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Background: Disparities in school attendance exist for children with medical complexity (CMC) due to COVID-19. Longitudinal changes in family-reported school safety perceptions and predictors of full-time, in-person school attendance are unknown. Methods: This was a prospective, longitudinal cohort study with 3 survey waves (June 2021-June 2022) among English- and Spanish-speaking families of CMC aged 5 to 17 years and pre-pandemic school attendance. Changes in Health Belief Model perceptions and full-time in-person school attendance were estimated using multivariate generalized linear modeling with repeated measures. Results: Among 1601 respondents (52.9% of 3073 invited), 86.8% participated in all 3 surveys. School safety perceptions improved with time; however, perceived susceptibility to COVID-19 increased. Full-time in-person school attendance rose from 48.4% to 90.0% from wave 1 to 3 (p < 0.0001), and was associated with motivation, benefits, and cues. For example, families with low compared to high motivation for in-person attendance had 76% versus 98% predicted probability for child's school attendance, respectively at wave 3 (p < 0.0001). Implications for School Health Policy, Practice, and Equity: Probability of full-time in-person school attendance was associated with several health belief model perceptions. School health policy and programs may benefit from promoting family motivation, benefits, and cues during future respiratory illness epidemics including COVID-19. Conclusions: In-person school attendance improved for CMC over time. Opportunities exist to continue optimizing in-person attendance and family-perceived safety for CMC at school.

An overview of Applied Behavior Analysis (ABA) and Autism Spectrum Disorder (ASD) in the Middle East was published by Kelly and colleagues in 2016. The focus of the review was to explore clinical services, educational opportunities, and published research in the six countries of the Gulf Cooperation Council, namely the Kingdom of Bahrain, the State of Kuwait, the Sultanate of Oman, the State of Qatar, the Kingdom of Saudi Arabia, and the United Arab Emirates. The objective of the current paper was to provide an update on the current status of ABA and ASD in the Gulf region, with a focus on successes, challenges, and recommendations for future directions.

ObjectivesChildren with medical complexity experienced health disparities during the coronavirus disease 2019 (COVID-19) pandemic. Language may compound these disparities since people speaking languages other than English (LOE) also experienced worse COVID-19 outcomes. Our objective was to investigate associations between household language for children with medical complexity and caregiver COVID-19 vaccine intentions, testing knowledge, and trusted sources of information.MethodsThis cross-sectional survey of caregivers of children with medical complexity ages 5 to 17 years was conducted from April-June 2022. Children with medical complexity had at least 1 Complex Chronic Condition. Households were considered LOE if they reported speaking any language other than English. Multivariable logistic regression examined associations between LOE and COVID-19 vaccine intentions, interpretation of COVID-19 test results, and trusted sources of information.ResultsWe included 1,338 caregivers of children with medical complexity (49% response rate), of which 133 (10%) had household LOE (31 total languages, 58% being Spanish). There was no association between household LOE and caregiver COVID-19 vaccine intentions. Caregivers in households with LOE had similar interpretations of positive COVID-19 test results, but significantly different interpretations of negative results. Odds of interpreting a negative test as expected (meaning the child does not have COVID-19 now or can still get the virus from others) were lower in LOE households (aOR [95% CI]: 0.56 [0.34-0.95]). Households with LOE were more likely to report trusting the US government to provide COVID-19 information (aOR [95% CI]: 1.86 [1.24-2.81]).ConclusionDifferences in COVID-19 test interpretations based on household language for children with medical complexity were observed and could contribute to disparities in outcomes. Opportunities for more inclusive public health messaging likely exist.

Lag schedules increase operant variability. Several researchers have explored their clinical and educational applications, especially to address repetitive behavior or limited repertoires in individuals with autism spectrum disorder. In the current study, we provide the first comprehensive synthesis and appraisal of lag schedule research in humans. A multistep search strategy was employed to identify all experimental studies of lag schedules in humans published in peer-reviewed journals. We identified 38 studies that met inclusion criteria, summarized the study and participant characteristics, and evaluated evidential certainty. The results suggest that lag schedules are emerging as a promising applied behavioral technology for increasing operant variability, especially in individuals with autism spectrum disorder. We conclude with preliminary practice guidelines based on evidential certainty provided by the studies and identify future avenues of research.

BackgroundPatient portals are a health information technology that allows patients and their proxies, such as caregivers and family members, to access designated portions of their electronic health record using mobile devices and web browsers. The Open Notes initiative in the United States, which became federal law in April 2021, has redrawn and expanded the boundaries of medical records. Only a few studies have focused on sharing notes with parents or caregivers of pediatric patients. ObjectiveThis study aimed to investigate the anticipated impact of increasing the flow of electronic health record information, specifically physicians’ daily inpatient progress notes, via a patient portal to parents during their child’s acute hospital stay—an understudied population and an understudied setting. MethodsA total of 5 in-person focus groups were conducted with 34 stakeholders most likely impacted by sharing of physicians’ inpatient notes with parents of hospitalized children: hospital administrators, hospitalist physicians, interns and resident physicians, nurses, and the parents themselves. ResultsDistinct themes identified as benefits of pediatric inpatient Open Notes for parents emerged from all the 5 focus groups. These themes were communication, recapitulation and reinforcement, education, stress reduction, quality control, and improving family-provider relationships. Challenges identified included burden on provider, medical jargon, communication, sensitive content, and decreasing trust. ConclusionsProviding patients and, in the case of pediatrics, caregivers with access to medical records via patient portals increases the flow of information and, in turn, their ability to participate in the discourse of their care. Parents in this study demonstrated not only that they act as monitors and guardians of their children’s health but also that they are observers of the clinical processes taking place in the hospital and at their child’s bedside. This includes the clinical documentation process, from the creation of notes to the reading and sharing of the notes. Parents acknowledge not only the importance of notes in the clinicians’ workflow but also their collaboration with providers as part of the health care team.

Enzymatic inactivation of Rho-family GTPases by the glucosyltransferase domain of Clostridioides difficile Toxin B (TcdB) gives rise to various pathogenic effects in cells that are classically thought to be responsible for the disease symptoms associated with C. difficile infection (CDI). Recent in vitro studies have shown that TcdB can, under certain circumstances, induce cellular toxicities that are independent of glucosyltransferase (GT) activity, calling into question the precise role of GT activity. Here, to establish the importance of GT activity in CDI disease pathogenesis, we generated the first described mutant strain of C. difficile producing glucosyltransferase-defective (GT-defective) toxin. Using allelic exchange (AE) technology, we first deleted tcdA in C. difficile 630Δerm and subsequently introduced a deactivating D270N substitution in the GT domain of TcdB. To examine the role of GT activity in vivo, we tested each strain in two different animal models of CDI pathogenesis. In the non-lethal murine model of infection, the GT-defective mutant induced minimal pathology in host tissues as compared to the profound caecal inflammation seen in the wild-type and 630ΔermΔtcdA (ΔtcdA) strains. In the more sensitive hamster model of CDI, whereas hamsters in the wild-type or ΔtcdA groups succumbed to fulminant infection within 4 days, all hamsters infected with the GT-defective mutant survived the 10-day infection period without primary symptoms of CDI or evidence of caecal inflammation. These data demonstrate that GT activity is indispensable for disease pathogenesis and reaffirm its central role in disease and its importance as a therapeutic target for small-molecule inhibition.

Clostridioides difficile is an opportunistic gut pathogen which causes severe colitis, leading to significant morbidity and mortality due to its toxins, TcdA and TcdB. Two intra-muscular toxoid vaccines entered Phase III trials and strongly induced toxin-neutralising antibodies systemically but failed to provide local protection in the colon from primary C. difficile infection (CDI). Alternatively, by immunising orally, the ileum (main immune inductive site) can be directly targeted to confer protection in the large intestine. The gut commensal, non-toxigenic C. difficile (NTCD) was previously tested in animal models as an oral vaccine for natural delivery of an engineered toxin chimera to the small intestine and successfully induced toxin-neutralising antibodies. We investigated whether NTCD could be further exploited to induce antibodies that block the adherence of C. difficile to epithelial cells to target the first stage of pathogenesis. In NTCD strain T7, the colonisation factor, CD0873, and a domain of TcdB were overexpressed. Following oral immunisation of hamsters with spores of recombinant strain, T7-0873 or T7-TcdB, intestinal and systemic responses were investigated. Vaccination with T7-0873 successfully induced intestinal antibodies that significantly reduced adhesion of toxigenic C. difficile to Caco-2 cells, and these responses were mirrored in sera. Additional engineering of NTCD is now warranted to further develop this vaccine.

Despite the fact that autism is on the rise, there is paucity in the literature examining the treatment of autism in the Middle East and specifically the Gulf Cooperation Council (GCC). The current review investigates the past, present, and future status of interventions for autism based on Applied Behavior Analysis (ABA) in the six countries of the GCC, namely the Kingdom of Bahrain, the State of Kuwait, the Sultanate of Oman, the State of Qatar, the Kingdom of Saudi Arabia, and the United Arab Emirates. The aims of this paper were to provide a brief overview of autism and ABA clinical services and educational opportunities and to investigate the relevant research published from each of the six states of the GCC.

Abstract Background Social relationships, which are contingent on access to social networks, promote engagement in social activities and provide access to social support. These social factors have been shown to positively impact health outcomes. In the current systematic review, we offer a comprehensive overview of the impact of social activities, social networks and social support on the cognitive functioning of healthy older adults (50+) and examine the differential effects of aspects of social relationships on various cognitive domains. Methods We followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines, and collated data from randomised controlled trials (RCTs), genetic and observational studies. Independent variables of interest included subjective measures of social activities, social networks, and social support, and composite measures of social relationships (CMSR). The primary outcome of interest was cognitive function divided into domains of episodic memory, semantic memory, overall memory ability, working memory, verbal fluency, reasoning, attention, processing speed, visuospatial abilities, overall executive functioning and global cognition. Results Thirty-nine studies were included in the review; three RCTs, 34 observational studies, and two genetic studies. Evidence suggests a relationship between (1) social activity and global cognition and overall executive functioning, working memory, visuospatial abilities and processing speed but not episodic memory, verbal fluency, reasoning or attention; (2) social networks and global cognition but not episodic memory, attention or processing speed; (3) social support and global cognition and episodic memory but not attention or processing speed; and (4) CMSR and episodic memory and verbal fluency but not global cognition. Conclusions The results support prior conclusions that there is an association between social relationships and cognitive function but the exact nature of this association remains unclear. Implications of the findings are discussed and suggestions for future research provided. Systematic review registration PROSPERO 2012: CRD42012003248 .

Clostridioides difficile is the main cause of health-care-associated infectious diarrhoea. Toxins, TcdA and TcdB, secreted by this bacterium damage colonic epithelial cells and in severe cases this culminates in pseudomembranous colitis, toxic megacolon and death. Vaccines in human trials have focused exclusively on the parenteral administration of toxin-based formulations. These vaccines promote toxin-neutralising serum antibodies but fail to confer protection from infection in the gut. An effective route to immunise against gut pathogens and stimulate a protective mucosal antibody response (secretory immunoglobulin A, IgA) at the infection site is the oral route. Additionally, oral immunisation generates systemic antibodies (IgG). Using this route, two different antigens were tested in the hamster model: The colonisation factor CD0873 and a TcdB fragment. Animals immunised with CD0873 generated a significantly higher titre of sIgA in intestinal fluid and IgG in serum compared to naive animals, which significantly inhibited the adherence of C. difficile to Caco-2 cells. Following challenge with a hypervirulent isolate, the CD0873-immunised group showed a mean increase of 80% in time to experimental endpoint compared to naïve animals. Survival and body condition correlated with bacterial clearance and reduced pathology in the cecum. Our findings advocate CD0873 as a promising oral vaccine candidate against C. difficile.

Alcohol binge-drinking (acute ethanol consumption) is immunosuppressive and alters both the innate and adaptive arms of the immune system. Antigen presentation by macrophages (and other antigen presenting cells) represents an important function of the innate immune system that, in part, determines the outcome of the host immune response. Ethanol has been shown to suppress antigen presentation in antigen presenting cells though mechanisms of this impairment are not well understood. The constitutive and immunoproteasomes are important components of the cellular proteolytic machinery responsible for the initial steps critical to the generation of MHC Class I peptides for antigen presentation. In this study, we used an in-vitro cell culture model of acute alcohol exposure to study the effect of ethanol on the proteasome function in RAW 264.7 cells. Additionally, primary murine peritoneal macrophages obtained by peritoneal lavage from C57BL/6 mice were used to confirm our cell culture findings. We demonstrate that ethanol impairs proteasome function in peritoneal macrophages through suppression of chymotrypsin-like (Cht-L) proteasome activity as well as composition of the immunoproteasome subunit LMP7. Using primary murine peritoneal macrophages, we have further demonstrated that, ethanol-induced impairment of the proteasome function suppresses processing of antigenic proteins and peptides by the macrophage and in turn suppresses the presentation of these antigens to cells of adaptive immunity. The results of this study provide an important mechanism to explain the immunosuppressive effects of acute ethanol exposure.

Abstract Background In-home direct antigen rapid testing (DART) plays a major role in COVID-19 mitigation and policy. However, perceptions of DART within high-risk, intellectually impaired child populations are unknown. This lack of research could negatively influence DART uptake and utility among those who stand to benefit most from DART. The purpose of this study was to describe caregivers’ perceptions of an in-home COVID-19 DART regimen in children with medical complexity, including the benefits and limitations of DART use. Methods This qualitative study was a subproject of the NIH Rapid Acceleration of Diagnostics Underserved Populations research program at the University of Wisconsin. We combined survey data and the thematic analysis of semi-structured interview data to understand caregivers’ perceptions of in-home COVID-19 testing and motivators to perform testing. Caregivers of children with medical complexity were recruited from the Pediatric Complex Care Program at the University of Wisconsin (PCCP). Data were collected between May and August 2021. Results Among n = 20 caregivers, 16/20 (80%) of their children had neurologic conditions and 12/20 (60%) used home oxygen. Survey data revealed that the largest caregiver motivators to test their child were to get early treatment if positive (18/20 [90%] of respondents agreed) and to let the child’s school know if the child was safe to attend (17/20 [85%] agreed). Demotivators to testing included that the child could still get COVID-19 later (7/20 [35%] agreed), and the need for officials to reach out to close contacts (6/20 [30%] agreed). From interview data, four overarching themes described perceptions of in-home COVID-19 testing: Caregivers perceived DART on a spectrum of 1) benign to traumatic and 2) simple to complex. Caregivers varied in the 3) extent to which DART contributed to their peace of mind and 4) implications of test results for their child. Conclusions Although participants often described DART as easy to administer and contributing to peace of mind, they also faced critical challenges and limitations using DART. Future research should investigate how to minimize the complexity of DART within high-risk populations, while leveraging DART to facilitate safe school attendance for children with medical complexity and reduce caregiver burden.

Introduction Physicians enter residency with varied knowledge regarding the purpose of progress notes and proficiency writing them. The objective of this study was to test whether resident knowledge, beliefs, and confidence writing inpatient progress notes improved after a 2.5-hour workshop intervention. Methods An educational workshop and note assessment tool was constructed by resident and faculty stakeholders based on a review of literature and institutional best practices. The Progress Note Assessment and Plan Evaluation (PNAPE) tool was designed to assess adherence to best practices in the assessment and plan section of progress notes. Thirty-four residents from a midsized pediatric residency program attended the workshop, which consisted of didactics and small-group work evaluating sample notes using the PNAPE tool. Participants completed a four-question online pre- and postworkshop survey to evaluate their knowledge of progress note components and attitudes regarding note importance. Pre-post analysis was performed with Chi-square testing for true/false questions, and Mann-Whitney testing for Likert scale questions and summative scores. Results A majority of pediatric residents completed the preintervention (n = 26, 76% response rate) and postintervention (n = 23, 68% response rate) surveys. Accurate response rate improved in 15 of 20 of the true/false items, with a statistically significant improvement in five items. Resident perceptions of note importance and confidence in note writing also increased. Discussion A workshop intervention may effectively educate pediatric residents about progress note best practices. Further studies should assess the impact of the intervention on sustained knowledge and beliefs about progress notes and subsequent note quality.

Genomic imprinting results in parent-of-origin-dependent monoallelic gene expression. Early work showed that distal mouse chromosome 2 is imprinted, as maternal and paternal duplications of the region (with corresponding paternal and maternal deficiencies) give rise to different anomalous phenotypes with early postnatal lethalities. Newborns with maternal duplication (MatDp(dist2)) are long, thin and hypoactive whereas those with paternal duplication (PatDp(dist2)) are chunky, oedematous, and hyperactive. Here we focus on PatDp(dist2). Loss of expression of the maternally expressed Gnas transcript at the Gnas cluster has been thought to account for the PatDp(dist2) phenotype. But PatDp(dist2) also have two expressed doses of the paternally expressed Gnasxl transcript. Through the use of targeted mutations, we have generated PatDp(dist2) mice predicted to have 1 or 2 expressed doses of Gnasxl, and 0, 1 or 2 expressed doses of Gnas. We confirm that oedema is due to lack of expression of imprinted Gnas alone. We show that it is the combination of a double dose of Gnasxl, with no dose of imprinted Gnas, that gives rise to the characteristic hyperactive, chunky, oedematous, lethal PatDp(dist2) phenotype, which is also hypoglycaemic. However PatDp(dist2) mice in which the dosage of the Gnasxl and Gnas is balanced (either 2∶2 or 1∶1) are neither dysmorphic nor hyperactive, have normal glucose levels, and are fully viable. But PatDp(dist2) with biallelic expression of both Gnasxl and Gnas show a marked postnatal growth retardation. Our results show that most of the PatDp(dist2) phenotype is due to overexpression of Gnasxl combined with loss of expression of Gnas, and suggest that Gnasxl and Gnas may act antagonistically in a number of tissues and to cause a wide range of phenotypic effects. It can be concluded that monoallelic expression of both Gnasxl and Gnas is a requirement for normal postnatal growth and development.

Clostridium difficile is a major cause of healthcare-associated infection and inflicts a considerable financial burden on healthcare systems worldwide. Disease symptoms range from self-limiting diarrhoea to fatal pseudomembranous colitis. Whilst C. difficile has two major virulence factors, toxin A and B, it is generally accepted that other virulence components of the bacterium contribute to disease. C. difficile colonises the gut of humans and animals and hence the processes of adherence and colonisation are essential for disease onset. Previously it has been suggested that flagella might be implicated in colonisation. Here we tested this hypothesis by comparing flagellated parental strains to strains in which flagella genes were inactivated using ClosTron technology. Our focus was on a UK-outbreak, PCR-ribotype 027 (B1/NAP1) strain, R20291. We compared the flagellated wild-type to a mutant with a paralyzed flagellum and also to mutants (fliC, fliD and flgE) that no longer produce flagella in vitro and in vivo. Our results with R20291 provide the first strong evidence that by disabling the motor of the flagellum, the structural components of the flagellum rather than active motility, is needed for adherence and colonisation of the intestinal epithelium during infection. Comparison to published data on 630Δerm and our own data on that strain revealed major differences between the strains: the R20291 flagellar mutants adhered less than the parental strain in vitro, whereas we saw the opposite in 630Δerm. We also showed that flagella and motility are not needed for successful colonisation in vivo using strain 630Δerm. Finally we demonstrated that in strain R20291, flagella do play a role in colonisation and adherence and that there are striking differences between C. difficile strains. The latter emphasises the overriding need to characterize more than just one strain before drawing general conclusions concerning specific mechanisms of pathogenesis.

Upstream events that trigger initiation of cell division, at a point called START in yeast, determine the overall rates of cell proliferation. The identity and complete sequence of those events remain unknown. Previous studies relied mainly on cell size changes to identify systematically genes required for the timely completion of START. Here, we evaluated panels of non-essential single gene deletion strains for altered DNA content by flow cytometry. This analysis revealed that most gene deletions that altered cell cycle progression did not change cell size. Our results highlight a strong requirement for ribosomal biogenesis and protein synthesis for initiation of cell division. We also identified numerous factors that have not been previously implicated in cell cycle control mechanisms. We found that CBS, which catalyzes the synthesis of cystathionine from serine and homocysteine, advances START in two ways: by promoting cell growth, which requires CBS's catalytic activity, and by a separate function, which does not require CBS's catalytic activity. CBS defects cause disease in humans, and in animals CBS has vital, non-catalytic, unknown roles. Hence, our results may be relevant for human biology. Taken together, these findings significantly expand the range of factors required for the timely initiation of cell division. The systematic identification of non-essential regulators of cell division we describe will be a valuable resource for analysis of cell cycle progression in yeast and other organisms.