Congenic hematopoietic stem cell transplantation promotes survival of heart allografts in murine models of acute and chronic rejection.

The ability to induce tolerance would be a major advance in the field of solid organ transplantation. Here, we investigated whether autologous (congenic) hematopoietic stem cell transplantation (HSCT) could promote tolerance to heart allografts in mice. In an acute rejection model, fully MHC-mismatched BALB/c hearts were heterotopically transplanted into C57BL/6 (CD45.2) mice. One week later, recipient mice were lethally irradiated and reconstituted with congenic B6 CD45.1 Lin-Sca1+ckit+ cells. Recipient mice received a 14-day course of rapamycin both to prevent rejection and to expand regulatory T cells (Tregs). Heart allografts in both untreated and rapamycin-treated recipients that did not undergo HSCT were rejected within 33 days (median survival time = 8 days for untreated recipients, median survival time = 32 days for rapamycin-treated recipients), whereas allografts in HSCT-treated recipients had a median survival time of 55 days (P < 0.001 vs. both untreated and rapamycin-treated recipients). Enhanced allograft survival following HSCT was associated with increased intragraft Foxp3+ Tregs, reduced intragraft B cells, and reduced serum donor-specific antibodies. In a chronic rejection model, Bm12 hearts were transplanted into C57BL/6 (CD45.2) mice, and congenic HSCT was performed two weeks following heart transplantation. HSCT led to enhanced survival of allografts (median survival time = 70 days vs. median survival time = 28 days in untreated recipients, P < 0.01). Increased allograft survival post-HSCT was associated with prevention of autoantibody development and absence of vasculopathy. These data support the concept that autologous HSCT can promote immune tolerance in the setting of allotransplantation. Further studies to optimize HSCT protocols should be performed before this procedure is adopted clinically.

Evaluation of a gene expression biomarker to identify operationally tolerant liver transplant recipients: the LITMUS trial.

LITMUS was a single-centre, Phase 2a study designed to investigate whether the gene biomarker FGL2/IFNG previously reported for the identification of tolerance in murine models could identify operationally tolerant liver transplant recipients. Multiplex RT-PCR was used to amplify eight immunoregulatory genes in peripheral blood mononuclear cells (PBMC) from 69 adult liver transplant recipients. Patients with PBMC FGL2/IFNG ≥ 1 and a normal liver biopsy underwent immunosuppression (IS) withdrawal. The primary end point was the development of operational tolerance. Secondary end points included correlation of tolerance with allograft gene expression and immune cell markers. Twenty-eight of 69 patients (38%) were positive for the PBMC tolerance biomarker and 23 proceeded to IS withdrawal. Nine of the 23 patients had abnormal baseline liver biopsies and were excluded. Of the 14 patients with normal biopsies, eight (57%) have achieved operational tolerance and are off IS (range 12-57 months). Additional studies revealed that all of the tolerant patients and only one non-tolerant patient had a liver gene ratio of FOXP3/IFNG ≥ 1 prior to IS withdrawal. Increased CD4+ T regulatory T cells were detected both in PBMC and livers of tolerant patients following IS withdrawal. Higher expression of SELE (gene for E-selectin) and lower expression of genes associated with inflammatory responses (GZMB, CIITA, UBD, LSP1, and CXCL9) were observed in the pre-withdrawal liver biopsies of tolerant patients by RNA sequencing. These results suggest that measurement of PBMC FGL2/IFNG may enrich for the identification of operationally tolerant liver transplant patients, especially when combined with intragraft measurement of FOXP3/IFNG. Clinical Trial Registration: ClinicalTrials.gov (LITMUS: NCT02541916).

Reframing How Early Pregnancy Loss Is Viewed in the Emergency Department.

Women experiencing early pregnancy loss frequently seek care in emergency departments or early pregnancy clinics. The existing qualitative literature on the experience of miscarriage has yet to address how to connect how these women perceive their care experience and the prevailing structures which may be at the root of why their experience continues to be challenging. This study aimed to look deeper into the sources of negative experiences of early pregnancy loss for insight into how to rethink where to make impactful changes to care. Phenomenologically informed interviews with 59 women revealed several points of tension in the framing of early pregnancy loss, including the view of miscarriage as common, of it as a medical versus emotional experience, and the assumptions around care needs. Our work suggests that these tensions need to be dismantled through more patient-centered approaches to patient-provider relationships, policies, models of care, and medical discourse.

Lumbosacral Spinal Imaging for Patients Presenting to the Emergency Department With Nontraumatic Low Back Pain.

BACKGROUND: Choosing Wisely Canada (CWC) guidelines recommend that in the absence of clinical indicators suggestive of serious underlying pathology, physicians should not order radiological imaging for patients presenting with nonspecific low back pain (LBP). OBJECTIVE: Our aim was to determine how many patients presenting to the emergency department (ED) with nontraumatic LBP had spinal imaging before and after the release of the CWC guideline. METHODS: We conducted a retrospective medical record review for patients aged 18-70 years presenting to an academic tertiary care ED with nontraumatic LBP from April 1, 2014 to March 31, 2015 (pre-guideline) and April 1, 2017 to March 31, 2018 (post-guideline). RESULTS: One-thousand and sixty (545 pre-guideline, 515 post-guideline) patients were included. Pre-guideline, 45 patients (8.3%) had spinal imaging compared to 39 (7.6%) post-guideline (Δ 0.7%; 95% confidence interval [CI] -2.6% to 4.0%). Of the 84 patients (7.9%) who had spinal imaging, 4 (8.9%) had pathologic findings pre-guideline compared to 11 patients (28.2%) post-guideline (Δ 19.3%; 95% CI 2.7% to 35.8%). CONCLUSIONS: CWC guidelines did not appear to alter the rate of imaging for patients presenting to the ED with nontraumatic LBP. Future clinical recommendations should consider active knowledge dissemination and education strategies to help facilitate guideline adoption.

Evaluation of the effectiveness of the Global Medical Student Partnership program in undergraduate medical education.

BACKGROUND: The Global Medical Student Partnership (GMSP) is a medical student-led international initiative to promote accessible global health learning. This study aims to evaluate the effectiveness of the GMSP program in meeting its learning objectives. METHODS: Canadian and international medical student pairs met online monthly (January-May 2018) to discuss global health-related medical cases. Students then reviewed cases with local GMSP peers and faculty experts. A mixed-methods study was performed to evaluate whether the objectives of the program had been achieved. 26 of 32 (81.3%) students completed a questionnaire, and 13 (40.6%) also participated in one-on-one semi-structured interviews. Descriptive statistics and thematic analysis were used to analyze students' perspectives on skill development through GMSP. RESULTS: GMSP students agreed or strongly agreed that international collaboration and communication skills were more important to them following program participation (92.3%, 92.3% respectively). Many expressed that after GMSP, they knew more about their healthcare system, practices abroad and how to solve complex health issues (92.3%, 84.6%, 61.5% respectively). Qualitative data showed GMSP improved students' communication and presentation skills, provided a foundation for international relationships, fostered appraisal of diverse health systems, and furthered students' understanding of health advocacy. CONCLUSIONS: Our findings demonstrate that GMSP met its original objectives by providing students with opportunities to engage in international collaborations and to further develop their skills in advocacy, communication, and health-systems research. This program may be an important addition to medical education as it makes use of technology and peer-to-peer exchange to enable global health learning.

CONTEXTE: Le Global Medical Student Partnership (GMSP) est une initiative d'envergure internationale menée par des étudiants en médecine qui vise à favoriser la formation en santé mondiale. La présente étude consiste à évaluer l'efficacité du programme GMSP pour atteindre ses objectifs d'apprentissage. MÉTHODOLOGIE: Des paires d'étudiants en médecine canadiens et étrangers se sont rencontrés en ligne tous les mois, entre janvier et mai 2018, pour discuter de situations cliniques en santé mondiale. Après la rencontre, ces situations cliniques ont été revues par des pairs locaux du programme GMSP et des experts du corps professoral. On a effectué une étude à devis mixte pour déterminer si les objectifs du programme avaient été atteints. 26 des 32 (81,3 %) étudiants ont répondu à un questionnaire et 13 (40,6 %) ont aussi pris part à des entrevues individuelles semi-dirigées. Des statistiques descriptives et une analyse thématique ont été utilisées analyser les perceptions des étudiants sur le développement d'habiletés par le programme GMSP. RÉSULTATS: Les étudiants participant au programme GMSP étaient d'accord ou très en accord pour dire que les habiletés à la collaboration internationale et à la communication étaient plus importantes à leurs yeux après la participation au programme (92.3%, 92,3%, respectivement). Bon nombre ont affirmé qu'après le programme GMSP, ils en connaissaient plus sur leur système de soins de santé, les pratiques à l'étranger et les façons de résoudre des problèmes de santé complexes (92,3 %, 84,6 %, 61,5 % respectivement). Des données qualitatives ont montré que le programme GMSP a amélioré les aptitudes à la communication et des techniques de présentation. Elles ont servi à établir des relations à l'international, à évaluer divers systèmes de soins de santé et à mieux comprendre la promotion de la santé et à militer en faveur de celle-ci. CONCLUSIONS: Nos résultats montrent que le programme GMSP a atteint ses objectifs de départ puisqu'il a donné aux étudiants des occasions de collaboration internationale et leur a permis de développer davantage leurs habiletés en matière de défense des droits, de communication, et de recherche sur les systèmes de soins de santé. Ce programme pourrait s'avérer un important complément à la formation médicale parce qu'il utilise la technologie et des échanges pairs-pairs pour l'apprentissage des enjeux de santé mondiaux.

The emergency department experience of patients with early pregnancy complications: A qualitative study.

OBJECTIVE: The purpose of this qualitative study was to explore the experiences and perceptions of care of women treated for early pregnancy complications in a Canadian emergency department (ED) and early pregnancy clinic (EPC). METHODS: We conducted a descriptive qualitative study to understand the perceptions, meanings, and perspectives of women of 18 years and older who presented to the ED or EPC of an urban, tertiary care hospital with early pregnancy complications or loss. Using a semi-structured interview guide, a 45- to 60-minute telephone interview was conducted by a trained qualitative interviewer at 4 to 6 weeks after the ED visit. All interviews were digitally recorded and transcribed verbatim for analysis. Data analysis occurred in conjunction with data collection in order to continuously monitor emerging themes and general areas for further exploration. Interviews were conducted until thematic saturation had occurred. RESULTS: Interviews were completed with 30 women between June and August 2018. Three key themes arose: disconnect of the ED's role in the provision of care, normalization of a chaotic healthcare experience, and finding connection through the institution's EPC. CONCLUSIONS: Perspectives of women with early pregnancy complications highlight the ways in which ED care often does not meet the expectations or needs of patients and their families. The emotional complexity of this medical situation is often overlooked by ED staff and can produce encounters that are distressing. However, negative experiences were often mitigated by follow-up care in the institution's EPC.

INTRODUCTION: L'étude qualitative portait sur l'expérience vécue par des femmes traitées pour des complications en début de grossesse dans un service des urgences (SU) au Canada ou dans une clinique spécialisée dans la prise en charge des troubles du début de la grossesse, ainsi que sur leur impression des soins reçus. MÉTHODE: Il s'agit d'une étude qualitative et descriptive visant à connaître l'impression que des femmes âgées de 18 ans et plus avaient des soins reçus dans un SU d'un centre hospitalier de soins tertiaires situé en milieu urbain pour des complications en début de grossesse ou un avortement, ou dans une clinique spécialisée en la matière; à cet élément s'ajoutent la portée de l'expérience vécue et le point de vue des participantes. Des entretiens téléphoniques semi-directifs, d'une durée de 45 à 60 minutes ont été effectués de 4 à 6 semaines après la consultation au SU, à l'aide d'un guide, par une personne ayant reçu une formation en recherche qualitative. Les entretiens ont tous été enregistrés sous forme numérique et transcrits textuellement aux fins d'analyse. La collecte de données ainsi que l'analyse des donnés se sont déroulées en parallèle afin de permettre un suivi continu de l'émergence de nouveaux thèmes ou d'éléments généraux nécessitant un examen approfondi. Les entretiens se sont poursuivis jusqu'à l'atteinte du point de saturation thématique. RÉSULTATS: Trente femmes ont participé à l'étude, entre juin et août 2018. Trois grands thèmes se sont dégagés des entretiens, soit le manque d'empathie du personnel au SU, la normalisation d'une prestation chaotique des soins de santé et, en revanche, le sentiment de compréhension ressenti à la clinique spécialisée, rattachée à l'établissement. CONCLUSIONS: Le point de vue des femmes ayant vécu des complications en début de grossesse met en lumière le fait que souvent la prestation des soins au SU ne répond pas aux besoins et aux attentes des patientes et de leur famille. La complexité de la charge émotive liée au problème médical est bien des fois négligée par le personnel au SU, ce qui peut donner lieu à des situations pénibles. Toutefois, l'expérience défavorable vécue par les femmes est souvent atténuée par le suivi assuré à la clinique spécialisée, rattachée à l'établissement.

Role of Regulatory T Cells (Treg) and the Treg Effector Molecule Fibrinogen-like Protein 2 in Alloimmunity and Autoimmunity.

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) are critical to the maintenance of immune tolerance. Treg are known to utilize a number of molecular pathways to control immune responses and maintain immune homeostasis. Fibrinogen-like protein 2 (FGL2) has been identified by a number of investigators as an important immunosuppressive effector of Treg, which exerts its immunoregulatory activity by binding to inhibitory FcγRIIB receptors expressed on antigen-presenting cells including dendritic cells, endothelial cells, and B cells. More recently, it has been suggested that FGL2 accounts for the immunosuppressive activity of a highly suppressive subset of Treg that express T cell immunoreceptor with Ig and ITIM domains (TIGIT). Here we discuss the important role of Treg and FGL2 in preventing alloimmune and autoimmune disease. The FGL2-FcγRIIB pathway is also known to be utilized by viruses and tumor cells to evade immune surveillance. Moving forward, therapies based on modulation of the FGL2-FcγRIIB pathway hold promise for the treatment of a wide variety of conditions ranging from autoimmunity to cancer.