Life underneath the VCA umbrella: Perspectives from the US Uterus Transplant Consortium

The parallel emergence of uterus transplantation (UTx) and other transplantation innovations including face and hand transplantation led to the categorization of the uterus as a vascular composite allograft (VCA). With >60 transplants and >20 births worldwide, UTx is transitioning rapidly from a research endeavor to an effective treatment option for women with uterine factor infertility. While it originally made sense to group the innovations under one umbrella, it is time to revisit the designation of UTx as a VCA. We describe how UTx needs unique policy, procedural codes, insurance contracts, and educational initiatives. We contend that separating UTx from VCAs may become necessary in the future to avoid hindering the growth and regulation of this field.     

Observations on the arterial baroreflex in neurally mediated vasodepressor syncope

The arterial baroreflex was studied in subjects who had recently had an episode of vasodepressor syncope. This was determined using 2–3 mcg/kg intravenous boluses of phenylephrine and assessing the bradycardic response. The values were measured in ms/mmHg and expressed as the angular coefficient of the regression line between the increase in R—R interval on the electrocardiograph and the systolic arterial pressure. In subjects examined immediately after the vasodepressor syncope episode the bradycardic response was much more marked than in controls (p < 0.01) and in the subjects themselves 6 months after the episode, provided that they were symptom-free (p < 0.01). It is concluded that in vasodepressor syncope there is a phase in which the baroreflex is highly sensitive and that this is due not to a lowering of the stimulation threshold but to a gain in the efferent arc, which explains a vagotonic response.     

Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant

BackgroundDiffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.MethodsImmunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.ResultsGD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.ConclusionOur study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.     

Chimeric antigen receptor-modified human regulatory T cells that constitutively express IL-10 maintain their phenotype and are potently suppressive

Clinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA-A2 CAR-Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL-10) and an imaging reporter as additional payloads. Cells were engineered to express combinations of these domains and assessed for phenotype and function. Cells expressing the full construct maintained a stable phenotype after transduction, were specifically activated by HLA-A2, and suppressed alloresponses potently. The addition of IL-10 provided an additional advantage to suppressive capacity. This study therefore provides an important proof-of-principle for this cell engineering approach for next-generation Treg therapy in transplantation.     

Influence of Oxynitrided Surface in the Production of a Less Susceptible Titanium Surface to Skin‐Borne Bacterial Adhesion

There is a growing quest for an ideal biomaterial that shows appropriate cellular response and is not susceptible to microbial adhesion. In this study, commercial grade II titanium was submitted to RF/DC plasma surface modification at 2.2 mbar, using gas mixtures of argon, nitrogen, and oxygen at proportions 4:1:2 and 4:1:3. The surfaces were physically and chemically characterized. In order to evaluate bacterial response, the surfaces were exposed to Staphylococcus epidermidis. Oxynitrided samples, although having a higher roughness as compared with untreated samples, exhibited lower bacterial growth. This observation is probably due to the formation of different crystalline phases of nitrides and oxides caused by plasma treatment. The surface with highest contact angle and highest surface tension showed lower bacterial adhesion. These results were confirmed by scanning electron microscopy. The role of nitrogen in reducing bacterial adhesion is clear when this material is compared with untreated titanium, on which only an oxide film is present.     

Influence of transmurality, infarct size, and severe microvascular obstruction on left ventricular remodeling and function after primary coronary angioplasty

Infarct size has been considered an established marker of left ventricular (LV) remodeling. We assessed the predictive value of myocardial/microvascular injury assessed by delayed enhanced magnetic resonance imaging (MRI) on LV remodeling and LV ejection fraction after primary coronary intervention (PCI) compared with peak troponin levels, an established index of myocardial infarct size. We performed MRI in 76 patients with first acute myocardial infarction 6 +/- 2 days after successful PCI. Necrosis was judged as transmural when delayed enhancement was extended to >or=75% of LV segment thickness. Severe microvascular obstruction was identified as areas of late hypoenhancement surrounded by delayed enhancement. Infarct size was expressed as an index by dividing the total percentage of delayed enhancement involvement by the number of LV segments. LV end-diastolic volume index and function were quantified by 2-dimensional echocardiography at 6 +/- 1 months after acute myocardial infarction. Remodeling was evaluated as a change in LV end-diastolic volume index at follow-up compared with baseline. At univariate analyses, transmural necrosis, severe microvascular obstruction, infarct size, and troponin level were correlated directly with remodeling and inversely with LV function at follow-up (p <0.001). At multiple regression, only transmural necrosis and troponin level remained independent predictors of LV remodeling and function. With respect to troponin, transmural necrosis improved the predictive power of LV remodeling (R2 for change = 0.19) and function (R2 for change = 0.16). In conclusion, in patients with acute myocardial infarction undergoing PCI, the amount of transmural necrosis as assessed by MRI is a major determinant of LV remodeling and function, with significant additional predictive value to infarct size and severe microvascular obstruction.     

Chronic Chagas' disease in rhesus monkeys (Macaca mulatta): evaluation of parasitemia,serology, electrocardiography,echocardiography, and radiology

Severe chronic damage to the heart and gastrointestinal tract in patients with Chagas' disease are often observed 10-20 years after the acute phase. The course of long-lasting infection with the Colombian strain of Trypanosoma cruzi was studied in seven rhesus monkeys infected for 15-19 years. Subpatent parasitemia was detected in all studied animals, using hemoculture (two of seven), artificial xenodiagnosis (three of seven), and a polymerase chain reaction PCR (six of six). High titers of specific IgG antibody to T. cruzi persisted throughout the chronic phase of infection. Abnormal electrocardiographic (three of six) and echocardiographic (one of six) patterns detected in the T. cruzi-infected monkeys were possibly related to parasite-triggered myocardial damage. The results suggest that rhesus monkeys experimentally infected with T. cruzi, besides reproducing the acute phase of Chagas' disease, also develop chronic chagasic cardiomyopathy.     

Clinical predictors of remission and low disease activity in Latin American early rheumatoid arthritis: data from the GLADAR cohort

Objectives

To identify baseline predictors of remission and low disease activity (LDA) in early rheumatoid arthritis (RA) from the GLADAR (Grupo Latino Americano De estudio de la Artritis Reumatoide) cohort.

Methods

Patients with 1- and 2-year follow-up visits were included. Remission and LDA were defined by DAS28-ESR (< 2.6 and ≤ 3.2, respectively). Baseline predictors examined were gender, ethnicity, age at diagnosis, socioeconomic status, symptoms’ duration, DMARDs, RF, thrombocytosis, anemia, morning stiffness, DAS28-ESR (and its components), HAQ-DI, DMARDs and corticosteroid use, and Sharp-VDH score. Multivariable binary logistic regression models (excluding DAS28-ESR components to avoid over adjustment) were derived using a backward selection method (α-level set at 0.05).

Results

Four hundred ninety-eight patients were included. Remission and LDA/remission were met by 19.3% and 32.5% at the 1-year visit, respectively. For the 280 patients followed for 2 years, these outcomes were met by 24.3% and 38.9%, respectively. Predictors of remission at 1 year were a lower DAS28-ESR (OR 1.17; CI 1.07–1.27; p = 0.001) and HAQ-DI (OR 1.48; CI 1.04–2.10; p = 0.028). At 2 years, only DAS28-ESR (OR 1.40; CI 1.17–1.6; p < 0.001) was a predictor. Predictors of LDA/remission at 1 year were DAS28-ESR (OR 1.42; CI 1.26–1.61; p < 0.001), non-use of corticosteroid (OR 1.74; CI 1.11–2.44; p = 0.008), and male gender (OR 1.77; CI 1.2–2.63; p = 0.036). A lower baseline DAS28-ESR (OR 1.45; CI 1.23–1.70; p < 0.001) was the only predictor of LDA/remission at 2 years.

Conclusions

A lower disease activity consistently predicted remission and LDA/remission at 1 and 2 years of follow-up in early RA patients from the GLADAR cohort.

Klebsiella pneumoniae Bloodstream Infection: Epidemiology and Impact of Inappropriate Empirical Therapy

Multidrug resistance associated with extended-spectrum beta-lactamase (ESBL) and Klebsiella pneumoniae carbapenemase (KPC) among K. pneumoniae is endemic in southern Europe. We retrospectively analyzed the impact of resistance on the appropriateness of empirical therapy and treatment outcomes of K. pneumoniae bloodstream infections (BSIs) during a 2-year period at a 1420-bed tertiary-care teaching hospital in northern Italy. We identified 217 unique patient BSIs, including 92 (42%) KPC-positive, 49 (23%) ESBL-positive, and 1 (0.5%) metallo-beta-lactamase-positive isolates. Adequate empirical therapy was administered in 74% of infections caused by non-ESBL non-KPC strains, versus 33% of ESBL and 23% of KPC cases (p < 0.0001). To clarify the impact of resistance on BSI treatment outcomes, we compared several different models comprised of non-antibiotic treatment-related factors predictive of patients’ 30-day survival status. Acute Physiology and Chronic Health Evaluation (APACHE) II score determined at the time of positive blood culture was superior to other investigated models, correctly predicting survival status in 83% of the study cohort. In multivariate analysis accounting for APACHE II, receipt of inadequate empirical therapy was associated with nearly a twofold higher rate of death (adjusted hazard ratio 1.9, 95% confidence interval 1.1–3.4; p = 0.02). Multidrug-resistant K. pneumoniae accounted for two-thirds of all K. pneumoniae BSIs, high rates of inappropriate empirical therapy, and twofold higher rates of patient death irrespective of underlying illness.     

A pilot study of capsule endoscopy after a standard meal for the detection and grading of oesophageal varices in cirrhotic patients

Background

Capsule endoscopy has been proposed as an alternative to fibreoptic endoscopy for oesophageal varices evaluation in cirrhotics. However, it shows only moderate sensitivity compared to fibreoptic endoscopy.

Aim

To compare post-meal capsule endoscopy to fibreoptic endoscopy, based on the hypothesis that meal-induced increase of portal pressure can enhance its sensitivity.

Methods

Twenty-five patients were submitted to fibreoptic endoscopy and, after a standard meal, capsule endoscopy.

Results

Post-meal capsule endoscopy detected varices in the 18 patients in whom fibreoptic endoscopy detected varices plus 3 more subjects (sensitivity 100%, specificity 70%); large varices in the 4 patients in whom fibreoptic endoscopy graded varices as large, plus 5 more subjects; red markers in the 5 patients in whom fibreoptic endoscopy detected red markers, plus 3 more subjects. High-risk varices were identified in 11 patients by post-meal capsule endoscopy and in 10 by fibreoptic endoscopy (sensitivity 100%, specificity 93.8%).

Conclusions

Post-meal capsule endoscopy identified more varices, large varices and red markers than fibreoptic endoscopy. The two methods detected similar proportions of high-risk varices. These data suggest that a standard meal can enhance the sensitivity of capsule endoscopy in the detection and grading of oesophageal varices in cirrhotics.