Knowledge, Attitudes, and Beliefs of Medical Students Toward Transgender Healthcare: A Community-Driven Initiative.

Introduction Transgender patients face substantial systemic healthcare barriers and inadequate care from providers who often demonstrate clinical gaps in the medical needs of the transgender community. Providing interventions in which affirming transgender healthcare is explored, is crucial to delivering competent transgender-patient care and building compassionate physician-patient relationships. The Northeast Pennsylvania (NEPA) Trans Health Conference was established to address the growing need for an educational forum where transgender people could voice their narratives. In this educational intervention study, changes in the knowledge, attitudes, and beliefs about the psychosocial and medical needs of the transgender community in first-year undergraduate medical students were examined pre- and post-trans health conference attendance. Materials and methods In the late spring of both 2018 and 2019, first-year medical students attended the NEPA Trans Health Conference, hosted by the Geisinger Commonwealth School of Medicine (GCSOM). Student knowledge, attitudes, and beliefs, regarding the healthcare needs of the transgender community were evaluated prior to and directly after the conference (intervention). Though the surveys shared thematic similarities, the 2018 and 2019 surveys were different and thus were not used comparatively. Results In 2018, 35.24% of first-year medical students (37/105 participants) completed both the pre- and post-survey. Overall, 62.5% (5/8) of survey items yielded significant differences. In 2019, 25.5%, of first-year medical students (28/110 participants) completed both the pre- and post-survey and 47.6% (9/21) of survey items yielded significant results. Overall, although the majority of first-year medical students displayed positive attitudes toward trans people pre-intervention, the students also demonstrated increased knowledge, empathy, and understanding of the transgender healthcare narrative post-intervention. Conclusion Providing medical students with a humanistic intervention within the medical curriculum that is focused on the transgender person, in addition to their past and present healthcare experiences, offers a bridge between academic content and providing inclusive gender-affirming healthcare to all patients.

The runaway kidney: a rare case of a parastomal hernia with partial kidney herniation.

Although parastomal hernias are a common complication of ostomy formation, herniation of intra-abdominal organs, aside from intestine, is infrequent. Furthermore, herniation of retroperitoneal organs, such as the kidney, is an extremely rare finding. We report the case of a 59-year-old male with a right ileostomy who presented with an acute kidney injury with suggestive urinary tract infection. A computed tomography scan revealed a left proximal ureteral stone with left hydronephrosis and a prominent right parastomal hernia with herniation of the mesenteric/retroperitoneal fat, portion of the right kidney, right proximal ureter and some bowel. The patient was taken to the operating room for a left cystourethroscopy with stent placement and made a full recovery. Due to the patient's extensive surgical history, high risk of postoperative infection and lack of evidence demonstrating functional impairment of the right kidney, surgical intervention was not recommended at the present time.

Breast Milk Enhances Growth of Enteroids: An Ex Vivo Model of Cell Proliferation.

Human small intestinal enteroids are derived from the crypts and when grown in a stem cell niche contain all of the epithelial cell types. The ability to establish human enteroid ex vivo culture systems are important to model intestinal pathophysiology and to study the particular cellular responses involved. In recent years, enteroids from mice and humans are being cultured, passaged, and banked away for future use in several laboratories across the world. This enteroid platform can be used to test the effects of various treatments and drugs and what effects are exerted on different cell types in the intestine. Here, a protocol for establishing primary stem cell-derived small intestinal enteroids derived from neonatal mice and premature human intestine is provided. Moreover, this enteroid culture system was utilized to test the effects of species-specific breast milk. Mouse breast milk can be obtained efficiently using a modified human breast pump and expressed mouse milk can then be used for further research experiments. We now demonstrate the effects of expressed mouse, human, and donor breast milk on the growth and proliferation of enteroids derived from neonatal mice or premature human small intestine.

IL-33 and the intestine: The good, the bad, and the inflammatory.

Interleukin-33 (IL-33) is a member of the IL-1 cytokine family that has been widely studied since its discovery in 2005 for its dichotomous functions in homeostasis and inflammation. IL-33, along with its receptor suppression of tumorigenicity 2 (ST2), has been shown to modulate both the innate and adaptive immune system. Originally, the IL-33/ST2 signaling axis was studied in the context of inducing type 2 immune responses with the expression of ST2 by T helper 2 (TH2) cells. However, the role of IL-33 is not limited to TH2 responses. Rather, IL-33 is a potent activator of TH1 cells, group 2 innate lymphoid cells (ILC2s), regulatory T (Treg) cells, and CD8+ T cells. The intestine is uniquely important in this discussion, as the intestinal epithelium is distinctively positioned to interact with both pathogens and the immune cells housed in the mucosa. In the intestine, IL-33 is expressed by the pericryptal fibroblasts and its expression is increased particularly in disease states. Moreover, IL-33/ST2 signaling aberrancy is implicated in the pathogenesis of inflammatory bowel disease (IBD). Accordingly, for this review, we will focus on the role of IL-33 in the regulation of intestinal immunity, involvement in intestinal disease, and implication in potential therapeutics.

The Role of Mucosal Immunity in the Pathogenesis of Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal disease of prematurity. Although the precise cause is not well understood, the main risk factors thought to contribute to NEC include prematurity, formula feeding, and bacterial colonization. Recent evidence suggests that NEC develops as a consequence of intestinal hyper-responsiveness to microbial ligands upon bacterial colonization in the preterm infant, initiating a cascade of aberrant signaling events, and a robust pro-inflammatory mucosal immune response. We now have a greater understanding of important mechanisms of disease pathogenesis, such as the role of cytokines, immunoglobulins, and immune cells in NEC. In this review, we will provide an overview of the mucosal immunity of the intestine and the relationship between components of the mucosal immune system involved in the pathogenesis of NEC, while highlighting recent advances in the field that have promise as potential therapeutic targets. First, we will describe the cellular components of the intestinal epithelium and mucosal immune system and their relationship to NEC. We will then discuss the relationship between the gut microbiota and cell signaling that underpins disease pathogenesis. We will conclude our discussion by highlighting notable therapeutic advancements in NEC that target the intestinal mucosal immunity.

Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner.

Enteroviruses are among the most common viral infectious agents of humans and are primarily transmitted by the fecal-oral route. However, the events associated with enterovirus infections of the human gastrointestinal tract remain largely unknown. Here, we used stem cell-derived enteroids from human small intestines to study enterovirus infections of the intestinal epithelium. We found that enteroids were susceptible to infection by diverse enteroviruses, including echovirus 11 (E11), coxsackievirus B (CVB), and enterovirus 71 (EV71), and that contrary to an immortalized intestinal cell line, enteroids induced antiviral and inflammatory signaling pathways in response to infection in a virus-specific manner. Furthermore, using the Notch inhibitor dibenzazepine (DBZ) to drive cellular differentiation into secretory cell lineages, we show that although goblet cells resist E11 infection, enteroendocrine cells are permissive, suggesting that enteroviruses infect specific cell populations in the human intestine. Taken together, our studies provide insights into enterovirus infections of the human intestine, which could lead to the identification of novel therapeutic targets and/or strategies to prevent or treat infections by these highly clinically relevant viruses.

Merkel cells are long-lived cells whose production is stimulated by skin injury.

Mechanosensitive Merkel cells are thought to have finite lifespans, but controversy surrounds the frequency of their replacement and which precursor cells maintain the population. We found by embryonic EdU administration that Merkel cells undergo terminal cell division in late embryogenesis and survive long into adulthood. We also found that new Merkel cells are produced infrequently during normal skin homeostasis and that their numbers do not change during natural or induced hair cycles. In contrast, live imaging and EdU experiments showed that mild mechanical injury produced by skin shaving dramatically increases Merkel cell production. We confirmed with genetic cell ablation and fate-mapping experiments that new touch dome Merkel cells in adult mice arise from touch dome keratinocytes. Together, these independent lines of evidence show that Merkel cells in adult mice are long-lived, are replaced rarely during normal adult skin homeostasis, and that their production can be induced by repeated shaving. These results have profound implications for understanding sensory neurobiology and human diseases such as Merkel cell carcinoma.

Ectopic Atoh1 expression drives Merkel cell production in embryonic, postnatal and adult mouse epidermis.

Merkel cells are mechanosensitive skin cells whose production requires the basic helix-loop-helix transcription factor Atoh1. We induced ectopic Atoh1 expression in the skin of transgenic mice to determine whether Atoh1 was sufficient to create additional Merkel cells. In embryos, ectopic Atoh1 expression drove ectopic expression of the Merkel cell marker keratin 8 (K8) throughout the epidermis. Epidermal Atoh1 induction in adolescent mice similarly drove widespread K8 expression in glabrous skin of the paws, but in the whisker pads and body skin ectopic K8+ cells were confined to hair follicles and absent from interfollicular regions. Ectopic K8+ cells acquired several characteristics of mature Merkel cells in a time frame similar to that seen during postnatal development of normal Merkel cells. Although ectopic K8+ cell numbers decreased over time, small numbers of these cells remained in deep regions of body skin hair follicles at 3 months post-induction. In adult mice, greater numbers of ectopic K8+ cells were created by Atoh1 induction during anagen versus telogen and following disruption of Notch signaling by conditional deletion of Rbpj in the epidermis. Our data demonstrate that Atoh1 expression is sufficient to produce new Merkel cells in the epidermis, that epidermal cell competency to respond to Atoh1 varies by skin location, developmental age and hair cycle stage, and that the Notch pathway plays a key role in limiting epidermal cell competency to respond to Atoh1 expression.

Unipotent, Atoh1+ progenitors maintain the Merkel cell population in embryonic and adult mice.

Resident progenitor cells in mammalian skin generate new cells as a part of tissue homeostasis. We sought to identify the progenitors of Merkel cells, a unique skin cell type that plays critical roles in mechanosensation. We found that some Atoh1-expressing cells in the hairy skin and whisker follicles are mitotically active at embryonic and postnatal ages. Genetic fate-mapping revealed that these Atoh1-expressing cells give rise solely to Merkel cells. Furthermore, selective ablation of Atoh1(+) skin cells in adult mice led to a permanent reduction in Merkel cell numbers, demonstrating that other stem cell populations are incapable of producing Merkel cells. These data identify a novel, unipotent progenitor population in the skin that gives rise to Merkel cells both during development and adulthood.