Post-Hoc Analysis of a Randomized, Double Blind, Prospective Study at the University of Chicago: Additional Standardizations of Trial Protocol are Needed to Evaluate the Effect of a CXCR1/2 Inhibitor in Islet Allotransplantation.

A recent randomized, multicenter trial did not show benefit of a CXCR1/2 receptor inhibitor (Reparixin) when analysis included marginal islet mass (>3,000 IEQ/kg) for allotransplantation and when immunosuppression regimens were not standardized among participating centers. We present a post-hoc analysis of trial patients from our center at the University of Chicago who received an islet mass of over 5,000 IEQ/kg and a standardized immunosuppression regimen of anti-thymocyte globulin (ATG) for induction. Twelve islet allotransplantation (ITx) recipients were randomized (2:1) to receive Reparixin (N = 8) or placebo (N = 4) in accordance with the multicenter trial protocol. Pancreas and donor characteristics did not differ between Reparixin and placebo groups. Five (62.5%) patients who received Reparixin, compared to none in the placebo group, achieved insulin independence after only one islet infusion and remained insulin-free for over 2 years (P = 0.08). Following the first ITx with ATG induction, distinct cytokine, chemokine, and miR-375 release profiles were observed for both the Reparixin and placebo groups. After excluding procedures with complications, islet engraftment on post-operative day 75 after a single transplant was higher in the Reparixin group (n = 7) than in the placebo (n = 3) group (P = 0.03) when islet graft function was measured by the ratio of the area under the curve (AUC) for c-peptide to glucose in mixed meal tolerance test (MMTT). Additionally, the rate of engraftment was higher when determined via BETA-2 score instead of MMTT (P = 0.01). Our analysis suggests that Reparixin may have improved outcomes compared to placebo when sufficient islet mass is transplanted and when standardized immunosuppression with ATG is used for induction. However, further studies are warranted. Investigation of Reparixin and other novel agents under more standardized and optimized conditions would help exclude confounding factors and allow for a more definitive evaluation of their role in improving outcomes in islet transplantation. Clinical trial reg. no. NCT01817959, clinicaltrials.gov.

Pregnancy-induced humoral sensitization overrides T cell tolerance to fetus-matched allografts in mice.

Immunological tolerance to semiallogeneic fetuses is necessary to achieving successful first pregnancy and permitting subsequent pregnancies with the same father. Paradoxically, pregnancy is an important cause of sensitization, resulting in the accelerated rejection of offspring-matched allografts. The underlying basis for divergent outcomes following reencounter of the same alloantigens on transplanted organs versus fetuses in postpartum females is incompletely understood. Using a mouse model that allows concurrent tracking of endogenous fetus-specific T and B cell responses in a single recipient, we show that semiallogeneic pregnancies simultaneously induce fetus-specific T cell tolerance and humoral sensitization. Pregnancy-induced antibodies, but not B cells, impeded transplantation tolerance elicited by costimulation blockade to offspring-matched cardiac grafts. Remarkably, in B cell-deficient mice, allogeneic pregnancy enabled the spontaneous acceptance of fetus-matched allografts. The presence of pregnancy-sensitized B cells that cannot secrete antibodies at the time of heart transplantation was sufficient to precipitate rejection and override pregnancy-established T cell tolerance. Thus, while induction of memory B cells and alloantibodies by pregnancies establishes formidable barriers to transplant success for multigravid women, our observations raise the possibility that humoral desensitization will not only improve transplantation outcomes, but also reveal an unexpected propensity of multiparous recipients to achieve tolerance to offspring-matched allografts.

How Should Shared Decision Making Be Taught?

As the field of medicine shifts from a paternalistic to a more patient-centered orientation, the dynamics of shared decision making become increasingly complicated. International globalization and national socioeconomic differences have added unintended difficulties to culturally sensitive communication between physician and patient, which can contribute to the growing erosion of clinician empathy. This article offers a strategy for teaching students how to enter into conversations about shared decision making by bolstering their empathy as a result of exposing them to the many variables outside of their patients' control. Patients' historical and cultural context, gender identity, sexual orientation, and common assumptions about clinicians as well as institutional biases can severely limit students' ability to integrate patients' value-laden preferences into shared decision making about health care.

A prospective, controlled clinical evaluation of surgical stabilization of severe rib fractures.

BACKGROUND: Previous studies of surgical stabilization of rib fractures (SSRF) have been limited by small sample sizes, retrospective methodology, and inclusion of only patients with flail chest. We performed a prospective, controlled evaluation of SSRF as compared with optimal medical management for severe rib fracture patterns among critically ill trauma patients. We hypothesized that SSRF improves acute outcomes. METHODS: We conducted a 2-year clinical evaluation of patients with any of the following rib fracture patterns: flail chest, three or more fractures with bicortical displacement, 30% or greater hemithorax volume loss, and either severe pain or respiratory failure despite optimal medical management. In the year 2013, all patients were managed nonoperatively. In the year 2014, all patients were managed operatively. Outcomes included respiratory failure, tracheostomy, pneumonia, ventilator days, tracheostomy, length of stay, daily maximum incentive spirometer volume, narcotic requirements, and mortality. Univariate and multivariable analyses were performed. RESULTS: Seventy patients were included, 35 in each group. For the operative group, time from injury to surgery was 2.4 day, operative time was 1.5 hours, and the ratio of ribs fixed to ribs fractured was 0.6. The operative group had a significantly higher RibScore (4 vs. 3, respectively, p < 0.01) and a significantly lower incidence of intracranial hemorrhage (5.7% vs. 28.6%, respectively, p = 0.01). After controlling for these differences, the operative group had a significantly lower likelihood of both respiratory failure (odds ratio, 0.24; 95% confidence interval, 0.06-0.93; p = 0.03) and tracheostomy (odds ratio, 0.18; 95% confidence interval, 0.04-0.78; p = 0.03). Duration of ventilation was significantly lower in the operative group (p < 0.01). The median daily spirometry value was 250 mL higher in the operative group (p = 0.04). Narcotic requirements were comparable between groups. There were no mortalities. CONCLUSION: In this evaluation, SSRF as compared with the best medical management improved acute outcomes among a group of critically ill trauma patients with a variety of severe fracture patterns. LEVEL OF EVIDENCE: Therapeutic study, level II.

Characterization of X-linked hypohidrotic ectodermal dysplasia (XL-HED) hair and sweat gland phenotypes using phototrichogram analysis and live confocal imaging.

Hypohidrotic ectodermal dysplasia (HED) is the most common type of ectodermal dysplasia (ED), which encompasses a large group of syndromes that share several phenotypic features such as missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. X-linked hypohidrotic ectodermal dysplasia (XL-HED) is associated with mutations in ectodysplasin (EDA1). Hypohidrosis due to hypoplastic sweat glands and thin, sparse hair are phenotypic features that significantly affect the daily lives of XL-HED individuals and therefore require systematic analysis. We sought to determine the quality of life of individuals with XL-HED and to quantify sweat duct and hair phenotypes using confocal imaging, pilocarpine iontophoresis, and phototrichogram analysis. Using these highly sensitive and non-invasive techniques, we demonstrated that 11/12 XL-HED individuals presented with a complete absence of sweat ducts and that none produced sweat. We determined that the thin hair phenotype observed in XL-HED was due to multiple factors, such as fewer terminal hairs with decreased thickness and slower growth rate, as well as fewer follicular units and fewer hairs per unit. The precise characterization of XL-HED phenotypes using sensitive and non-invasive techniques presented in our study will improve upon larger genotype-phenotype studies and the assessment of future therapies in XL-HED.