We demonstrate that secretion is largely independent of the cargo protein's chemical properties and appears to be constrained only by protein length. We show that a varied range of bioactive sequences, including an antibacterial protein, a microbial signaling factor, a protease inhibitor, and a human hormone, can all be secreted and elicit their intended biological effect. Secretion through this system is not limited to E. coli, and we demonstrate its function in additional Gram-negative species that can inhabit the gastrointestinal tract. Our findings uncover the highly promiscuous nature of small-protein export through the microcin V T1SS, which has implications for native-cargo capacity and the use of this system in Gram-negative bacteria for small-protein research and delivery. IMPORTANCE Type I secretion systems for microcin export in Gram-negative bacteria transport small antibacterial proteins from the cytoplasm to the extracellular environment in a single step. In nature, each secretion system is generally paired with a specific small protein. We know little about the export capacity of these transporters and how cargo sequence influences secretion. Here, we investigate the microcin V type I system. Remarkably, our studies show that this system can export small proteins of diverse sequence composition and is only limited by protein length. Furthermore, we demonstrate that a wide range of bioactive small proteins can be secreted and that this system can be used in Gram-negative species that colonize the gastrointestinal tract. These findings expand our understanding of secretion through type I systems and their potential uses in a variety of small-protein applications.

Design of the think PHRESH longitudinal cohort study: Neighborhood disadvantage, cognitive aging, and alzheimer's disease risk in disinvested, black neighborhoods.

BACKGROUND: Black Americans have disproportionately higher rates and earlier onset of Alzheimer's disease and related dementias (ADRD) relative to White Americans. We currently lack a comprehensive understanding of how the lived experience and broader societal factors, including cumulative exposure to structural racism and the mechanisms underlying the risks, may contribute to elevated ADRD risk in Black Americans. METHODS: The Think PHRESH study builds on existing, community-based research infrastructure, from the ongoing Pittsburgh Hill/Homewood Research on Neighborhood Change and Health (PHRESH) studies, to examine the contributions of dynamic neighborhood socioeconomic conditions across the lifecourse to cognitive outcomes in mid- and late-life adults living in two historically disinvested, predominantly Black communities (anticipated n = 1133). This longitudinal, mixed-methods study rests on the premise that neighborhood racial segregation and subsequent disinvestment contributes to poor cognitive outcomes via factors including (a) low access to educational opportunities and (b) high exposure to race- and socioeconomically-relevant stressors, such as discrimination, trauma, and adverse childhood events. In turn, these cumulative exposures foster psychological vigilance in residents, leading to cardiometabolic dysregulation and sleep disruption, which may mediate associations between neighborhood disadvantage and ADRD risk. This premise recognizes the importance of potential protective factors that may promote cognitive health, including neighborhood social cohesion, safety, and satisfaction. The proposed study will leverage our existing longitudinal data on risk/protective factors and biobehavioral mediators and will include: (1) up to three waves of cognitive assessments in participants ages 50 years + and one assessment in participants ages 35-49 years; clinical adjudication of ADRD will be completed in participants who are 50+, (2) extensive surveys of risk and protective factors, (3) two assessments of blood pressure and objectively measured sleep, (4) a comprehensive assessment of life and residential history; and (5) two rounds of in-depth qualitative interviews to reveal lifecourse opportunities and barriers experienced by Black Americans in achieving optimal cognitive health in late life. DISCUSSION: Understanding how structural racism has influenced the lived experience of Black Americans, including dynamic changes in neighborhood conditions over time, is critical to inform multi-level intervention and policy efforts to reduce pervasive racial and socioeconomic disparities in ADRD.

Biopsychosocial, work-related, and environmental factors affecting work participation in people with Osteoarthritis: a systematic review.

PURPOSE: Osteoarthritis (OA) causes pain and disability, with onset often during working age. Joint pain is associated with functional difficulties and may lead to work instability. The aims of this systematic review are to identify: the impact of OA on work participation; and biopsychosocial and work-related factors associated with absenteeism, presenteeism, work transitions, work impairment, work accommodations, and premature work loss. METHODS: Four databases were searched, including Medline. The Joanna Briggs Institute Critical Appraisal tools were used for quality assessment, with narrative synthesis to pool findings due to heterogeneity of study designs and work outcomes. RESULTS: Nineteen studies met quality criteria (eight cohort; 11 cross-sectional): nine included OA of any joint(s), five knee-only, four knee and/or hip, and one knee, hip, and hand OA. All were conducted in high income countries. Absenteeism due to OA was low. Presenteeism rates were four times greater than absenteeism. Performing physically intensive work was associated with absenteeism, presenteeism, and premature work loss due to OA. Moderate-to-severe joint pain and pain interference were associated with presenteeism, work transition, and premature work loss. A smaller number of studies found that comorbidities were associated with absenteeism and work transitions. Two studies reported low co-worker support was associated with work transitions and premature work loss. CONCLUSIONS: Physically intensive work, moderate-to-severe joint pain, co-morbidities, and low co-worker support potentially affects work participation in OA. Further research, using longitudinal study designs and examining the links between OA and biopsychosocial factors e.g., workplace accommodations, is needed to identify targets for interventions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2019 CRD42019133343 .

High Protein Whole Food Snack and Albumin Outcomes in Patients With Dialysis-Dependent Chronic Kidney Disease.

OBJECTIVE: Protein-energy wasting is common among patients on hemodialysis (HD). This study sought to define effects that a novel, post-HD, high-calorie, high-protein whole food snack had on patients' serum albumin (serum alb), serum phosphorus and equilibrated normalized protein catabolic rate (enPCR). METHODS: A 12-month (6 months intervention, 6 months pre/post data collection), single-center, unblinded study was conducted. Participants (n = 67) consumed, ad libitum, a whole food snack post-HD for 6 treatments each month. Upon analysis, regression models identified relationships between serum alb and whole food snack consumption across follow up. Predefined effect size anticipated was + 0.2 g/dL. Patients were stratified by high (≥4 g/dL) or low (<4 g/dL) mean serum alb during a 3-month baseline period. Paired t-tests compared mean per patient difference in serum alb, enPCR and serum phosphorus from baseline to each month of follow up, stratified by high (≥640 g) or low (<640 g) consumption of the whole food snack (a priori caloric estimation). RESULTS: Linear regression models showed positive associations between higher serum alb and enPCR with higher whole food snack consumption across follow up (all P < .05). Assessments from baseline to each follow-up month show some increases in serum alb, yet t test comparisons were not significant. No significant changes were seen in serum phosphorus levels during follow-up. CONCLUSION: Albeit the catabolic effects of HD are well-known, effective nutritional interventions are scarce. Results showed that providing a whole food snack post-HD to individuals with serum alb <4.0 g/dL may be beneficial but further studies are recommended.

Understanding the Role of Adipocytes and Fibroblasts in Cancer.

ABSTRACT: Cancer is currently the second leading cause of death in the United States. There is increasing evidence that the tumor microenvironment (TME) is pivotal for tumorigenesis and metastasis. Recently, adipocytes and cancer-associated fibroblasts (CAFs) in the TME have been shown to play a major role in tumorigenesis of different cancers, specifically melanoma. Animal studies have shown that CAFs and adipocytes within the TME help tumors evade the immune system, for example, by releasing chemokines to blunt the effectiveness of the host defense. Although studies have identified that adipocytes and CAFs play a role in tumorigenesis, adipocyte transition to fibroblast within the TME is fairly unknown. This review intends to elucidate the potential that adipocytes may have to transition to fibroblasts and, as part of the TME, a critical role that CAFs may play in affecting the growth and invasion of tumor cells. Future studies that illuminate the function of adipocytes and CAFs in the TME may pave way for new antitumor therapies.

Consent in surgery.

This article will focus on obtaining informed consent from the perspective of a surgical advanced clinical practitioner (SACP). There are many considerations regarding obtaining informed consent and it is recognised that the duty of this role will vary within each NHS trust. This article will reflect on whether SACPs should obtain consent for surgical procedures.

Top Chief: A Critical Assessment of a Cross-disciplinary Case Study as Common Intellectual Experience.

Common intellectual experiences (CIEs) are one of the lesser-known modalities that have been identified as a high impact practice (HIP) in higher education. This mixed-methods study assesses the outcomes of a short-term CIE, which took the form of a multi-disciplinary, multi-classroom case study focused on Danny Meyer, CEO of Union Square Hospitality group (the titular Top Chief), and his handling of the challenges faced by the hospitality industry under the conditions of the global pandemic. The findings suggest that such CIEs can be effective in fostering integrative thinking both within and across curricula, though the benefits may not accrue equally across all student populations. The study has implications for how universities develop and diversify their HIP portfolios, how faculty implement CIEs in their classrooms, and how students develop their capabilities as wicked problem solvers.

Microcins reveal natural mechanisms of bacterial manipulation to inform therapeutic development.

Microcins are an understudied and poorly characterized class of antimicrobial peptides. Despite the existence of only 15 examples, all identified from the Enterobacteriaceae, microcins display diversity in sequence, structure, target cell uptake, cytotoxic mechanism of action and target specificity. Collectively, these features describe some of the unique means nature has contrived for molecules to cross the 'impermeable' barrier of the Gram-negative bacterial outer membrane and inflict cytotoxic effects. Microcins appear to be widely dispersed among different species and in different environments, where they function in regulating microbial communities in diverse ways, including through competition. Growing evidence suggests that microcins may be adapted for therapeutic uses such as antimicrobial drugs, microbiome modulators or facilitators of peptide uptake into cells. Advancing our biological, ecological and biochemical understanding of the roles of microcins in bacterial interactions, and learning how to regulate and modify microcin activity, is essential to enable such therapeutic applications.

Peptides Derived from Vascular Endothelial Growth Factor B Show Potent Binding to Neuropilin-1.

Vascular endothelial growth factors (VEGFs) regulate significant pathways in angiogenesis, myocardial and neuronal protection, metabolism, and cancer progression. The VEGF-B growth factor is involved in cell survival, anti-apoptotic and antioxidant mechanisms, through binding to VEGF receptor 1 and neuropilin-1 (NRP1). We employed surface plasmon resonance technology and X-ray crystallography to analyse the molecular basis of the interaction between VEGF-B and the b1 domain of NRP1, and developed VEGF-B C-terminus derived peptides to be used as chemical tools for studying VEGF-B - NRP1 related pathways. Peptide lipidation was used as a means to stabilise the peptides. VEGF-B-derived peptides containing a C-terminal arginine show potent binding to NRP1-b1. Peptide lipidation increased binding residence time and improved plasma stability. A crystal structure of a peptide with NRP1 demonstrated that VEGF-B peptides bind at the canonical C-terminal arginine binding site. VEGF-B C-terminus imparts higher affinity for NRP1 than the corresponding VEGF-A165 region. This tight binding may impact on the activity and selectivity of the full-length protein. The VEGF-B167 derived peptides were more effective than VEGF-A165 peptides in blocking functional phosphorylation events. Blockers of VEGF-B function have potential applications in diabetes and non-alcoholic fatty liver disease.

Evidence for Widespread Class II Microcins in Enterobacterales Genomes.

Microcins are a class of antimicrobial peptides produced by certain Gram-negative bacterial species to kill or inhibit the growth of competing bacteria. Only 10 unique, experimentally validated class II microcins have been identified, and the majority of these come from Escherichia coli. Although the current representation of microcins is sparse, they exhibit a diverse array of molecular functionalities, uptake mechanisms, and target specificities. This broad diversity from such a small representation suggests that microcins may have untapped potential for bioprospecting peptide antibiotics from genomic data sets. We used a systematic bioinformatics approach to search for verified and novel class II microcins in E. coli and other species within its family, Enterobacteriaceae. Nearly one-quarter of the E. coli genome assemblies contained one or more microcins, where the prevalence of hits to specific microcins varied by isolate phylogroup. E. coli isolates from human extraintestinal and poultry meat sources were enriched for microcins, while those from freshwater were depleted. Putative microcins were found in various abundances across all five distinct phylogenetic lineages of Enterobacteriaceae, with a particularly high prevalence in the "Klebsiella" clade. Representative genome assemblies from species across the Enterobacterales order, as well as a few outgroup species, also contained putative microcin sequences. This study suggests that microcins have a complicated evolutionary history, spanning far beyond our limited knowledge of the currently validated microcins. Efforts to functionally characterize these newly identified microcins have great potential to open a new field of peptide antibiotics and microbiome modulators and elucidate the ways in which bacteria compete with each other. IMPORTANCE Class II microcins are small bacteriocins produced by strains of Gram-negative bacteria in the Enterobacteriaceae. They are generally understood to play a role in interbacterial competition, although direct evidence of this is limited, and they could prove informative in developing new peptide antibiotics. However, few examples of verified class II microcins exist, and novel microcins are difficult to identify due to their sequence diversity, making it complicated to study them as a group. Here, we overcome this limitation by developing a bioinformatics pipeline to detect microcins in silico. Using this pipeline, we demonstrate that both verified and novel class II microcins are widespread within and outside the Enterobacteriaceae, which has not been systematically shown previously. The observed prevalence of class II microcins suggests that they are ecologically important, and the elucidation of novel microcins provides a resource that can be used to expand our knowledge of the structure and function of microcins as antibacterials.

Evaluation of four gamma-based methods for calculating confidence intervals for age-adjusted mortality rates when data are sparse.

BACKGROUND: Equal-tailed confidence intervals that maintain nominal coverage (0.95 or greater probability that a 95% confidence interval covers the true value) are useful in interval-based statistical reliability standards, because they remain conservative. For age-adjusted death rates, while the Fay-Feuer gamma method remains the gold standard, modifications have been proposed to streamline implementation and/or obtain more efficient intervals (shorter intervals that retain nominal coverage). METHODS: This paper evaluates three such modifications for use in interval-based statistical reliability standards, the Anderson-Rosenberg, Tiwari, and Fay-Kim intervals, when data are sparse and sample size-based standards alone are overly coarse. Initial simulations were anchored around small populations (P = 2400 or 1200), the median crude all-cause US mortality rate in 2010-2019 (833.8 per 100,000), and the corresponding age-specific probabilities of death. To allow for greater variation in the age-adjustment weights and age-specific probabilities, a second set of simulations draws those at random, while holding the mean number of deaths at 20 or 10. Finally, county-level mortality data by race/ethnicity from four causes are selected to capture even greater variation: all causes, external causes, congenital malformations, and Alzheimer disease. RESULTS: The three modifications had comparable performance when the number of deaths was large relative to the denominator and the age distribution was as in the standard population. However, for sparse county-level data by race/ethnicity for rarer causes of death, and for which the age distribution differed sharply from the standard population, coverage probability in all but the Fay-Feuer method sometimes fell below 0.95. More efficient intervals than the Fay-Feuer interval were identified under specific circumstances. When the coefficient of variation of the age-adjustment weights was below 0.5, the Anderson-Rosenberg and Tiwari intervals appeared to be more efficient, whereas when it was above 0.5, the Fay-Kim interval appeared to be more efficient. CONCLUSIONS: As national and international agencies reassess prevailing data presentation standards to release age-adjusted estimates for smaller areas or population subgroups than previously presented, the Fay-Feuer interval can be used to develop interval-based statistical reliability standards with appropriate thresholds that are generally applicable. For data that meet certain statistical conditions, more efficient intervals could be considered.

National Health Interview Survey, COVID-19, and Online Data Collection Platforms: Adaptations, Tradeoffs, and New Directions.

High-quality data are accurate, relevant, and timely. Large national health surveys have always balanced the implementation of these quality dimensions to meet the needs of diverse users. The COVID-19 pandemic shifted these balances, with both disrupted survey operations and a critical need for relevant and timely health data for decision-making. The National Health Interview Survey (NHIS) responded to these challenges with several operational changes to continue production in 2020. However, data files from the 2020 NHIS were not expected to be publicly available until fall 2021. To fill the gap, the National Center for Health Statistics (NCHS) turned to 2 online data collection platforms-the Census Bureau's Household Pulse Survey (HPS) and the NCHS Research and Development Survey (RANDS)-to collect COVID-19‒related data more quickly. This article describes the adaptations of NHIS and the use of HPS and RANDS during the pandemic in the context of the recently released Framework for Data Quality from the Federal Committee on Statistical Methodology. (Am J Public Health. 2021;111(12):2167-2175. https://doi.org/10.2105/AJPH.2021.306516).

Recruitment and retention in randomized controlled trials with urban American Indian/Alaska Native adolescents: Challenges and lessons learned.

BACKGROUND: Although the majority of American Indians/Alaska Natives reside in urban areas, there are very few randomized controlled trials analyzing culturally centered substance use prevention interventions for this population. METHODS: We describe methods employed to recruit and retain urban American Indian/Alaska Native adolescents into a randomized controlled trial, which was focused on testing the potential benefits of a substance use prevention intervention for this population. We also report challenges encountered in recruitment and retention of participants and strategies employed addressing these challenges. Data collection occurred from August 2014 to October 2017. RESULTS: We partnered with two community-based organizations in different cities in California. We utilized American Indian/Alaska Native recruiters from communities, placed flyers in community-based organizations, and asked organizations to post flyers on their web and social media sites. We also offered gift cards for participants. Our initial recruitment and retention model was moderately successful; however, we encountered five main challenges: (1) transportation, (2) increasing trust and interest, (3) adding research sites, (4) getting the word out about the project, and (5) getting youth to complete follow-up surveys. Strategies employed to overcome transportation challenges included shortening the number of sessions, offering sessions on both weekends and weekdays, and increasing bus tokens and transportation options. We hired more staff from American Indian/Alaska Native communities, added more research sites from our previously established relationships, and were more proactive in getting the word out on the project in American Indian/Alaska Native communities. We also utilized more field tracking and emailed and mailed survey invitations to reach more participants for their follow-up surveys. Because of our efforts, we were nearly able to reach our initial recruitment and retention goals. CONCLUSION: Although our research team had previously established relationships with various urban American Indian/Alaska Native communities, we encountered various recruitment and retention challenges in our study. However, by identifying challenges and employing culturally appropriate strategies, we were able to collect valuable data on the potential effectiveness of a substance use prevention intervention for urban American Indian/Alaska Native adolescents. Findings from this study assist toward the development of potentially successful strategies to successfully recruit and retain urban American Indian/Alaska Native adolescents in randomized controlled trials.

Factors associated with parents' experiences using a knowledge translation tool for vaccination pain management: a qualitative study.

BACKGROUND: Vaccination is a common painful procedure for children. Parents' concern regarding vaccination pain is a significant driver of vaccine hesitancy. Despite the wealth of evidence-based practices available for managing vaccination pain, parents lack knowledge of, and access to, these strategies. Knowledge translation (KT) tools can communicate evidence-based information to parents, however little is known about what factors influence parents' use of these tools. A two-page, electronic KT tool on psychological, physical, and pharmacological vaccination pain management strategies for children, was shared with parents as part of a larger mixed methods study, using explanatory sequential design, exploring factors related to uptake of this KT tool. The aim of this qualitative study was to understand what influenced parents' perceptions of the relevance of the KT tool, as well as their decision as to whether to use the tool. METHODS: A qualitative descriptive design was used. A total of 20 parents of children aged 0-17 years (n = 19 mothers) reviewed the KT tool ahead of their child's upcoming vaccination and participated in a semi-structured interview at follow-up. Interviews were recorded, transcribed verbatim, and analyzed with reflexive thematic analysis using an inductive approach. RESULTS: The analysis generated three interrelated themes which described factors related to parents' use of the KT tool: (1) Relevance to parents' needs and circumstances surrounding their child's vaccination; (2) Alignment with parents' personal values around, and experiences with, vaccination pain management (e.g., the importance of managing pain); and (3) Support from the clinical environment for implementing evidence-based strategies (e.g., physical clinical environment and quality of interactions with the health care provider). CONCLUSIONS: Several factors were identified as central to parents' use of the KT tool, including the information itself and the clinical environment. When the tool was perceived as relevant, aligned with parents' values, and was supported by health care providers, parents were more inclined to use the KT tool to manage their children's vaccination pain. Future research could explore other factors related to promoting engagement and uptake when creating parent-directed KT tools for a range of health-related contexts.

Psoriasiform dermatitis during dupilumab treatment for moderate-to-severe atopic dermatitis in children.

BACKGROUND/OBJECTIVES: Psoriasiform eruptions after initiation of dupilumab have been previously described in adults. This report details the risk of developing or unmasking psoriasiform eruptions after initiation of dupilumab in children. METHODS: Records of patients ≤18 years of age with atopic dermatitis who developed psoriasiform dermatitis during treatment with dupilumab were reviewed retrospectively. RESULTS: Six children, 4-18 years of age, on dupilumab for severe atopic dermatitis developed new-onset psoriasiform dermatitis at a median duration of 8 months (range, 6-12 months) after dupilumab initiation. Typical locations of psoriasis were involved (face, scalp, trunk, and extensor extremities). The majority showed clearance or near clearance with the use of medium-strength to potent topical corticosteroid ointments and 83% continued use of the dupilumab. A 7th patient had psoriasis, in addition to severe atopic dermatitis, and the psoriasis was unmasked by its failure to respond to dupilumab. CONCLUSION: Although unusual, psoriasiform lesions can appear during effective treatment with dupilumab for atopic dermatitis, potentially reflecting a shift toward cutaneous IL-23/TH 17 pathway activation with dupilumab-induced suppression of type 2 immunity.

Characterization of the microbiota and resistome of bulk tank milk samples from Prince Edward Island dairy farms.

Bulk tank milk (BTM) is regularly used for surveillance on dairy farms for disease conditions such as mastitis and Johne's disease. In this study, we used 16S rRNA sequencing and bait-capture enrichment to characterize the microbiota and resistome of BTM, and investigate potential differences between the cream or pellet fractions. A total of 12 BTM samples were taken from 12 Prince Edward Island dairy farms, in Atlantic Canada, in duplicates. The DNA was analyzed by high-throughput sequencing of the 16S rRNA gene and a suite of antimicrobial resistance (AMR) genes. Target-capture enrichment of AMR genes was conducted before shotgun sequencing. The bioinformatics pipelines QIIME 2 and AMR++ were used for microbiota and resistome analysis, respectively. Differences between microbiotae were evaluated qualitatively with nonmetric multidimensional scaling and quantitatively with permutational ANOVA of UniFrac distances. A total of 47 phyla were present across the BTM samples. Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria were the most abundant phyla. At the genus level, Corynebacterium, Acinetobacter, Lactobacillus, and Turicibacter were the most abundant. There was no significant difference in the Faith's phylogenetic diversity between the cream and pellet fraction. Faith's phylogenetic diversity differed marginally by stall type. There were 10,217 hits across 80 unique AMR genes, with tetracycline resistance being the most common class.

The effect on work presenteeism of job retention vocational rehabilitation compared to a written self-help work advice pack for employed people with inflammatory arthritis: protocol for a multi-centre randomised controlled trial (the WORKWELL trial).

BACKGROUND: Work problems are common in people with inflammatory arthritis. Up to 50% stop work within 10 years due to their condition and up to 67% report presenteeism (i.e. reduced work productivity), even amongst those with low disease activity. Job retention vocational rehabilitation (JRVR) may help prevent or postpone job loss and reduce presenteeism through work assessment, work-related rehabilitation and enabling job accommodations. This aims to create a better match between the person's abilities and their job demands. The objectives of the Workwell trial are to test the overall effectiveness and cost-effectiveness of JRVR (WORKWELL) provided by additionally trained National Health Service (NHS) occupational therapists compared to a control group who receive self-help information both in addition to usual care. METHODS: Based on the learning from a feasibility trial (the WORK-IA trial: ISRCTN76777720 ), the WORKWELL trial is a multi-centre, pragmatic, individually-randomised parallel group superiority trial, including economic evaluation, contextual factors analysis and process evaluation. Two hundred forty employed adults with rheumatoid arthritis, undifferentiated inflammatory arthritis or psoriatic arthritis (in secondary care), aged 18 years or older with work instability will be randomised to one of two groups: a self-help written work advice pack plus usual care (control intervention); or WORKWELL JRVR plus a self-help written work advice pack and usual care. WORKWELL will be delivered by occupational therapists provided with additional JRVR training from the research team. The primary outcome is presenteeism as measured using the Work Limitations Questionnaire-25. A comprehensive range of secondary outcomes of work, health, contextual factors and health resource use are included. Outcomes are measured at 6- and 12- months (with 12-months as the primary end-point). A multi-perspective within-trial cost-effectiveness analyses will also be conducted. DISCUSSION: This trial will contribute to the evidence base for provision of JRVR to people with inflammatory arthritis. If JRVR is found to be effective in enabling people to keep working, the findings will support decision-making about provision of JRVR by rheumatology teams, therapy services and healthcare commissioners, and providing evidence of the effectiveness of JRVR and the economic impact of its implementation. TRIAL REGISTRATION: Clinical Trials.Gov: NCT03942783 . Registered 08/05/2019 ( https://clinicaltrials.gov/ct2/show/NCT03942783 ); ISRCTN Registry: ISRCTN61762297 . Registered:13/05/2019 ( http://www.isrctn.com/ISRCTN61762297 ). Retrospectively registered.