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Champlain BASE™ (Building Access to Specialists through eConsultation) is a web-based asynchronous electronic communication service that allows primary-care- practitioners (PCPs) to submit \"elective\" clinical questions to a specialist. For adults, PCPs have reported improved access and timeliness to specialist advice, averted face-to-face specialist referrals in up to 40% of cases and high provider satisfaction. To determine whether the expansion of eConsult to a pediatric setting would result in similar measures of improved healthcare system process and high provider acceptance reported in adults. Prospective observational cohort study. Single Canadian tertiary-care academic pediatric hospital (June 2014-16) servicing 1.2 million people. 1. PCPs already using eConsult. 2.Volunteer pediatric specialists provided services in addition to their regular workload. 3.Pediatric patients (< 18 years-old) referred for none-acute care conditions. Specialty service utilization and access, impact on PCP course-of-action and referral-patterns and survey-based provider satisfaction data were collected. 1064 eConsult requests from 367 PCPs were answered by 23 pediatric specialists representing 14 specialty-services. The top three specialties represented were: General Pediatrics 393 cases (36.9%), Orthopedics 162 (15.2%) and Psychiatry 123 (11.6%). Median specialist response time was 0.9 days (range <1 hour-27 days), most consults (63.2%) required <10minutes to complete and 21/21(100%) specialist survey-respondents reported minimal workload burden. For 515/1064(48.4%) referrals, PCPs received advice for a new or additional course of action; 391/1064(36.7%) referrals resulted in an averted face-to-face specialist visit. In 9 specialties with complete data, the median wait-time was significantly less (p<0.001) for an eConsult (1 day, 95%CI:0.9-1.2) compared with a face-to-face referral (132 days; 95%CI:127-136). The majority (>93.3%) of PCPs rated eConsult as very good/excellent value for both patients and themselves. All specialist survey-respondents indicated eConsult should be a continued service. Similar to adults, eConsult improves PCP access and timeliness to elective pediatric specialist advice and influences their care decisions, while reporting high end-user satisfaction. Further study is warranted to assess impact on resource utilization and clinical outcomes.

Acute lymphoblastic leukemia is the most common leukemia of childhood. It commonly presents with nonspecific symptoms, such as fatigue and irritability, along with symptoms secondary to bone marrow failure. In pediatric acute lymphoblastic leukemia, 48% of patients will have petechiae or purpura on presentation.1 Occasionally, leukemia can present directly in the skin and is referred to as leukemia cutis. Although leukemia cutis tends to present with other features of leukemia, it can occasionally precede the development of blast cells in the marrow and blood.1 The condition is then known as aleukemic leukemia cutis.1,2 Leukemia cutis is an infiltration of the skin by neoplastic leukocytes (myeloid or lymphoid), resulting in clinically identifiable cutaneous lesions.3 It is seen most commonly in congenital leukemia and acute myelogenous leukemia.3 In adults with acute myelogenous leukemia, leukemia cutis represents a higher tumour burden and tends to be predictive of a prolonged and less favourable course.4 These tendencies do not seem to be the case in congenital leukemia, where the presence of this rash does not alter the expected course.5 In the pediatric population, the frequency of leukemia cutis is higher in pediatric acute myelogenous leukemia (approximately 10%) than in pediatric acute lymphoblastic leukemia (1%).1,2 The clinical appearance of leukemia cutis is variable. The most common manifestation is described as erythematous or violaceous plaques, papules or nodules involving the face, trunk and extremities.4 Less common appearances include macules, maculopapules or plaques.4 In the setting of acute myelogenous leukemia, leukemia cutis presents as a firm nodule with a greenish hue, known as a chloroma or granulocytic sarcoma.1 In the neonate, leukemia cutis often presents as sites of extramedullary hematopoiesis in the skin, imparting a \"blueberry muffin\" appearance.5 In our patient, the appearance of leukemia cutis was typical.

Throughout the COVID-19 pandemic there has been a documented decline in reports to child protective services, despite an increased incidence of child maltreatment. This is concerning for increasing missed cases. This study aims to examine if and how Canadian paediatricians are identifying maltreatment in virtual medical appointments. A survey was sent through the Canadian Paediatric Surveillance Program (CPSP) to 2770 practicing general and subspecialty paediatricians. Data was collected November 2021 to January 2022. With a 34% (928/2770) response rate, 704 surveys were eligible for analysis. At least one case of child maltreatment was reported by 11% (78/700) of respondents following a virtual appointment. The number of cases reported was associated with years in medical practice (P = 0.026) but not with the volume (P = 0.735) or prior experience (P = 0.127) with virtual care, or perceived difficulty in identifying cases virtually (Cramer's V = 0.096). The most common factors triggering concern were the presence of social stressors, or a clear disclosure. The virtual physical exam was not contributory. Nearly one quarter (24%, 34/143) required a subsequent in-person appointment prior to reporting the case and 32% (207/648) reported concerns that a case had been identified late, or missed, following a virtual appointment. Some commented that clear harm resulted. Many barriers to detecting child maltreatment were identified by paediatricians who used virtual care. This survey reveals that virtual care may be an important factor in missed cases of child maltreatment and may present challenges to timely identification.

Socioeconomic status (SES), often conceptualized as income, education, or occupation, is associated with risk for disease morbidity and psychopathology. Recent research has focused on the potential biological mechanisms linking lower SES and poor outcomes; much of this work has examined the relationship between SES and markers of systemic inflammation. The strength of the estimated association between SES and inflammatory markers varies widely across individual studies. Thus, we used meta-analytic techniques to quantify the magnitude of this relationship. To accomplish this, PubMed and PsycINFO were searched for papers that reported on SES and two commonly measured systemic inflammatory markers, C-reactive protein (CRP) and interleukin-6 (IL-6). Peer-reviewed, empirical papers conducted in non-patient populations were included. Data from 43 papers (N = 111,156) reporting a total of 63 relevant effect sizes were included in analyses. SES, broadly defined, was significantly associated with both levels of CRP (Z = 0.12; 95% CI, 0.09–0.16) and IL-6 (Z = 0.15; 95% CI, 0.12–0.18); individuals with lower SES showed higher levels of systemic inflammation. Subanalyses demonstrated that studies operationalizing SES as either levels of income or educational attainment also found significant associations with both CRP and IL-6. Moderator analyses revealed that effect sizes varied based on sample characteristics and analysis approaches. Lower SES is associated with significantly elevated levels of inflammatory markers of disease risk. Thus, pro-inflammatory pathways are likely an important mechanism translating socioeconomic inequalities into mental and physical health disparities.

ObjectiveAntibiotic use is associated with an increased risk of developing multiple inflammatory disorders, which in turn are linked to alterations in the intestinal microbiota. How these alterations in the intestinal microbiota translate into an increased risk for inflammatory responses is largely unknown. Here we investigated whether and how antibiotics promote inflammation via the translocation of live native gut commensal bacteria.DesignOral antibiotics were given to wildtype and induced mutant mouse strains, and the effects on bacterial translocation, inflammatory responses and the susceptibility to colitis were evaluated. The sources of the bacteria and the pathways required for bacterial translocation were evaluated using induced mutant mouse strains, 16s rRNA sequencing to characterise the microbial communities, and in vivo and ex vivo imaging techniques.ResultsOral antibiotics induced the translocation of live native commensal bacteria across the colonic epithelium, promoting inflammatory responses, and predisposing to increased disease in response to coincident injury. Bacterial translocation resulted from decreased microbial signals delivered to colonic goblet cells (GCs), was associated with the formation of colonic GC-associated antigen passages, was abolished when GCs were depleted and required CX3CR1+ dendritic cells. Bacterial translocation occurred following a single dose of most antibiotics tested, and the predisposition for increased inflammation was only associated with antibiotics inducing bacterial translocation.ConclusionsThese findings reveal an unexpected outcome of antibiotic therapy and suggest that bacterial translocation as a result of alterations in the intestinal microflora may provide a link between increasing antibiotic use and the increased incidence of inflammatory disorders.

Goblet cells in the small intestine act as passages delivering small antigens to tolerance-inducing dendritic cells in the lamina propria. Striking an immunological balance in the small intestine How the balance between tolerance and immunity is maintained is an important question in immunology, and is of particular relevance to the small intestine, where innocuous antigens from the diet and potential pathogens are encountered simultaneously. McDole et al . show that goblet cells in the epithelium of the small intestine act as conduits through which small luminal antigens can be delivered to tolerance-inducing dendritic cells in the lamina propria, a layer of connective tissue beneath the epithelium. Through this mechanism, goblet cells could play a key part in promoting intestinal immune homeostasis. The intestinal immune system is exposed to a mixture of foreign antigens from diet, commensal flora and potential pathogens. Understanding how pathogen-specific immunity is elicited while avoiding inappropriate responses to the background of innocuous antigens is essential for understanding and treating intestinal infections and inflammatory diseases. The ingestion of protein antigen can induce oral tolerance, which is mediated in part by a subset of intestinal dendritic cells (DCs) that promote the development of regulatory T cells 1 . The lamina propria (LP) underlies the expansive single-cell absorptive villous epithelium and contains a large population of DCs (CD11c + CD11b + MHCII + cells) comprised of two predominant subsets: CD103 + CX 3 CR1 − DCs, which promote IgA production, imprint gut homing on lymphocytes and induce the development of regulatory T cells 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , and CD103 − CX 3 CR1 + DCs (with features of macrophages), which promote tumour necrosis factor-α (TNF-α) production, colitis, and the development of T H 17 T cells 5 , 6 , 7 , 10 . However, the mechanisms by which different intestinal LP-DC subsets capture luminal antigens in vivo remains largely unexplored. Using a minimally disruptive in vivo imaging approach we show that in the steady state, small intestine goblet cells (GCs) function as passages delivering low molecular weight soluble antigens from the intestinal lumen to underlying CD103 + LP-DCs. The preferential delivery of antigens to DCs with tolerogenic properties implies a key role for this GC function in intestinal immune homeostasis.

Intestinal goblet cells maintain the protective epithelial barrier through mucus secretion and yet sample lumenal substances for immune processing through formation of goblet cell associated antigen passages (GAPs). The cellular biology of GAPs and how these divergent processes are balanced and regulated by goblet cells remains unknown. Using high-resolution light and electron microscopy, we found that in mice, GAPs were formed by an acetylcholine (ACh)-dependent endocytic event remarkable for delivery of fluid-phase cargo retrograde into the trans-golgi network and across the cell by transcytosis – in addition to the expected transport of fluid-phase cargo by endosomes to multi-vesicular bodies and lysosomes. While ACh also induced goblet cells to secrete mucins, ACh-induced GAP formation and mucin secretion were functionally independent and mediated by different receptors and signaling pathways, enabling goblet cells to differentially regulate these processes to accommodate the dynamically changing demands of the mucosal environment for barrier maintenance and sampling of lumenal substances. Cells in the gut need to be protected against the many harmful microbes which inhabit this environment. Yet the immune system also needs to ‘keep an eye’ on intestinal contents to maintain tolerance to innocuous substances, such as those from the diet. The ‘goblet cells’ that are part of the gut lining do both: they create a mucus barrier that stops germs from invading the body, but they also can pass on molecules from the intestine to immune cells deep in the tissue to promote tolerance. This is achieved through a ‘GAP’ mechanism. A chemical messenger called acetylcholine can trigger both mucus release and the GAP process in goblet cells. Gustafsson et al. investigated how the cells could take on these two seemingly opposing roles in response to the same signal. A fluorescent molecule was introduced into the intestines of mice, and monitored as it pass through the goblet cells. This revealed how the GAP process took place: the cells were able to capture molecules from the intestines, wrap them in internal sack-like vesicles and then transport them across the entire cell. To explore the role of acetylcholine, Gustafsson et al. blocked the receptors that detect the messenger at the surface of goblet cells. Different receptors and therefore different cascades of molecular events were found to control mucus secretion and GAP formation; this explains how the two processes can be performed in parallel and independently from each other. Understanding how cells relay molecules to the immune system is relevant to other tissues in contact with the environment, such as the eyes, the airways, or the inside of the genital and urinary tracts. Understanding, and then ultimately harnessing this mechanism could help design of new ways to deliver drugs to the immune system and alter immune outcomes.

Tolerance to innocuous antigens from the diet and the commensal microbiota is a fundamental process essential to health. Why tolerance is efficiently induced to substances arising from the hostile environment of the gut lumen is incompletely understood but may be related to how these antigens are encountered by the immune system. We observed that goblet cell associated antigen passages (GAPs), but not other pathways of luminal antigen capture, correlated with the acquisition of luminal substances by lamina propria (LP) antigen presenting cells (APCs) and with the sites of tolerance induction to luminal antigens. Strikingly this role extended beyond antigen delivery. The GAP function of goblet cells facilitated maintenance of pre-existing LP T regulatory cells (Tregs), imprinting LP-dendritic cells with tolerogenic properties, and facilitating LP macrophages to produce the immunomodulatory cytokine IL-10. Moreover, tolerance to dietary antigen was impaired in the absence of GAPs. Thus, by delivering luminal antigens, maintaining pre-existing LP Tregs, and imprinting tolerogenic properties on LP-APCs GAPs support tolerance to substances encountered in the hostile environment of the gut lumen.

Atopic disorders including allergic rhinitis, asthma, food allergy, and dermatitis, are increasingly prevalent in Western societies. These disorders are largely characterized by T helper type 2 (Th2) immune responses to environmental triggers, particularly inhaled and dietary allergens. Exposure to such stimuli during early childhood reduces the frequency of allergies in at-risk children. These allergic responses can be restrained by regulatory T cells (Tregs), particularly Tregs arising in the gut. The unique attributes of how early life exposure to diet and microbes shape the intestinal Treg population is a topic of significant interest. While imprinting during early life promotes the development of a balanced immune system and protects against immunopathology, it remains unclear if Tregs that develop in early life continue to restrain systemic inflammatory responses throughout adulthood. Here, an inducible deletion strategy was used to label Tregs at specified time points with a targeted mechanism to be deleted later. Deletion of the Tregs labeled peri-weaning at day of life 24, but not before weaning at day of life 14, resulted in increased circulating IgE and IL-13, and abrogated induction of tolerance towards new antigens. Thus, Tregs developing peri-weaning, but not before day of life 14 are continually required to restrain allergic responses into adulthood.