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Objective To determine the impact of an adherence packaging and medication synchronization program on hospital visits for older people living independently in the community. Design A retrospective pre-post study that evaluated patient outcomes over a 24-month period was conducted. Patient-specific socio-demographic, medical, and hospital visit-related data were collected for 12 months before and after patient enrollment in the adherence packaging program. Setting The study was conducted at Rx Partners LTC, LLC, a University of Pittsburgh Medical Center (UPMC) pharmacy in Pittsburgh, Pennsylvania. Participants Patients 65 years of age or older, of any gender, with UPMC Health Plan insurance coverage, who enrolled in the adherence packaging program between July 2019 and December 2019. Intervention Enrollment in the adherence packaging program included medication synchronization and packaging in prefilled medication sets delivered to the patient’s home monthly. Monthly medication reconciliation and review by clinical pharmacists was an included value-added service. Results Of the 92 patients included in the analysis, 60 had hospital visits during their pre-enrollment period for a total of 146 visits, compared with 54 patients in the postenrollment period totaling 126 visits; however, the mean rate of hospital visits was not statistically significant (1.59 versus 1.37; P = 0.48). Pharmacists prevented 1.87 medication errors/patient in the postenrollment setting. Conclusion Enrollment in the program was associated with fewer hospital visits, though not statistically significant, and pharmacists had abundant opportunity to prevent medication errors and optimize regimens. Further evaluation is warranted in a larger cohort.

Chronic lung allograft dysfunction is the major barrier to long-term survival in lung transplant recipients. Evidence supports type 1 alloimmunity as the predominant response in acute/chronic lung rejection, but the immunoregulatory mechanisms remain incompletely understood. We studied the combinatorial F-box E3 ligase system: F-box protein 3 (FBXO3; proinflammatory) and F-box and leucine-rich repeat protein 2 (FBXL2; anti-inflammatory and regulates TNFR-associated factor [TRAF] protein). Using the mouse orthotopic lung transplant model, we evaluated allografts from BALB/c → C57BL/6 (acute rejection; day 10) and found significant induction of FBXO3 and diminished FBXL2 protein along with elevated T-bet, IFN-γ, and TRAF proteins 1–5 compared with isografts. In the acute model, treatment with costimulation blockade (MR1/CTLA4-Ig) resulted in attenuated FBXO3, preserved FBXL2, and substantially reduced T-bet, IFN-γ, and TRAFs 1–5, consistent with a key role for type 1 alloimmunity. Immunohistochemistry revealed significant changes in the FBXO3/FBXL2 balance in airway epithelia and infiltrating mononuclear cells during rejection compared with isografts or costimulation blockade–treated allografts. In the chronic lung rejection model, DBA/2J/C57BL/6F1 > DBA/2J (day 28), we observed persistently elevated FBXO3/FBXL2 balance and T-bet/IFN-γ protein and similar findings from lung transplant recipient lungs with chronic lung allograft dysfunction versus controls. We hypothesized that FBXL2 regulated T-bet and found FBXL2 was sufficient to polyubiquitinate T-bet and coimmunoprecipitated with T-bet on pulldown experiments and vice versa in Jurkat cells. Transfection with FBXL2 diminished T-bet protein in a dose-dependent manner in mouse lung epithelial cells. In testing type 1 cytokines, TNF-α was found to negatively regulate FBXL2 protein and mRNA levels. Together, our findings show the combinatorial E3 ligase FBXO3/FBXL2 system plays a role in the regulation of T-bet through FBXL2, with negative cross-regulation of TNF-α on FBXL2 during lung allograft rejection.

Chronic lung allograft dysfunction (CLAD) is the major complication limiting long-term survival in lung transplant recipients (LTRs), with those developing donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) previously found to have increased risk for CLAD. However, as DSA responses vary in timing of development, specificity, breadth, persistence, and complement-binding capacity, we hypothesized that these characteristics would impact CLAD and survival outcomes.We retrospectively analyzed DSA characteristics and outcomes in a single-center cohort of 582 LTRs who had serum samples collected prospectively from 2010 to 2016. Luminex-based single antigen bead assays were performed to assess DSA.DSAs were detected in 247 LTRs (42%), of which 124 (21.3%) were de novo DSAs and 53 (9.1%) were complement-binding (C1q+). CLAD developed in 208 LTRs (35.7%) during the follow-up period, with 67.8% determined as bronchiolitis obliterans syndrome phenotype and 32.2% as restrictive allograft syndrome phenotype. We found a shorter time to CLAD in LTRs with persistent DSAs (p = 0.04) and HLA-DQ-specific DSAs (p = 0.03). LTRs who developed C1q+ DSAs had significantly shorter time to CLAD (p0.001), with 100% of C1q+ DSAs being persistent and no differences between CLAD phenotypes. CLAD-free survival was significantly reduced in LTRs who developed C1q+ DSAs (p = 0.001), HLA-DQ-specific DSAs (p = 0.03), and multiple DSAs (p = 0.02).Together, our findings demonstrate that DSA characteristics of persistence, HLA-DQ specificity, and C1q+ DSAs are associated with shorter time to CLAD. Additionally, C1q+, HLA-DQ-specific, and multiple DSAs are associated with decreased CLAD-free survival. These characteristics may improve DSA risk stratification for deleterious outcomes in LTRs.

Study objective Studies on the use of direct oral anticoagulants (DOACs) in obese patients are limited. Current guidelines advise against DOAC use in patients with a body weight more than 120 kg or body mass index higher than 40 kg/m2 . Therefore, the aim of this study was to evaluate the effectiveness and safety of DOACs versus warfarin for the treatment of acute venous thromboembolism (VTE) in obese patients. Design Retrospective matched cohort study. Setting Integrated delivery system of 40 academic, community, and specialty hospitals. Patients A total of 1840 adults with a primary admission diagnosis of acute VTE who received a DOAC (apixaban, dabigatran, or rivaroxaban [632 patients] or warfarin [1208 patients]) while hospitalized between January 1, 2011, and October 1, 2015, and who had a body weight more than 100 kg and less than 300 kg, were included. Patients in the warfarin group were matched in a 2:1 ratio to patients who received a DOAC based on history of VTE, chronic kidney disease, race, and age. Measurements and main results The primary outcome was recurrence of VTE within 12 months of the index admission date. Secondary outcomes included occurrence of pulmonary embolism (PE) and deep vein thrombosis (DVT) events separately within the study time frame, as well as bleeding within 12 months of the index admission date. No significant difference in the recurrence of VTE was observed between patients who received a DOAC compared with those who received warfarin (6.5% vs 6.4%, p=0.93). Likewise, no significant differences in the occurrence of PE and DVT were seen between the DOAC- and warfarin-treated patients (3.7% vs 3.8%, p=0.94, and 3% vs 3.5%, p=0.56, respectively). Bleeding occurred in 1.7% and 1.2% of patients in the DOAC and warfarin groups, respectively (p=0.31). Conclusion To our knowledge, this is the largest clinical study to date showing that patients with obesity can be treated effectively and safely with a DOAC compared with warfarin for acute VTE. Thus DOACs should be considered a reasonable alternative to warfarin for treatment of acute VTE in obese patients.

RATIONALE: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. OBJECTIVES: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. METHODS: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. MEASUREMENTS AND MAIN RESULTS: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4(+) lymphopenia predominated, with lower CD4(+)/CD8(+) ratios in severe COVID-19 compared with patients with mild disease (P < 0.0001). In severe disease, immunodominant CD4(+) T-cell responses to Spike-1 (S1) produced increased in vitro TNF-alpha (tumor necrosis factor-alpha) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4(+) TNF-alpha(+) T-cell responses inversely correlated with absolute CD4(+) counts from patients with severe COVID-19 (n = 76; R = - 0.797; P < 0.0001). In vitro TNF-alpha blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4 (+) T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFKB signaling in S1-stimulated CD4(+) cells with infliximab treatment. We also evaluated BAL and lung explant CD4(+) T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-alpha compared with peripheral blood mononuclear cells. CONCLUSIONS: Together, our findings show CD4(+) dysfunction in severe COVID-19 is TNF-alpha/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-alpha blockade may be beneficial in severe COVID-19.

Although the incidence of bronchial dehiscence following lung transplantation has decreased significantly due to improvements in perioperative managements and surgical techniques, it remains a devastating postoperative complication associated with high morbidity and mortality.We retrospectively reviewed 811 lung transplantation performed at our institution between January 2011 and December 2020. Bronchial dehiscence was confirmed with flexible bronchoscopy, computed tomography (CT) scan, or clinical findings grade using International Society for Heart and Lung Transplantation recommendations.Bronchial dehiscence was diagnosed in 38 patients (4.7%). The overall survival rates of the patients with bronchial dehiscence were significantly worse than those of the patients without bronchial dehiscence (p = .003). Multivariate analysis identified use of our basiliximab induction protocol (odds ratio = 3.03, p = .008) as an independent predictive factor of postoperative airway dehiscence in our multivariable model, along with total ventilator duration (odds ratio = 1.02, p = .002).Based on our analysis, patients that underwent our basiliximab induction protocol for lung transplantation experienced a higher rate of postoperative bronchial dehiscence when compared with patients who receive alemtuzumab induction. We believe this may be associated with a higher steroid exposure in this population. Additional studies are necessary to further characterize the relationship between different induction protocols and bronchial dehiscence following transplantation.

Alveolar macrophages (AM) play critical roles in lung tissue homeostasis, host defense, and modulating lung injury. The rate of AM turnover (donor AM replacement by circulating monocytes) after transplantation has been incompletely characterized. Furthermore, the anatomic pattern of recipient-derived lung macrophages repopulation has not been reported, nor has their ability to accumulate and present donor major histocompatibility complex (a process we refer to as MHC cross-decoration). We longitudinally characterized the myeloid content of bronchoalveolar lavage (BAL) and biopsy specimens of lung transplant recipients and found a biphasic rate in AM turnover in the allograft, with a rapid turnover perioperatively, accelerated by both the type of induction immunosuppression and the presence of primary graft dysfunction. We found that recipient myeloid cells with cell surface AM phenotype repopulated the lung in a disorganized pattern, comprised mainly of large clusters of cells. Finally, we show that recipient AM take up and present donor peptide-MHC complexes yet are not able to independently induce an in vitro alloreactive response by circulating recipient T cells.

Lymphopenia is common in severe COVID-19 disease, yet the mechanisms are poorly understood. In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared to recovered, mild disease (p+ T cell responses to Spike-1(S1) produced increased in vitro TNF-α, but impaired proliferation and increased susceptibility to activation-induced cell death (AICD). CD4+TNF-α+ T cell responses inversely correlated with absolute CD4+ counts from severe COVID-19 patients (n=76; R=-0.744, P+ proliferation and abrogated S1-AICD in severe COVID-19 patients (P+ cells with infliximab treatment. Lung CD4+ T cells in severe COVID-19 were reduced and produced higher TNF-α versus PBMC. Together, our findings show COVID-19-associated CD4+ lymphopenia and dysfunction is autocrine TNF-α/TNFRI-dependent and therapies targeting TNF-α may be beneficial in severe COVID-19.One Sentence SummaryAutocrine TNF-α/TNFRI regulates CD4+ T cell lymphopenia and dysfunction in severe COVID-19 disease.

Chronic lung allograft dysfunction (CLAD) remains the major complication limiting long-term survival among lung transplant recipients (LTRs). Limited understanding of CLAD immunopathogenesis and a paucity of biomarkers remain substantial barriers for earlier detection and therapeutic interventions for CLAD. We hypothesized the airway transcriptome would reflect key immunologic changes in disease. We compared airway brush-derived transcriptomic signatures in CLAD (n =24) versus non-CLAD (n=21) LTRs. A targeted assessment of the proteome using concomitant bronchoalveolar lavage (BAL) fluid for 24 cytokines/chemokines and alloimmune T cell responses was performed to validate the airway transcriptome. We observed an airway transcriptomic signature of differential genes expressed (DGEs) in CLAD marked by Type-1 immunity and striking upregulation of two endogenous immune regulators: indoleamine 2, 3 dioxygenase 1 (IDO-1) and tumor necrosis factor receptor superfamily 6B (TNFRSF6B). Advanced CLAD staging was associated with a more intense airway transcriptome signature. In a validation cohort using the identified signature, we found an area under the curve (AUC) of 0.77 for CLAD LTRs. Targeted proteomic analyses revealed a predominant Type-1 profile with detection of IFN-γ, TNF-α, and IL-1β as dominant CLAD cytokines, correlating with the airway transcriptome. The airway transcriptome provides novel insights into CLAD immunopathogenesis and biomarkers that may impact diagnosis of CLAD.

Objective. To design, integrate the curriculum for, and evaluate an innovative program to facilitate placement of students into postgraduate pharmacy residency training programs involving direct patient care. Methods. The Pharmacotherapy Scholars Program (PSP) was designed to prepare fourth-professional year students to become highly proficient in a direct patient care role and to successfully match with postgraduate residency training programs. The following elements were included in the year-long curriculum: integrated synchronous advanced pharmacy practice experiences with personal advising, team-based mentoring, peer-to-peer learning, longitudinal research, and professional development. Program goals were modeled after the accreditation standards for postgraduate year one (PGY1) pharmacy residency programs. Program faculty members ensured that the PSP had a broad scope, included rigorous student assessments, had a strong research focus, and provided scholarship opportunities. Results. Sixty-eight students completed the program from fall 2013 through spring 2019. The overall residency match rate was 93%. Students' performance on both knowledge and clinical skills assessments significantly improved after completing the program. There was an approximately 15% increase in knowledge and a 30% improvement in clinical skills based on comprehensive readiness assessments and an intermittent clinical examination that used patient simulation, respectively. Conclusion. The Pharmacotherapy Scholars Program is an innovative training program designed to enhance PharmD students' preparation for advanced clinical training. Students who completed the PSP achieved a high PGY1 residency placement rate while demonstrating significant improvements in pharmacotherapy knowledge and clinical skills in direct patient care activities.

Purpose Lung transplant recipients (LTRs) are at an increased risk for venous thromboembolism (VTE) after transplant, necessitating the use of anticoagulation. Guidelines recommend direct oral anticoagulants (DOACs) over warfarin for most patients and indications; however, many of the studies upon which these recommendations were made excluded high-risk patient populations, including transplant recipients. The purpose of this study was to compare rates of new or recurrent VTE and bleeding in patients receiving DOAC versus warfarin after lung transplant. Methods This retrospective cohort study was approved by the local institutional review board. Adult lung transplant recipients transplanted at a single center from 2010 - 2018 who received an oral anticoagulant for treatment of VTE were included. Re-transplants, patients with a diagnosis of atrial fibrillation/flutter, and those taking oral anticoagulation prior to transplant were excluded. The primary outcome was new or recurrent VTE within 1 year of starting oral anticoagulation, as determined by review of radiology reports. Safety was evaluated by assessment of 1-year rate of bleeding requiring emergency department visit or admission. Propensity matching in a 1:1 ratio using was used to control for confounders. Variables chosen for inclusion in the propensity score were sex, age, and chronic kidney disease. Clinical outcomes were assessed using chi-2 or Fisher's exact test. Results 366 LTRs met inclusion criteria. Of these, 68 received DOACs and 298 received warfarin. The analysis cohort included 132 LTRs who were successfully propensity matched, 66 in each group. After matching, patient demographics and comorbidities were similar at baseline. In the 1-year follow up period, 17 patients (12.9%) experienced new or recurrent VTE. There was no difference in the rate of VTE between the DOAC and warfarin groups (13.6% vs 12.1%, p=0.80). Six total bleeding events requiring hospital visits were observed, 4 in the DOAC group and 2 in the warfarin group (p=0.68). Conclusion No difference in the rates of new or recurrent VTE or bleeding for DOAC versus warfarin were observed in this propensity-matched, single-center retrospective cohort study of LTRs. DOACs appear to be safe and effective alternatives to warfarin in LTRs. Larger studies are needed to confirm these findings.

Background: Triple antithrombotic therapy is used in patients who require systemic anticoagulation and undergo percutaneous coronary intervention (PCI) requiring dual antiplatelet therapy. Bleeding with this combination is significant; however, few studies have described outcomes with the use of newer oral P2Y12 inhibitors in this setting. Objectives: We aimed to compare outcomes among patients prescribed triple therapy with prasugrel or ticagrelor compared to triple therapy with clopidogrel in patients who underwent PCI and required warfarin. Methods: We retrospectively evaluated 168 patients who received either prasugrel (n = 32) or ticagrelor (n = 10) and were matched (1:3) to those who received clopidogrel (n = 126) at the time of discharge from the index PCI visit. Matching was performed based on age ±10 years, sex, and indication for PCI. The primary outcome was the incidence of any bleeding during the 12-month follow-up. We also evaluated major adverse cardiovascular and cerebrovascular events (MACCEs). Results: Patient baseline characteristics were similar between groups. There was a significant excess of bleeding in patients who received prasugrel or ticagrelor compared to clopidogrel as part of triple therapy (28.6% vs 12.7%; odds ratio, 3.3; 95% confidence interval, 1.38-8.34). No differences were seen between groups in MACCEs. Conclusions: The use of prasugrel or ticagrelor as part of triple antithrombotic therapy among patients who underwent PCI and received warfarin was associated with significantly more bleeding compared to patients who received clopidogrel. Therefore, higher potency P2Y12 inhibitors should be used cautiously in these patients.

Hepatotoxic adverse drug reactions are associated with significant morbidity and mortality and are the leading cause of postmarketing regulatory action in the United States. They are classified as Type A (intrinsic) or Type B (idiosyncratic). Type A are predictable, dose-related toxicities, often identified in preclinical or clinical trials, and usually occur in overdose settings or with pre-existing hepatic impairment. Type B are not clearly related to increasing dose and are associated with drug-specific and patient-specific characteristics and environmental risks. Rare Type B reactions are often identified postmarketing. Identification and management, including electronic resources, has evolved.

Inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway for immunosuppression in solid organ transplantation is appealing due to its specificity for immune cell function, particularly for JAK3. This is due to its unique association with only the common gamma chain (γc). The γc is an appealing immunosuppression target in transplantation because of the critically important lymphokines that act at it, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Tofacitinib was initially purported to selectively inhibit solely JAK3, but subsequent analyses have also demonstrated its activity at the other members of the JAK family. Clinical outcomes have validated tofacitinib's pan-JAK activity in kidney transplantation after demonstrating an increased risk of infection and malignancy as compared to CNI-based regimens. After these trials, tofacitinib investigation for use in transplantation has effectively ceased. However, a post-hoc analysis has shed new light on the monitoring of tofacitinib exposure in order to predict infection and oncologic events. With new methods to monitor tofacitinib exposure, clinicians may be able to effectively reduce toxicities while providing a high level of immunosuppression. The purpose of this review to identify when, and for whom, JAK inhibitors may provide benefit in solid organ transplantation.

Purpose Chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs) limits long-term survival compared to other solid organ transplants. Underlying mechanisms of CLAD are poorly understood. To address the pathogenesis of CLAD at the molecular level, we performed RNA-seq analysis of airway brush samples in LTRs with and without CLAD. Methods LTRs with and without CLAD were evaluated for inclusion. CLAD was staged using ISHLT criteria. RNA was extracted from airway brush samples and sequenced to obtain bulk RNA-seq data. These were subsequently analyzed for differential gene expression (DGE) profiling using false-discovery rate (FDR) p-value of 0.05 and absolute log2 fold change > 2 as thresholds for significance. Gene enrichment and gene and cell ontology analyses of DGE profile was completed to predict canonical pathways and cellular upstream regulator of activated signal pathways where p Results 24 CLAD and 21 stable control LTRs were included for RNA-seq analysis. The majority of cells identified from brushing were epithelial cells (54%). 293 genes were deferentially expressed between CLAD and non-CLAD. Gene enrichment analyses revealed activation TNF- α (p Conclusion Transcriptome analyses of bronchial brush samples revealed activation of Type-1 immune responses. Furthermore, this signature appears to strengthen over time as patients progress to CLAD and in later stages of CLAD. Further analyses may provide the rationale for testing select immune targets in CLAD and uncover distinct immune endotypes within CLAD.

Purpose Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a seven-year period. Methods All LTRs transplanted from 2010 to 2016 were included. LTRs who died within 3 months or were lost to follow-up were excluded. Sex, age, EBV serostatus, induction agent, indication agent, and survival were collected via chart review. The primary outcome was development of PTLD. Secondary endpoints were early and late PTLD and survival. Primary and secondary outcomes were assessed using Kaplan-Meier methods and Cox proportional hazards models. Results Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed an increased rate of PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (p Conclusion IPF-LTRs are at increased susceptibility for PTLD compared to non-IPF LTRs. LTRs who received alemtuzumab induction were at increased risk for PTLD, particularly those who were EBV mismatches. Ongoing studies are being conducted to understand the mechanisms driving PTLD in IPF-LTRs and develop strategies to mitigate risk.

BACKGROUND A lung transplant patient with invasive aspergillosis (IA) manifested symptoms of voriconazole-induced transaminitis with systemic voriconazole and progression of IA after switching to oral posaconazole. With limited options for standard triazole therapy, aerosolized delivery with one of the second-generation triazoles was considered. METHODS Feasibility for aerosolized delivery was evaluated using cascade impactor and analysis of physicochemical characteristics of voriconazole (10 mg/mL) and posaconazole (6, 12 mg/mL) solutions. RESULTS Both triazoles showed favorable characteristics for aerosol delivery with mass median aerodynamic diameter, geometric standard deviation, respirable fraction (

Depression and coronary artery disease (CAD) are leading causes of death and disability and commonly co-occur. Different antidepressant classes have similar efficacy for depressed patients with CAD, but cardiovascular implications are unclear. Selective serotonin reuptake inhibitors (SSRIs) and mirtazapine are first-line options for depressed patients with CAD. SSRIs, but not mirtazapine, have known antiplatelet effects. Whether this affects risk of bleeding and major adverse cardiac events (MACE) in patients requiring dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is unknown. The aim of this analysis is to examine the impact of SSRI treatment on the co-primary endpoints of composite MACE (death, myocardial infarction, or stroke) and composite bleeding events in patients treated with clopidogrel-based DAPT after PCI. We conducted a retrospective study with co-primary endpoints of bleeding and MACE within 1 year of PCI. Three groups were compared: SSRI patients, mirtazapine patients, and patients on neither agent. Mirtazapine acted as a comparator to control for depression, for which diagnosis coding was inadequate. Time-to-event analyses were performed with Kaplan–Meier estimators and adjusted analyses utilized Cox proportional hazards. There were 6874 (820 SSRI, 55 mirtazapine, 5999 neither) patients included. SSRI patients had lower MACE risk than mirtazapine patients (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.38–0.97, p = 0.036) but higher MACE risk than patients on neither agent (HR 1.21, 95% CI 1.02–1.43, p = 0.030) in adjusted analyses. No significant differences were associated with bleeding risk (SSRI vs. neither adjusted HR 1.07, 95% CI 0.93–1.24, p = 0.36). SSRI use was associated with a significant decrease in MACE rates compared with patients receiving mirtazapine. Bleeding risk was not affected by either antidepressant treatment. SSRIs may have cardioprotective benefits compared with mirtazapine.

Rationale: Cytomegalovirus (CMV)-related morbidities remain one of the most common complications after lung transplantation and have been linked to allograft dysfunction, but the factors that predict high risk for CMV complications and effective immunity are incompletely understood. Objectives: To determine if short telomeres in idiopathic pulmonary fibrosis (IPF) lung transplant recipients (LTRs) predict the risk for CMV-specific T-cell immunity and viral control. Methods: We studied IPF-LTRs (n = 42) and age-matched non-IPF-LTRs (n = 42) and assessed CMV outcomes. We measured lymphocyte telomere length and DNA sequencing, and assessed CMV-specific T-cell immunity in LTRs at high risk for CMV events, using flow cytometry and fluorescence in situ hybridization. Measurements and Main Results: We identified a high prevalence of relapsing CMV viremia in IPF-LTRs compared with non-IPF-LTRs (69% vs. 31%; odds ratio, 4.98; 95% confidence interval, 1.95–12.50; P

Anti-factor Xa (anti-Xa) monitoring of unfractionated heparin (UFH) is associated with less time to achieve therapeutic anticoagulation compared to the activated partial thromboplastin time (aPTT). However, it is unknown whether clinical outcomes differ between these methods of monitoring. The aim of this research was to compare the rate of venous thrombosis and bleeding events in patients that received UFH monitored by anti-Xa compared to the aPTT. A retrospective review of electronic health records identified adult patients that received UFH given intravenously (IV) for ≥2 days, with either anti-Xa or aPTT monitoring at an academic tertiary care hospital. This was a pre/post study design conducted between January 1 to December 30, 2014 (aPTT), and January 1 to December 30, 2016 (anti-Xa). All UFH adjustments were based on institutional nomograms. The primary outcome was venous thrombosis and the secondary outcome was bleeding, both of which occurred between UFH administration and discharge from the index hospitalization. A total of 2500 patients were in the anti-Xa group and 2847 patients aPTT group. Venous thrombosis occurred in 10.2% vs 10.8% of patients in the anti-Xa and aPTT groups, respectively (P = .49). Bleeding occurred in 33.7% vs 33.6% of patients in the anti-Xa and aPTT groups, respectively (P = .94). Anti-Xa monitoring was not an independent predictor of either outcome in multivariate logistic regression analyses. Our study found no difference in clinical outcomes between anti-Xa and aPTT-based monitoring of UFH IV.

Purpose Chronic lung allograft dysfunction (CLAD) significantly limits long-term survival in lung transplant recipients (LTRs) and episodes of acute cellular rejection (ACR) are the major risk factor for CLAD. To study the immune mechanisms leading to ACR/CLAD, we have characterized donor-specific alloreactive effector lung T (bronchoalveolar lavage; BAL) cells and peripheral blood mononuclear cells (PBMC) via indirect/direct allorecognition responses in LTRs with/without histologic evidence of ACR and into those who developed CLAD. Understanding these mechanisms may lead to new therapies to prevent CLAD. Methods To assess alloeffector T cell responses from LTRs cells in BAL and PBMC, we used an ex vivo flow cytometric assay and donor alloantigen. LTRs with/without ACR (median 4 months), and a subset who developed CLAD (median 20 months) were studied. The effector responses (IFN-γ, TNF-α, CD107a, IL-17a, IL-13, IL-2 and the costimulation surface molecule, CD154) to donor alloantigen were measured using either donor lysate or irradiated cells in a 6 h in vitro re-stimulation assay. We also used single cell RNAseq analysis to analyze the transcriptome in response to alloantigen in isolated BAL T cells from LTRs with CLAD. Results The predominant BAL alloeffector responses during active ACR were similar between CD8+ and CD4+ T cells, with a Type-1 effector profile and IFN-γ responses predominant. The CD4+ T cells alloeffector responses were higher in BAL>PBMC (p Conclusion Type-1 alloeffector responses during ACR are similar between CD8+ and CD4+ T cells, with the latter predominant in BAL. Progression into CLAD is associated with persistently elevated CD4+ alloeffector responses with a potential cytotoxic CD4+ subset playing an important role.

Introduction The number of solid organ transplants completed annually continues to trend upwards each year. Despite this, maintenance immunosuppression available on the market has remained relatively stagnant. Standard triple immunosuppression, composed typically of tacrolimus, mycophenolate, and steroids, lead to many side effects that limit the use of these medications. Tacrolimus, specifically, causes nephrotoxicity that can lead to renal dysfunction requiring a kidney transplant down the road. Alternative therapies for the management of immunosuppression need to be identified to try to mitigate these adverse effects. Body Cytokines are responsible for facilitating T cell differentiation and lead to the activation of inflammatory mediators that can contribute to graft damage and ultimately rejection. IL-4, IL-6, IL-12/23, and IL-15 are attractive targets for medications to try to ameliorate graft rejection. Various cytokine-targeted medications are currently available on the market for the treatment of inflammatory and autoimmune conditions such as rheumatoid arthritis, psoriatic arthritis, Crohn’s, and multiple sclerosis. Conclusion This article reviews cytokine involvement in alloimmunity and the potential role cytokine-targeted therapy may play in prevention of allograft rejection in solid organ transplant recipients.

Current immunosuppressive regimens with calcineurin inhibitors have improved the management of patients after transplantation. However, their adverse effects are linked to increased morbidity and limit the long-term survival of heart and lung transplant recipients. Belatacept, a costimulation inhibitor interfering with the interaction between CD28 on T cells and the B7 ligands on antigen presenting cells, has shown success and is currently approved for use in renal transplant recipients. Furthermore, it lacks many of the cardiovascular, metabolic, neurologic, and renal adverse of effects of calcineurin inhibitors that have the largest impact on long-term survival in cardiothoracic transplant. Additionally, it requires no therapeutic drug monitoring and is only administered once a month. Limitations to belatacept use have been observed that must be considered when comparing immunosuppression options. Despite this, maintenance immunosuppression with belatacept has the potential to improve outcomes in cardiothoracic transplant recipients, as it has with kidney transplant recipients. However, no large clinical trials investigating belatacept for maintenance immunosuppression in heart and lung transplant recipients exist. There is a large need for focused research of belatacept in cardiothoracic transplantation. Belatacept is a viable treatment option for maintenance immunosuppression, and it is reasonable to pursue more evidence in cardiothoracic transplant recipients.

Purpose Long-term survival in lung transplant recipients (LTR) is limited in large part due to chronic lung allograft dysfunction (CLAD). Donor-specific antibodies (DSA) have been previously associated with more rapid high-grade rejection and mortality. Characteristics of these DSA may predict which antibodies are more harmful than others. The purpose of this investigation was to determine if C1q+ DSA is associated with increased CLAD in LTRs versus no DSA and C1q- DSA. Methods This was a single-center, retrospective cohort study of adult LTRs. Clinical data was extracted from the electronic medical record and laboratory systems. Patients were tested by Luminex Single Antigen Bead (SAB) IgG and C1q. IgG-SAB MFI > 1000 and C1q-SAB MFI > 500 were considered positive. DSA that were positive at more than one time point were classified as persistent, while those that were not were considered transient. Patients were grouped as no DSA, C1q- DSA, or C1q+ DSA. The primary outcome was CLAD. Secondary outcomes included CLAD subtypes of bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Outcomes were assessed using Kaplan-Meier methods and multivariable Cox regression with a time-dependent covariate. Results 582 LTRs were analyzed. 335 (57.6%) had no DSA, 194 (33.3%) were DSA+ C1q-, and 53 (9.1%) were DSA+ C1q+. Of 247 LTRs who developed any DSA, Class II DSA (206 LTRs, 84%) were more common than Class I DSA (106, 43%), including those with both classes. 177 LTRs (72%) had persistent DSA, including all 53 with C1q+ DSA . There was no difference in time to CLAD for any DSA vs no DSA (p=0.26). Patients with persistent DSA had shorter time to CLAD vs no DSA and transient DSA (p=0.04) and trended towards significance on multivariable assessment (HR: 1.70 95%CI: 1.00-2.92, p=0.05). DSA+ Cq1+ had shorter time to CLAD vs no DSA and DSA+ C1q- (p Conclusion Persistent DSA were associated with shorter time to CLAD. C1q+ DSA were associated with increased hazard of CLAD, BOS, and RAS. Larger cohorts are needed to evaluate other clinical outcomes.

Calcineurin inhibitors (CNIs) are the backbone of traditional immunosuppressive regimens for lung transplant recipients (LTR). The CNIs are both narrow therapeutic index drugs with significant interpatient and intrapatient variability that require therapeutic drug monitoring to ensure safety and effectiveness. We hypothesized that tacrolimus time-in-therapeutic range (TTR) affects acute and chronic rejection rates in LTRs. This was a single-center, observational, cross-sectional study of 292 adult LTRs. Subjects who received tacrolimus posttransplant for the first year were included. TTR was calculated at 1 year using protocol goal ranges (12-15 mg/mL months 0-6; 10-12 mg/mL for months 7-12). The primary outcome was acute cellular rejection (ACR) burden at 1 year. Chronic lung allograft dysfunction (CLAD), mortality, and infection rate were assessed as secondary outcomes at 1 year. Primary and secondary outcomes were assessed using logistic regression. Increasing TTR by 10% was associated with a significantly lower likelihood of high-burden ACR at 1 year on univariable (OR 0.46, 95% CI 0.40-0.54, P

Traditional immunosuppressive regimens (ISR) used in lung transplantation rely on calcineurin inhibitors (CNI) that occasionally cause severe adverse reactions necessitating discontinuation. Belatacept is a novel costimulation antagonist approved for use in renal transplantation which lacks data in lung transplantation. This series aims to describe the response to belatacept ISR in 11 lung transplantation recipients after CNI failure.Single-center, retrospective medical record review of adult lung transplant recipients (LTR) before and after conversion to belatacept-based ISR. Patients were evaluated at fixed time points before and after belatacept initiation. Primary outcome was incidence of acute cellular rejection (ACR). Secondary outcomes included incidence of infection, chronic lung allograft dysfunction (CLAD) progression, death, change in mean arterial pressure, and estimated glomerular filtration rate.Eleven LTRs received belatacept with a mean of 246 (91-1064) days of follow-up after conversion. Four were changed to belatacept for thrombotic thrombocytopenic purpura, 3 for posterior reversible encephalopathy syndrome, 2 for recurrent ACR, 1 for CLAD, and 1 for renal-sparing. ACR was not different before and after belatacept (P = 0.17). Mean estimated glomerular filtration rate was significantly higher postbelatacept (32.53 vs 45.26, P = 0.04). Mean incidence of infections (24.4% vs 16.0%, P = 0.55) and mean arterial pressure (97.5 vs 92.1 P = 0.38) were not different. Progression of CLAD occurred in 2 patients. At the end of follow-up, 7 of 11 patients were alive.Belatacept-based ISR appear to produce reasonable results in LTRs who fail CNI-based ISR. Larger prospective trials appear warranted in lung transplantation.

Background: Dual antiplatelet therapy is a mainstay of care for percutaneous coronary intervention (PCI) patients; however, uncertainty exists in real-world practice about comparative effectiveness and safety outcomes. Objective: To evaluate outcomes of different oral P2Y12 inhibitors in PCI patients. Methods: We retrospectively studied patients treated between July 1, 2010, and December 31, 2013. Patients received clopidogrel, prasugrel, ticagrelor, or more than 1 antiplatelet (switch) during PCI. Outcomes were evaluated for major adverse cardiovascular events (MACE) and bleeding at 1 year. Propensity score matching with Cox proportional hazards analysis was used to determine predictors of MACE and bleeding. Results: A total of 8127 patients were included: clopidogrel (n = 6872), prasugrel (n = 605), ticagrelor (n = 181), and switch (n = 469). Treatment with prasugrel was associated with the lowest risk of MACE using multivariate regression (odds ratio [OR] = 0.57; 95% CI = 0.36-0.92; P = 0.02). In the propensity score–matched analysis, only the prasugrel group was associated with a lower risk of MACE compared with the clopidogrel group. Clopidogrel was associated with the lowest risk of major bleeding using multivariate regression (OR = 0.64; 95% CI = 0.42-0.98; P = 0.042). Both ticagrelor (hazard ratio [HR] = 2.00; 95% CI = 1.11-3.59) and the switch groups (HR = 1.65; 95% CI = 1.09-2.50) were associated with a greater risk of major bleeding compared with clopidogrel. However, no differences were found in the propensity score–matched analysis. Conclusions: Dual antiplatelet therapies differed in both MACE and bleeds in a real-world setting of PCI. Prasugrel was associated with fewer MACE, whereas clopidogrel had fewer major bleeding events.

Hepatotoxic adverse drug reactions are associated with significant morbidity and mortality and are the leading cause of postmarketing regulatory action in the United States. They are classified as Type A (intrinsic) or Type B (idiosyncratic). Type A are predictable, dose-related toxicities, often identified in preclinical or clinical trials, and usually occur in overdose settings or with pre-existing hepatic impairment. Type B are not clearly related to increasing dose and are associated with drug-specific and patient-specific characteristics and environmental risks. Rare Type B reactions are often identified postmarketing. Identification and management, including electronic resources, has evolved.

Purpose Lung transplantation remains the only therapeutic option for select patients with end-stage lung diseases, however chronic lung allograft dysfunction (CLAD) significantly limits long-term survival in lung transplant recipients (LTRs). Episodes of acute cellular rejection (ACR) are common and the major risk factor for developing CLAD, however little is known about donor-specific cellular T cell responses, as these have not been previously characterized in LTRs. Methods We used a novel ex vivo flow cytometric assay to assess donor-specific alloimmune responses from LTRs cells in lung allograft resident effector T cells (BAL-derived) and PBMC. Using a 6h in vitro re-stimulation protocol with either irradiated donor cells or donor lysate, we measured the frequencies of effector responses (IFN-γ, TNF-α, the cytotoxic marker CD107a, IL-17a, IL-13, IL-2 and the costimulation surface molecule, CD154) from CD4+ and CD8+ lung resident or blood compartment T cells. Results Overall the predominant alloreactive effector responses were donor-specific CD154 surface expression following in vitro re-stimulation with donor lysate in lung resident CD4+ T cells compared to the PBMC compartment, with minimal to absent expression on CD8+ T cells. Expression of surface CD154 was highly co-expressed with allospecific CD4+ T cells producing the Type-1 cytokines IFN-γ, TNF-α and CD107a suggesting CD154 as a marker for Type-1 effector function, but not Type-2 or Type-17 responses. In fact, donor-specific IL-13 and IL-17 responses were detectable in some patients but at significantly lower frequencies compared to Type-1 effector responses, suggesting a hierarchy of alloeffector immune responses. Comparison between the lung resident T cells and blood T cells revealed consistently increased donor-specific alloreactive frequencies in the lung allograft versus the periphery. Ongoing experiments are assessing the proliferative capacities of donor-specific alloreactive T cell populations in the blood compartment. Conclusion Together, these data indicate donor-specific alloreactive effector CD4+CD154+ lung resident T cells activated via the indirect allorecognition pathway are present in high frequencies in LTRs with histologic evidence or history of ACR and segregate to Type-1 effector cytokine responses.

Purpose Chronic lung allograft dysfunction (CLAD) is the major limitation to long-term survival in lung transplant recipients (LTRs). The underlying biologic mechanisms that drive CLAD are poorly understood. To address the pathogenesis of CLAD at the molecular level, we performed RNA-seq analysis of airway brush samples and Meso Scale Discovery (MSD) multiplex cytokine and chemokine measurements in bronchial lavage (BAL) samples. Methods Total RNA was extracted from distal bronchial brush samples and sequenced using an Illumina instrument to obtain bulk RNA-seq data which were subsequently analyzed for differential gene expression (DGE) profiling with correction for a potential batch effect. Gene enrichment and gene and cell ontology analyses of DGE profile was done and used to predict canonical pathways and cellular upstream regular of activated signal pathways. False discovery rate (FDR) p Results 21 CLAD and 18 stable control LTRs were included for RNA-seq analysis. Corresponding MSD measurements were performed on 17 CLAD and 11 control BAL samples. 1031 DEGs were overrepresented in CLAD samples. Gene analyses revealed enrichment of the Type-1 adaptive immune response and the inflammasome. TNF- α (p Conclusion Transcriptome analyses and the lung allograft BAL immune proteome, provide novel insights into the immune activation pathways prevalent in CLAD versus controls. Further analyses may provide the rationale for testing select immune targets in CLAD and uncover distinct immune endotypes within CLAD.

A systematic review of papers in English on Post-transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTR) using MEDLINE, EMBASE, SCOPUS, and Cochrane databases was performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were strictly adhered to. Pooled odds ratios (pOR) were calculated from a random-effects model and heterogeneity among studies was quantitated using I(2) values. 14 studies published from 2005 to 2015 were included in the meta-analysis. 164 lung transplant recipients were included. LTRs who received single versus bilateral were associated with a 7.67-fold risk of death after PTLD (6 studies with 64 LTRs; pOR 7.67 95% CI 1.98–29.70; p = 0.003). pOR of death for early onset PTLD (

Approximately 20% of patients on oral anticoagulation require percutaneous coronary intervention (PCI). In these patients, triple therapy (TT) with aspirin, clopidogrel, and warfarin reduces the risk of major adverse cardiovascular events but at the expense of a significantly increased risk of major