Intramedullary brachytherapy for the treatment of long bone metastatic disease: A case report.

Case: A 56-year-old woman with metastatic melanoma and femoral lesions with impending pathologic fracture was indicated for intramedullary brachytherapy (IMBT) and intramedullary nail. Conclusions: IMBT + intramedullary nail is a new technique for the treatment of long bone metastases. IMBT maximizes radiation to the tumor and minimizes radiation to surrounding tissues. It allows the patient to resume systemic treatment expediently. Our cadaver model and patient were both treated for femoral metastases; however, this technique allows for the treatment of any long bone. This is a safe technique that minimizes treatment time compared with other standard radiation regimens.

A risk assessment study of SARS-CoV-2 propagation in the manufacturing of cellular products.

The potential infection of cellular therapies by SARS-CoV-2 present high risks, as the target patients for these treatments are often immunocompromised or have chronic diseases associated with a higher risk of serious illness and death by COVID-19. The multicellular tropism of this virus presents challenges for the manufacturing of cell therapies, whereby the material could potentially become infected at the source or during cell processing. In this review we assess the risk of a SARS-CoV-2 propagation in cell types used to date in cellular therapies. Altogether, the risk of SARS-CoV-2 contamination of cellular products remains low. This risk should be evaluated on an individual basis, considering ACE2 and TMPRSS2 expression, existing literature regarding the susceptibility to infection, and single cell RNA sequencing data of COVID-19 patients. This analysis should ideally be performed for both the cells being manufactured and the cells used to produce the vector to ensure patient safety.

Cell therapies are medicines based on the utilization of different cell types that are manufactured in special facilities. SARS-CoV-2, the virus that causes COVID-19, can infect a wide range of cell types. Patients requiring a cell therapy may be at higher risk of severe COVID-19 due to their underlying medical conditions. In this context, it is of importance to evaluate the risk of a SARS-CoV-2 contamination during the production of cell therapies to avoid possible infections. In this review, the authors assess the risk of an infection for cells being used as therapies to date and propose a systematic way to evaluate this risk.

Percutaneous screw fixation of the pubic symphysis versus plate osteosynthesis: a biomechanical study.

Objectives: To compare the stability of screw fixation with that of plate fixation for symphyseal injuries in a vertically unstable pelvic injury (AO/Tile 61-C1) associated with complete disruption of the sacroiliac joint and the pubic symphysis. Methods: Eight fourth-generation composite pelvis models with sacroiliac and pubic symphyseal disruption (Sawbones, Vashon Island, WA) underwent biomechanical testing simulating static single-leg stance. Four were fixed anteriorly with a symphyseal screw, and 4 with a symphyseal plate. All had single transsacral screw fixation posteriorly. Displacement and rotation were monitored at both sacroiliac joint and pubic symphysis. Results: There was no significant difference between the 2 groups for mean maximum force generated. There was no significant difference in net displacement at both sacroiliac joint and pubic symphysis. There was significantly less rotation but more displacement in the screw group in the Z-axis. The screw group showed increased stiffness compared with the plate group. Conclusions: This is the first biomechanical study to compare screw versus plate symphyseal fixation in a Tile C model. Our biomechanical model using anterior and posterior fixation demonstrates that symphyseal screws may be a viable alternative to classically described symphyseal plating.

Biomechanical Comparison of 4 Transsacral Fixation Constructs in a Type 61C, Zone II Pelvic Fracture Model.

OBJECTIVES: OTA/AO 61C pelvic ring injuries are vertically unstable because of complete sacral fractures combined with anterior ring injury. The objective of this study was to compare the biomechanical characteristics of 4 transsacral screw constructs for posterior pelvic ring fixation, including one that uses a novel fixation method with a pair of locked washers with interdigitating cams. METHODS: Type C pelvic ring disruptions were created on 16 synthetic pelvis models. Each pelvis was fixated with an S2 screw in addition to being allocated to 1 of 4 transsacral constructs through S1: (1) 8.0-mm screw, (2) 8.0-mm bolt, (3) 8.0-mm screw locked with a nut, and (4) 8.00-mm screw locked with a nut with the addition of interdigitating washers between the screw head and ilium on the near cortex, and ilium and nut on the far cortex. The anterior ring fractures were not stabilized. Each pelvis underwent 100,000 cycles at 250 N and was then loaded to failure using a unilateral stance testing model. The anterior and posterior osteotomy sites were instrumented with pairs of infrared (IR) light-emitting markers, and the relative displacement of the markers was monitored using a three-dimensional (3D) motion capture system. Displacement measurements at 25,000; 50,000; 75,000; and 100,000 cycles and failure force were recorded for each pelvis. RESULTS: The novel washer design construct performed better than the screw construct with less posterior ring motion at 75,000 ( P = 0.029) and 100,000 cycles ( P = 0.029). CONCLUSIONS: The novel interdigitating washer design may be superior to using a screw construct alone to achieve rigid, locked posterior ring fixation in a synthetic pelvis model with a Type C pelvic ring disruption.

A Prospective Observational Cohort Comparison of SARS-CoV-2 Seroprevalence Between Paramedics and Matched Blood Donors in Canada During the COVID-19 Pandemic.

STUDY OBJECTIVE: SARS-CoV-2 represents an occupational risk to paramedics, who work in uncontrolled environments. We sought to identify the occupation-specific risk to paramedics by comparing their seroprevalence of SARS-CoV-2 infection-specific antibodies to that of blood donors in Canada. METHODS: In this prospective cohort study, we performed serology testing (Elecsys Anti-SARS-CoV-2 nucleocapsid assay) on samples from paramedics and blood donors (January to July 2021) in Canada. Paramedic samples were compared to blood donor samples through 1:1-matched (based on age, sex, location, date of blood collection, and vaccination status) and raking weighted comparisons. We compared the seroprevalence with a risk difference (and 95% confidence interval [CI]) and performed secondary analyses within subgroups defined by vaccination status. RESULTS: The 1:1 match included 1,627 cases per group; in both groups, 723 (44%) were women, with a median age of 38. The raking weighted comparison included 1,713 paramedic samples and 19,515 blood donor samples, with similar characteristics. In the 1:1 match, the seroprevalence was similar (difference 1.2; 95% CI -0.20 to 2.7) between paramedics (5.2%) and blood donors (3.9%). The raking weighted comparison was consistent (difference 0.97; 95% CI -0.10 to 2.0). The unvaccinated paramedic samples, in comparison to the blood donor samples, demonstrated a higher seroprevalence in the 1:1 (difference 5.9; 95% CI 1.8 to 10) and weighted (difference 6.5; 95% CI 1.8 to 10) comparisons. Among vaccinated cases, the between-group seroprevalence was similar. CONCLUSION: Overall, paramedics demonstrated similar evidence of prior SARS-CoV-2 infection to that of blood donors. However, among unvaccinated individuals, evidence of prior infection was higher among paramedics compared to blood donors.

Pharmacists' views on the impact of the Falsified Medicines Directive on community pharmacies: A cross-sectional survey.

Background: The Falsified Medicines Directive (FMD) was implemented to minimise the circulation of falsified medicines in the legal pharmaceutical supply chain. Whilst pharmacists are involved in the final step of the FMD requirements with the decommissioning of medicines at the point of supply to patients, limited research has been conducted to investigate the impact of fulfilling these requirements on the relevant stakeholders. Objective: To examine community pharmacists' views on how the FMD has affected their practice. Methods: An online survey was disseminated via email in June 2020 to pharmacists in Ireland (n = 4727), who were invited to participate if practising full time or part time in community pharmacies. Quantitative data were captured through multiple option and Likert-scale questions, and analysed using descriptive and inferential statistics. Qualitative data were captured by use of a free-text box, with the open comments analysed thematically. Results: In total, 618 valid responses were received (13.1% response rate). Most perceived that FMD requirements increased waiting times for patients (82%) and reduced time interacting with patients (65%). Only 28% agreed/strongly agreed that the introduction of the FMD legislation improves patient safety. In the open comments, the need for medicine authentication was acknowledged, but it was believed that this should be the wholesalers' responsibility, not pharmacists' responsibility. The additional step of medicines decommissioning was viewed as a time-consuming distraction to clinical checks that increased the risk for error. Pharmacists complained that they were not remunerated for the lost staff productivity or the additional software and equipment costs. Many pharmacists felt that the increased workload was disproportionate to the small risk of patients receiving falsified medicines. Conclusions: Key stakeholder engagement is required to optimise the implementation and integration of the FMD procedures into community pharmacy practice with minimal impact on dispensing and without compromising patient care.

Low Risk of Wound Complications With Sinus Tarsi Approach for Treatment of Calcaneus Fractures.

BACKGROUND: Operative management displaced intra-articular calcaneus fractures is commonly associated with wound complications. Open reduction internal fixation is traditionally performed through the extensile lateral approach has relatively high rates of wound complications. The sinus tarsi approach to displaced intra-articular calcaneus fractures is a less invasive approach to achieve fracture reduction and fixation as well as reduce wound healing complications. The purpose of this study is to report the rates of wound complications associated with the sinus tarsi approach in the treatment of displaced intra-articular calcaneus fractures. METHODS: We retrospectively identified patients treated with a limited sinus tarsi approach for displaced intra-articular calcaneus fractures from January 2009 to December 2018. Demographic and radiographic data were collected including age, gender, mechanism of injury, occupation, presence of diabetes mellitus, smoking status, Sanders classification, Bohler and Gissane angles. Postoperatively, we recorded the presence of complications, return-to-work time, and radiographic measurements. RESULTS: One hundred and five fractures were identified in 100 patients who underwent open reduction internal fixation for displaced intra-articular calcaneus fractures. Using the Sanders computed tomographic classification, we identified 32% Type 2, 48% Type 3, 18% Type 4, and 2% tongue-type variants. For the preoperative Bohler's angle, 38% of fractures displayed a negative angle, 50% had an angle 0° to 20°, and 12% over 20°. Postoperatively, all patients demonstrated an improvement in Bohler's angle with 13% with 0° to 20° and 87% over 20°. Approximately, 72% of patients working prior to the injury had returned to work by 6 months, and 89% by 12 months. The wound complication rate was 11.9% (12/105), with 1.9% (2/105) requiring additional procedures. There was no significant difference in wound complication rates in smokers versus nonsmokers (11.9% vs 12.2%, p = .55). CONCLUSION: Operative management of displaced intra-articular calcaneus fractures through the sinus tarsi approach allows restoration of calcaneal height with a low rate of wound complications, even among active smokers.

Acute-Phase Reactants in Operatively Treated Upper Extremity Infections: A Retrospective Review.

Background: There are limited data on the use of acute-phase markers in the diagnosis of upper extremity infections. The goal of this study was to determine the percentage of patients with elevated white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) in the setting of an upper extremity infection requiring operative debridement. Methods: In a retrospective review over 12 years, 61 patients who met the inclusion criteria were identified. Results: C-reactive protein was the most sensitive test in the detection of culture-positive infection compared with ESR and WBC (P < .001, P < .0001, respectively). Ninety percent of patients (55 of 61) presented with an abnormal CRP value. The WBC count and ESR were abnormal in 54% and 67% of our cohort, respectively. Conclusions: C-reactive protein is the most sensitive laboratory test when evaluating upper extremity infections that necessitate debridement. The WBC count and ESR should be interpreted with caution and can be normal even in the presence of an infection.

Does Size Matter for Cephalomedullary Nails in Geriatric Intertrochanteric Fractures?

OBJECTIVES: To evaluate the need for reoperation of geriatric intertrochanteric hip fractures treated with 10-mm cephalomedullary nails versus those treated with nails larger than 10 mm. DESIGN: Retrospective review at a single institution. SETTING: Level I trauma center. PATIENTS/PARTICIPANTS: All patients age 60 and over treated with cephalomedullary fixation for an intertrochanteric femur fracture at a single institution. INTERVENTION: Cephalomedullary fixation with variable nail diameters. MAIN OUTCOME MEASUREMENTS: Reoperation rates of geriatric intertrochanteric fractures treated with a size 10-mm diameter cephalomedullary nail compared with patients treated with nails larger than 10 mm. RESULTS: There were no significant differences in reoperation rates when the 10-mm cohort was compared with an aggregate cohort of all nails larger than 10 mm (P = 0.99). This result was true for both all-cause reoperation and noninfectious reoperation. There was no difference between cohorts in regards to age, gender, or fracture pattern. CONCLUSIONS: A 10-mm cephalomedullary nail can be used in lieu of a larger diameter fixation in patients age 60 and older with intertrochanteric femur fractures while still maintaining a comparable rate of reoperation. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Discovery of Small-Molecule Selective mTORC1 Inhibitors via Direct Inhibition of Glucose Transporters.

The mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolic processes. Dysregulation of this kinase complex can result in a variety of human diseases. Rapamycin and its analogs target mTORC1 directly; however, chronic treatment in certain cell types and in vivo results in the inhibition of both mTORC1 and mTORC2. We have developed a high-throughput cell-based screen for the detection of phosphorylated forms of the mTORC1 (4E-BP1, S6K1) and mTORC2 (Akt) substrates and have identified and characterized a chemical scaffold that demonstrates a profile consistent with the selective inhibition of mTORC1. Stable isotope labeling of amino acids in cell culture-based proteomic target identification revealed that class I glucose transporters were the primary target for these compounds yielding potent inhibition of glucose uptake and, as a result, selective inhibition of mTORC1. The link between the glucose uptake and selective mTORC1 inhibition are discussed in the context of a yet-to-be discovered glucose sensor.

Developing and integrating nursing competence through authentic technology-enhanced clinical simulation education: Pedagogies for reconceptualising the theory-practice gap.

The aim of this review and discussion paper is to advance the debate on competence in nursing, simulation education, and literacy in simulation education pedagogy. Building on our previous patient-safety critical translational research work on drug dosage calculation-competence modelling, and safeMedicate® virtual learning and diagnostic assessment environment design, we introduce three new concepts. First, we re-conceptualise the cognitive and physical modalities of a theory-practice gap, created by the traditional organisation of health professional education practice. Second, that simulated clinical environments occupy the liminal spaces between the ordered, symbolic and abstract world of the classroom, and the situated, messy world of clinical healthcare practice. Third, technology-enhanced boundary objects (TEBOs) function as simulation pedagogy modalities that (a) support students' transition across the liminal space and boundaries between classroom and practice setting, and (b) support competence development and integration in nursing. We use a constructivist-based clinical simulation education model as a guiding pedagogical framework for applying TEBOs and an integrated nursing competence model. The e-version of the paper has embedded animation and illustrative video content to demonstrate these constructivist principles, using technology and computer animation to make complex education ideas accessible to experienced educators and clinicians, early-stage educators, and nursing and healthcare students.

Discovery of NV-5138, the first selective Brain mTORC1 activator.

The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full mTORC1 activation. The cytoplasmic proteins Sestrin1 and Sestrin2 specifically bind to the multiprotein complex GATOR2 and communicate leucine sufficiency to the mTORC1 pathway activation complex. Herein, we report NV-5138, a novel orally bioavailable compound that binds to Sestrin2 and activates mTORC1 both in vitro and in vivo. NV-5138 like leucine transiently activates mTORC1 in several peripheral tissues, but in contrast to leucine uniquely activates this complex in the brain due lack of metabolism and utilization in protein synthesis. As such, NV-5138 will permit the exploration in areas of unmet medical need including neuropsychiatric conditions and cognition which have been linked to the activation status of mTORC1.

The use of clade-specific PCR assays to identify novel nitrilase genes from environmental isolates.

Nitrilase enzymes (EC 3.5.5.1) are responsible for the direct hydration of nitriles to their corresponding carboxylic acids and ammonia. The utilization of nitrilase enzymes in biocatalysis toward bio-pharmaceuticals and industrial applications facilitates the move towards green chemistry. The body of research presented describes a novel clade-specific touchdown PCR protocol for the detection of novel nitrilase genes. The presented study identified partial sequences of 15 novel nitrilase genes across 7 genera, with partial DNA sequence homology (%) displayed across an additional 16 genera. This research will prove valuable in the screening of microorganisms for the identification of novel clade-specific nitrilase genes, with predicted enantioselective profiles as determined by their clade characterizations.

Potential for noninvasive assessment of lung inhomogeneity using highly precise, highly time-resolved measurements of gas exchange.

Inhomogeneity in the lung impairs gas exchange and can be an early marker of lung disease. We hypothesized that highly precise measurements of gas exchange contain sufficient information to quantify many aspects of the inhomogeneity noninvasively. Our aim was to explore whether one parameterization of lung inhomogeneity could both fit such data and provide reliable parameter estimates. A mathematical model of gas exchange in an inhomogeneous lung was developed, containing inhomogeneity parameters for compliance, vascular conductance, and dead space, all relative to lung volume. Inputs were respiratory flow, cardiac output, and the inspiratory and pulmonary arterial gas compositions. Outputs were expiratory and pulmonary venous gas compositions. All values were specified every 10 ms. Some parameters were set to physiologically plausible values. To estimate the remaining unknown parameters and inputs, the model was embedded within a nonlinear estimation routine to minimize the deviations between model and data for CO2, O2, and N2 flows during expiration. Three groups, each of six individuals, were studied: young (20-30 yr); old (70-80 yr); and patients with mild to moderate chronic obstructive pulmonary disease (COPD). Each participant undertook a 15-min measurement protocol six times. For all parameters reflecting inhomogeneity, highly significant differences were found between the three participant groups ( P < 0.001, ANOVA). Intraclass correlation coefficients were 0.96, 0.99, and 0.94 for the parameters reflecting inhomogeneity in deadspace, compliance, and vascular conductance, respectively. We conclude that, for the particular participants selected, highly repeatable estimates for parameters reflecting inhomogeneity could be obtained from noninvasive measurements of respiratory gas exchange. NEW & NOTEWORTHY This study describes a new method, based on highly precise measures of gas exchange, that quantifies three distributions that are intrinsic to the lung. These distributions represent three fundamentally different types of inhomogeneity that together give rise to ventilation-perfusion mismatch and result in impaired gas exchange. The measurement technique has potentially broad clinical applicability because it is simple for both patient and operator, it does not involve ionizing radiation, and it is completely noninvasive.

A mechanistic physicochemical model of carbon dioxide transport in blood.

A number of mathematical models have been produced that, given the Pco2 and Po2 of blood, will calculate the total concentrations for CO2 and O2 in blood. However, all these models contain at least some empirical features, and thus do not represent all of the underlying physicochemical processes in an entirely mechanistic manner. The aim of this study was to develop a physicochemical model of CO2 carriage by the blood to determine whether our understanding of the physical chemistry of the major chemical components of blood together with their interactions is sufficiently strong to predict the physiological properties of CO2 carriage by whole blood. Standard values are used for the ionic composition of the blood, the plasma albumin concentration, and the hemoglobin concentration. All Km values required for the model are taken from the literature. The distribution of bicarbonate, chloride, and H+ ions across the red blood cell membrane follows that of a Gibbs-Donnan equilibrium. The system of equations that results is solved numerically using constraints for mass balance and electroneutrality. The model reproduces the phenomena associated with CO2 carriage, including the magnitude of the Haldane effect, very well. The structural nature of the model allows various hypothetical scenarios to be explored. Here we examine the effects of 1) removing the ability of hemoglobin to form carbamino compounds; 2) allowing a degree of Cl- binding to deoxygenated hemoglobin; and 3) removing the chloride (Hamburger) shift. The insights gained could not have been obtained from empirical models. NEW & NOTEWORTHY: This study is the first to incorporate a mechanistic model of chloride-bicarbonate exchange between the erythrocyte and plasma into a full physicochemical model of the carriage of carbon dioxide in blood. The mechanistic nature of the model allowed a theoretical study of the quantitative significance for carbon dioxide transport of carbamino compound formation; the putative binding of chloride to deoxygenated hemoglobin, and the chloride (Hamburger) shift.

In-airway molecular flow sensing: A new technology for continuous, noninvasive monitoring of oxygen consumption in critical care.

There are no satisfactory methods for monitoring oxygen consumption in critical care. To address this, we adapted laser absorption spectroscopy to provide measurements of O2, CO2, and water vapor within the airway every 10 ms. The analyzer is integrated within a novel respiratory flow meter that is an order of magnitude more precise than other flow meters. Such precision, coupled with the accurate alignment of gas concentrations with respiratory flow, makes possible the determination of O2 consumption by direct integration over time of the product of O2 concentration and flow. The precision is illustrated by integrating the balance gas (N2 plus Ar) flow and showing that this exchange was near zero. Measured O2 consumption changed by <5% between air and O2 breathing. Clinical capability was illustrated by recording O2 consumption during an aortic aneurysm repair. This device now makes easy, accurate, and noninvasive measurement of O2 consumption for intubated patients in critical care possible.

The day we started HPV triage.

AIMS: Following the introduction of the triage test in cervical screening, which was designed to identify a subgroup who were at risk of underlying high-grade cervical intraepithelial neoplasia (CIN), there has been a significant change in the number and profile of cervical biopsies. In this study, analysis of the progressive change in diagnostic categories has been performed to identify the impact of the triage test on the service. METHODS: Cases referred for colposcopy, with corresponding subsequent tissue diagnoses, were identified by electronic search of the histopathology accession database using suitable coding terms for the period between October and April of four consecutive years. A likelihood ratio test was devised to assess the significance of the observed progressive increase in total numbers of cervical biopsies. RESULTS: As anticipated from the pilot studies, implementation of the new guidelines led to a significant increase in the number of women referred for colposcopy. However, the annual increase was greater than expected. During this period, there was a change in the profile of histological diagnoses, characterised by: conspicuous rise in the number of cervical biopsies reported as 'human papillomavirus change only' or 'CIN1' (21-29% and 12-21%, of the total cervical biopsies, respectively); fall in mean CIN scores. CONCLUSIONS: The change in guidelines has led to an increase in patients referred for colposcopy; in turn this has led to an increase in number of specimens (particularly those with lower grades of dysplasia) submitted for histological assessment. This change of workload profile has implications for resourcing services for colposcopy and histopathology.

A cross-sectional study of the prevalence and associations of iron deficiency in a cohort of patients with chronic obstructive pulmonary disease.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Iron deficiency, with or without anaemia, is associated with other chronic conditions, such as congestive heart failure, where it predicts a worse outcome. However, the prevalence of iron deficiency in COPD is unknown. This observational study aimed to determine the prevalence of iron deficiency in COPD and associations with differences in clinical phenotype. SETTING: University hospital outpatient clinic. PARTICIPANTS: 113 adult patients (65% male) with COPD diagnosed according to GOLD criteria (forced expiratory volume in 1 s (FEV1): forced vital capacity (FVC) ratio <0·70 and FEV1 <80% predicted); with age-matched and sex-matched control group consisting of 57 healthy individuals. MAIN OUTCOME MEASURES: Prevalence of iron deficiency, defined as: any one or more of (1) soluble transferrin receptor >28.1 nmol/L; (2) transferrin saturation <16% and (3) ferritin <12 µg/L. Severity of hypoxaemia, including resting peripheral arterial oxygen saturation (SpO2) and nocturnal oximetry; C reactive protein (CRP); FEV1; self-reported exacerbation rate and Shuttle Walk Test performance. RESULTS: Iron deficiency was more common in patients with COPD (18%) compared with controls (5%). In the COPD cohort, CRP was higher in patients with iron deficiency (median 10.5 vs 4.0 mg/L, p<0.001), who were also more hypoxaemic than their iron-replete counterparts (median resting SpO2 92% vs 95%, p<0.001), but haemoglobin concentration did not differ. Patients with iron deficiency had more self-reported exacerbations and a trend towards worse exercise tolerance. CONCLUSIONS: Non-anaemic iron deficiency is common in COPD and appears to be driven by inflammation. Iron deficiency associates with hypoxaemia, an excess of exacerbations and, possibly, worse exercise tolerance, all markers of poor prognosis. Given that it has been shown to be beneficial in other chronic diseases, intravenous iron therapy should be explored as a novel therapeutic option in COPD.

Human graft-derived mesenchymal stromal cells potently suppress alloreactive T-cell responses.

After organ transplantation, recipient T cells contribute to graft rejection. Mesenchymal stromal cells from the bone marrow (BM-MSCs) are known to suppress allogeneic T-cell responses, suggesting a possible clinical application of MSCs in organ transplantation. Human liver grafts harbor resident populations of MSCs (L-MSCs). We aimed to determine the immunosuppressive effects of these graft-derived MSCs on allogeneic T-cell responses and to compare these with the effects of BM-MSCs. BM-MSCs were harvested from aspirates and L-MSCs from liver graft perfusates. We cultured them for 21 days and compared their suppressive effects with the effects of BM-MSCs on allogeneic T-cell responses. Proliferation, cytotoxic degranulation, and interferon-gamma production of alloreactive T cells were more potently suppressed by L-MSCs than BM-MSCs. Suppression was mediated by both cell-cell contact and secreted factors. In addition, L-MSCs showed ex vivo a higher expression of PD-L1 than BM-MSCs, which was associated with inhibition of T-cell proliferation and cytotoxic degranulation in vitro. Blocking PD-L1 partly abrogated the inhibition of cytotoxic degranulation by L-MSCs. In addition, blocking indoleamine 2,3-dioxygenase partly abrogated the inhibitive effects of L-MSCs, but not BM-MSCs, on T-cell proliferation. In conclusion, liver graft-derived MSC suppression of allogeneic T-cell responses is stronger than BM-MSCs, which may be related to in situ priming and mobilization from the graft. These graft-derived MSCs may therefore be relevant in transplantation by promoting allohyporesponsiveness.