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We present the case of a 41-year-old female who underwent bilateral lung transplantation after the donor lungs were placed on a normothermic ex vivo lung perfusion and ventilation device and flown nearly 5000 miles from Honolulu, Hawaii to Durham, North Carolina. The patient experienced no primary graft dysfunction. One year after transplantation she has remained rejection-free and exhibits excellent pulmonary function. This case highlights the challenge that active organ preservation systems pose to questions of organ allocation and geographic sharing.

Our objective was to examine variability in pain levels following lung transplantation, and examine individual biopsychosocial factors influencing changes in pain.We performed a retrospective study of a cohort of 150 patients transplanted and discharged from Duke University Hospital between January 2015 and September 2016. During hospitalization and at clinic visits up to two months after discharge, subjective pain ratings were obtained using a 0-10 Numeric Rating Scale. Psychiatric diagnoses of anxiety and depression and Center for Epidemiological Studies - Depression (CES-D) scores collected after hospital discharge were examined as predictors of post-surgery pain. Medical and surgical variables were examined as covariates.During hospitalization, pain ratings decreased over time (p0.001). Predictors of higher pain levels included pre-transplant history of depression (p=0.001) and anxiety (p=0.04), bilateral lung transplant (p=0.03), and lower six-minute walk distance (p=0.02). Two months after discharge, 18% of patients reported continued pain and 34% remained on opioid pain medications. Two months after discharge, more frequent post-operative complications predicted higher pain levels in a univariate analysis (p=0.02) although this relationship was attenuated after adjustment for depression. In a multivariate analysis, elevated CES-D scores (p=0.002), and greater opioid use (p=0.031) predicted higher pain levels 2-months post-discharge.We conclude that patients with psychiatric comorbidities may be at risk for greater pain, and may require additional strategies for more effective pain management.

Purpose Acute cellular rejection (ACR) is a histopathologic diagnosis made by assessment of transbronchial biopsies (TBBX). Consensus guidelines recommend a minimum of 5 alveolated samples for histologic adequacy; it is not uncommon for samples to be inadequate for diagnosis. This study was designed to determine what factors impact the recovery of adequate specimens for ACR grading, as well as explore discrepancies in “sample calling” between the pathologist & bronchoscopist. Methods Observational, single center study including retrospective chart review of 142 bronchoscopies with TBBX performed on 128 lung transplant recipients (LTRs) who underwent surveillance bronchoscopy between May 2017 & May 2018. For the purpose of our study we defined inadequate samples as Results Of 142 TBBX procedures, 22 (15.5%), resulted in inadequate sampling. Of note, pathologists called less sample fragments than bronchoscopists 70% of the time. Characteristics associated with inadequate sampling included both LTR & procedural characteristics (Table 1 & 2). Conclusion Bronchoscopists may overestimate the number of total fragments obtained compared with pathologists. Both demographic & procedure characteristics may aid in identifying LTRs at higher risk for inadequate sampling during TBBx.

Purpose Gastroesophageal reflux disease is common in lung transplant recipients and is thought to cause lung graft injury through aspiration of gastric contents. Bile acids in bronchoalveolar lavage (BAL) are putative markers of gastric microaspiration and associated with inflammation and earlier chronic lung allograft dysfunction (CLAD). Microaspiration is thought to augment CLAD risk through potentiation of acute rejection (AR), although this has not been demonstrated. We hypothesized that BAL bile acid levels would be associated with AR presence and severity. Methods Among all adult, first, bilateral lung transplants, performed at two large lung transplant centers 2010-2015, transbronchial biopsies obtained within the first-year post-transplant were categorized as spirometrically-significant or stable based on the presence or absence of ≥10% concurrent drop in FEV1. AR diagnosis was based histology and biopsies with concurrent infection were excluded. BAL supernatant levels of bile acids (taurocholic acid (TCA), glycocholic acid (GCA), cholic acid), and inflammatory proteins (IL6, CXCL8, S100A8, CCL2, IL1β, CCL5, IL1α, RAGE, S100A12, IL12) were compared between patient groups. Association between BA levels and subsequent CLAD or death/retransplant was assessed using Cox Proportional Hazards models, adjusted for relevant peri-transplant clinical covariates and AR group. Endpoints We identified 42 patients with spirometrically-significant AR, 56 patients with stable AR, and 81 patients with stable no-AR with available BAL samples (one sample per patient). BAL at time of spirometrically-significant AR, compared to other groups, had elevated levels of TCA (ANOVA

Purpose In lung transplant candidates with a high-calculated panel reactive antibodies (cPRA), the waitlist time and risk of death are considerable. Additionally, the presence of post-transplant HLA antibodies is associated with chronic lung allograft dysfunction (CLAD) and mortality. Our center designed a post-transplant multimodal antibody management protocol (PMAMP) in an effort to alter immune response and minimize antibody development of highly sensitized recipients (cPRA > 80) with the goal of improving transplant outcomes. Methods This is a single center, retrospective evaluation of our PMAMP. Lung transplant recipients with cPRA >80% were eligible for our PMAMP (Table 1). From April 2019 to April 2020, there were 5 eligible patients who underwent transplant. For comparison, matched historical control data was collected from 7 highly sensitized patients who underwent transplant from March 2003 to September 2008 but did not receive PMAMP. Demographics and outcome data were collected. Results Demographics and outcomes are described in Table 2. To date, all 5 patients who underwent PMAMP are alive with CLAD-free survival and no episodes of rejection with a median transplant follow-up time of 427 days. Of note, all patients in both groups experienced at least one infectious complication following transplant. Conclusion Our PMAMP shows promise for mediating CLAD-free survival, rejection, and extending post-transplant survival in highly sensitized candidates undergoing lung transplant; however, more data and follow-up is needed to ensure the safety and efficacy of this protocol.

The effect of drag reducing riblets on the flow structure was examined experimentally for a turbulent boundary layer at Reθ = 9890 and riblet spacing s+ = 13.4. Trapezoidal riblets were used, which were attached to the water tunnel wall as a coating. Force measurements were performed to quantify the amount of drag reduction. Then, the mechanism underlying this reduction was investigated by stereo-PIV measurements in the cross-stream plane. To determine the effect of the drag reducing riblets, the results were compared with the smooth flat plate. Time-averaged turbulent statistics such as turbulent kinetic energy and Reynolds shear stress were found to be lower over the riblets compared to the flat surface. Two-point correlations of the fluctuating velocity components were calculated to elucidate the average flow structure size and strength, where riblets significantly suppressed the turbulent structures. Quadrant analysis of the Reynolds shear stress was performed to assess the change in ejection and sweep events and the results were found to be in correspondence with previous works.

Severe acute respiratory virus syndrome 2 (SARS-CoV-2) has led to a worldwide pandemic. Early studies in solid organ transplant (SOT) recipients suggested a wide variety of presentations, however, there remains a paucity of robust data in this population. We conducted a systematic review and meta-analysis of SOT recipients with SARS-CoV-2 infection from January 1st t October 9th, 2020. Pooled incidence of symptoms, treatments and outcomes were assessed. Two hundred and fifteen studies were included for systematic review and 60 for meta-analysis. We identified 2,772 unique SOT recipients including 1,500 kidney, 505 liver, 141 heart and 97 lung. Most common presenting symptoms were fever and cough in 70.2% and 63.8% respectively. Majority (81%) required hospital admission. Immunosuppressive medications, especially antimetabolites, were decreased in 76.2%. Hydroxychloroquine and interleukin six antagonists were administered in59.5% and 14.9% respectively, while only few patients received remdesivir and convalescent plasma. Intensive care unit admission was 29% from amongst hospitalized patients. Only few studies reported secondary infections. Overall mortality was 18.6%. Our analysis shows a high incidence of hospital admission in SOT recipients with SARS-CoV-2 infection. As management of SARS-CoV-2 continues to evolve, long-term outcomes among SOT recipients should be assessed in future studies.

Purpose CLAD, mainly manifest as bronchiolitis obliterans syndrome (BOS), is the leading cause of late death in lung recipients. BOS develops despite routine immunosuppression and its pathogenesis is poorly understood. The histological correlate of BOS is bronchiolitis obliterans (BO), or airways fibrosis. We quantified over 700 immune-related genes in BO affected airways to better understand immune responses active in end-stage BOS. Methods Formalin fixed paraffin embedded lung tissue was procured at retransplantation for BOS (n=6). Unused donor tissue was used as normal control (n=5). Histologies of interest were isolated using laser capture microdissection (LCMD). Within each BOS lung, airways histologically affected by BO pathology, defined as intraluminal fibrous expansion, were isolated. Additionally, airways unaffected by evident fibrosis were isolated. Within each donor lung, histologically normal airways were isolated. Cellular RNA was extracted and multiplex gene expression analysis was performed using the NanoString PanCancer Immune Profiling Panel. Linear regression was used to compare gene expression among groups. The primary comparison was differential expression in BO affected vs. normal donor airways. We also compared expression in BO affected vs. unaffected airways within BOS explant lungs. P-values were corrected for multiple comparisons using Benjamini-Hochberg. Results Sixty-seven genes were significantly different between BO affected vs. normal donor airways, of which 52 had a fold change (FC) 2. Along with genes in adaptive immunity, several genes related to innate and humoral activation were significantly increased in BO affected airways. Among the innate immune genes with increased expression in BO were toll-like receptor 1 (FC 2.31) and its adaptor molecule CD14 (FC 5.26) in addition to the complement subcomponent C1s (FC 3.06), while those in humoral immunity included bone marrow stromal antigen 2 (FC 3.41), important to the growth and development of B-cells. No genes were significantly differentially expressed between BO affected vs. unaffected airways within BOS explant lungs. Conclusion Our results suggest innate and humoral immune responses are active in airways affected by BO pathology, and also in airways without evident fibrosis. Ongoing analyses of BO lesions through LCMD will provide new insights into CLAD pathogenesis.

Purpose The pulmonary microbiome modulates the immune milieu in the lung allograft and is in turn influenced by external factors such as microaspiration of oropharyngeal contents. A potential driver of microaspiration is gastroesophageal reflux disease (GERD), which has been associated with poor outcomes after lung transplantation. We aimed to compare the pulmonary microbiome in lung transplant recipients with and without GERD, and correlate microbial composition with concurrent lung inflammation. Methods We selected 22 GERD patients and 49 no-GERD controls from adult lung transplant recipients with 24-hour pH-impedance testing and bronchoalveolar lavage fluid (BAL) collection at 3 months post-transplant. BAL microbial communities were characterized by 16S rRNA gene sequencing. Ten inflammatory protein markers in BAL were measured by multiplex assay. Results Baseline patient characteristics including age, sex, primary disease, and transplant type were comparable between GERD and no-GERD groups. Shannon diversity index was lower (MD=-0.33, p=0.04), while Berger-Parker dominance index was higher (MD=0.10, p=0.03), in GERD patients compared to no-GERD controls. Hierarchical clustering of all samples by Bray-Curtis dissimilarity identified three distinct pneumotypes (Figure 1). GERD was significantly associated with one of these pneumotypes, PT1, which was enriched in multiple anaerobic oropharyngeal taxa including Prevotella and Veillonella. In GERD patients, the presence of PT1 compared to all others was associated with higher levels of IL-8 (p=0.03). Conclusion At time of GERD diagnosis, lung transplant recipients are more likely to have a pulmonary microbiome lower in diversity and enriched in oropharyngeal taxa. These perturbations are consistent with microaspiration and may contribute to allograft inflammation. Future studies are warranted to assess how the pulmonary microbiome changes over time in the context of GERD and its correlation with rejection and long-term outcomes.

Purpose Frailty is gaining increased recognition in the evaluation of lung transplant (LTx) candidates. The Fried Frailty Phenotype (FFP) index has been the most commonly used instrument and is associated with pre- and post-transplant morbidity and mortality. A novel, alternative approach to assessing frailty is the Cumulative Deficits Frailty Index (CFI), which evaluates health deficits across multiple domains that may aid in refining candidacy evaluation. As a preliminary assessment, we aimed to understand the distribution of frailty scores among LTx candidates and assess agreement between the FFP and the CFI. Methods This was a prospective, multi-center study of a subset of participants in the Clinical Trials in Organ Transplantation-20 cohort who completed both the FFP and CFI assessments pre-transplant. FFP was characterized using 5 criteria (unintentional weight loss, grip strength, energy levels, gait speed and physical activity), with FFP frailty defined (≥3 criteria frail; 1-2 pre-frail; and 0 not frail). The CFI was comprised of 40 health items abstracted from medical records with frailty defined as >10/40 (score of 0.25) deficits. Agreement between total FFP and CFI scores was assessed using Cohen's Kappa statistic and we also evaluated the distribution of CFI scores by each sub-component of the FFP. Results The cohort was comprised of 124 LTx candidates (median age 62 years, 56% male, median LAS 39) with 57% having restrictive lung disease. 11 (9%) LTx candidates were frail on the FFP, whereas 85 (69%) were pre-frail (grouped as non-frail). The median CFI score for the cohort was 0.23 (IQR 0.15-0.28) with 48 (39%) deemed frail. 79 (64%) had matching frail and non-frail statuses between the indices with agreement assessed as poor [Kappa 0.11 95% CI (-0.02 to 0.24)]. The median CFI scores were more concordant with FFP domains of weight loss [Frail FFP: 0.26 (IQR 0.20-0.29) vs. Not Frail FFP: 0.21 (0.15-0.28)], physical activity [0.25 (0.21-0.28) vs. 0.21 (0.15-0.28)], and gait speed [0.25 (0.19-0.33) vs. 0.21 (0.15-0.28)], but not with grip strength or energy levels. Conclusion In this multi-center study, agreement between frailty indices was poor suggesting the CFI potentially captures a different construct than FFP. The study is ongoing evaluating the prognostic utility of these indices with early post-transplant outcomes.

Purpose The occurrence of acute allograft injuries remains one of the most important factors responsible for the development of early chronic lung allograft dysfunction. We and others have previously demonstrated a consistent association between acute lung injury (ALI), acute perivascular rejection (AR) and lymphocytic bronchiolitis (LB) and the subsequent development of CLAD. However, the pathogenesis of these allograft injuries remains poorly understood. CXCL9, CXCL10, and CXCL11 are CXC chemokines induced by interferon-γ and act as potent chemoattractants of mononuclear cells (e.g., activated T-cells and NK cells). We hypothesized that episodes of ALI, AR and LB would be associated with increased activity of these CXCR3 chemokines, as measured in the BAL at the time of the injury. Methods The study cohort consisted of the first 200 lung transplant recipients enrolled in Clinical Trials in Organ Transplantation-20 (NCT02631720), a prospective multi-center observational study collecting serial clinical data and biologic samples from 5 North American transplant centers. Recipients received a median (Q1,Q3) of 5 (3, 6) bronchoscopies during the first-year post-transplant. Transbronchial biopsies (TBBXs) with no histopathologic evidence of allograft injury were classified as “healthy”. BALF CXCL9, CXCL10 and CXCL11 mean fluorescence intensities (MFIs) were measured using luminex bead assays. To evaluate differences in CXCR3 chemokine levels between allograft injuries and healthy biopsies, multivariable linear mixed effects models were constructed taking into account repeated measurements from recipients. Results There were 844 TBBXs with 249(30%) episodes of allograft injury observed. There were 173(20%) episodes of AR, 30(4%) episodes of LB and 42(5%) episodes of ALI. Biopsies with AR, LB or ALI were associated with significant elevations in all three chemokines compared with healthy biopsies (p Conclusion We demonstrate for the first time in a multicenter study, CXCR3 chemokine elevations during episodes of acute allograft injury. These findings support the association of CXCR3 chemokines during episodes of AR, LB and ALI, and may potentially offer novel therapeutic targets to prevent and treat these deleterious events.

Purpose Diagnosis of CLAD after lung transplantation (LT) requires sustained decline in lung function and exclusion of other etiologies for the decline. The limitations of relying primarily on pulmonary function test (PFT) decline to define CLAD onset for large cohort studies are not well characterized. Using a large, prospective, multicenter cohort of LT recipients, we sought to implement a rigorous approach to identify and confirm CLAD using automated analysis of serial PFT trajectory combined with local site adjudication to rule out exclusionary conditions. Methods The CTOT-20 cohort consists of 803 adult first LT recipients enrolled between 2015 and 2018 from 5 North American centers. PFT data transfers occurred monthly from sites to the data coordinating center, which applied an automated process using SAS code to identify potential CLAD in subjects who survived at least 90 days and had at least 5 PFTs. Potential CLAD cases, defined by sustained PFT decline per ISHLT definition, were sent to the local site to either identify alternative reasons for the decline or confirm CLAD. The site adjudication process included systematic assessment of clinical findings, bronchoscopy, microbiology, pathology, and radiographic information. Results 746 subjects were included in the analysis and had on average 18.9 (range 5-77) PFTs. Potential CLAD was identified a total of 379 times in 195 subjects based on PFT decline. CLAD was confirmed by the local site PI in 108/195 subjects (55.4%) and the mean time to CLAD onset was 14.8 (range 3.6-39.6) months. CLAD was confirmed even less frequently during earlier timepoints (28% in months 0-6, 43% in months 7-12, and 52% in months 13-18). The most frequent concurrent conditions excluding CLAD diagnosis were active infection (34.4%), airways stenosis (16.0%), pleural effusion/disease (14.9%), and acute rejection (14.1%). Conclusion Utilizing an automated approach to identify potential CLAD supplemented by local site adjudication, we found that the majority of potential CLAD qualifying events by PFT decline had evident alternative explanations. Our results indicate that CLAD adjudication utilizing a broad spectrum of clinical information is critical. This approach was used effectively across multiple centers and provides a robust strategy that can be leveraged in future multicenter CLAD studies.

Purpose Despite the importance of AR and LB in lung recipients, the incidence and associated clinical factors have not been prospectively studied in a contemporary cohort. We used a multicenter lung transplant cohort to describe the incidence of AR and LB over the first posttransplant year, examine concurrent histology at the time of an AR/LB event, and determine recipient factors associated with AR or LB. Methods The cohort was drawn from CTOT-20 (NCT02631720), an observational study collecting prospective clinical outcome data on lung recipients at 5 North American centers. The first 200 enrolled, transplanted subjects with ≥1 lung biopsy within the first posttransplant year were included. Recipients were managed according to center-specific clinical care practices. Descriptive statistics were used to summarize AR or LB events and concurrent histology. Univariate Cox modeling was used to evaluate the impact of select recipient factors on the time to first occurrence of AR or LB. Results 1007 biopsies were performed over the first posttransplant year in this cohort. 56% and 17% of patients experienced at least one AR or LB episode, respectively. Rates of minimal and mild AR and minimal LB were similar on for cause vs. surveillance biopsies. While a majority of LB events were concurrent with AR, AR events generally occurred in isolation or were concurrent with non-rejection histopathology. Univariate analyses suggested a protective effect of induction immunosuppression on the risk for AR. We also observed a significant decrease in the hazard of AR and LB in bilateral, as compared to single, lung recipients (Figure). Conclusion We observed a higher incidence of AR than that reported by the ISHLT registry. This may, in part, be attributed to the practice of surveillance biopsies in all CTOT-20 centers. While the impact of induction on AR risk is consistent with ISHLT data, the novel association between transplant type and AR/LB will be further validated over extended cohort follow up using multivariable approaches.

Purpose Respiratory syncytial virus infection (RSVI) in lung transplant recipients (LTRs) has been associated with bronchiolitis obliterans syndrome (BOS) development and progression, but data have been derived from small studies. Methods This is a retrospective study of RSVI in LTRs at Duke University from Jan 2013 - May 2017. Decrement in FEV1 was determined by comparison of the FEV1 at 90 days post-RSVI to pre-RSVI baseline. Results Of 114 LTRs with RSVI, 15 had preexisting BOS and 99 did not have preexisting BOS. Those with preexisting BOS had a longer duration from transplant surgery to RSVI, more concomitant respiratory bacterial pathogens and less acute cellular rejection (ACR) within 90 days preceding RSVI compared to those without. Within 1-year of RSVI, 7/15 (46.7%) patients with preexisting BOS had BOS progression and 25/99 (25.3%) patients developed new BOS. In patients with documented FEV1 measured pre- and post-RSVI, 6/12 (50%) with preexisting BOS and 23/90 (25.5%) without preexisting BOS had FEV1 decline ≥ 5%. Kaplan-Meier analysis showed patients with decline in FEV1 ≥ 5% at 90 days post-RSVI had a higher 1-year mortality (p=0.003). Conclusion Our experience supports an increase in BOS development post-RSVI. While BOS progression post-RSVI was common in patients with pre-existing BOS, rates of progression were not greater than those described for the natural history of BOS post-lung transplant. FEV1 decline ≥ 5% at 90 days post-RSVI was associated with higher mortality regardless of BOS status prior to RSVI.

Purpose ALI and OP are histologic patterns of lung damage associated with poor long-term outcomes after lung transplantation. Yet the incidence of ALI and OP and associated clinical factors remain poorly understood. Methods The cohort was drawn from CTOT-20 (NCT02631720), a multicenter prospective lung transplant cohort study. The first 200 enrolled, transplanted subjects with ≥ 1 lung biopsy in the first year after transplant were included. Descriptive statistics were used to summarize ALI or OP events in the 1007 biopsies performed over the first posttransplant year in this cohort. Univariate Cox regression models were used to evaluate the impact of recipient factors on the time to first ALI or OP event. Time independent covariates included age, sex, native disease, transplant type, use of induction immunosuppression, type of primary maintenance immunosuppression, HLA mismatch, and grade 3 primary graft dysfunction (PGD) within 72 hours. Time dependent covariates included a positive fungal, bacterial, mycobacterial, or respiratory viral organism on a respiratory specimen and development of a donor specific antibody. Results Forty-eight patients (24%) experienced at least one ALI event over the first posttransplant year (max 4 per patient). Similarly, 50 patients (25%) experienced at least one OP event (max 3 per patient). The median time to first ALI event was 44 (IQR 24,90) days while the time to first OP was somewhat longer at 92 (IQR 35,203) days. Both ALI and OP were identified slightly more often on for cause vs. surveillance biopsies. The majority of ALI and OP events were not concurrent with other histologic findings, such as acute rejection. Cox analyses identified PGD (HR 2.27, p=0.01) and cyclosporine-based maintenance therapy (HR 2.15, p=0.01) as risk factors for ALI. Analyses for the outcome of OP also implicated PGD (HR 1.97, p=0.03) and cyclosporine maintenance (HR 2.59, p Conclusion OP and ALI are common patterns of lung allograft injury. We identified clinical risk factors for ALI and OP that are potentially modifiable. Ongoing analyses will validate these risks over extended cohort follow up using multivariable approaches. As such, this work may identify strategies to mitigate ALI and OP and improve lung recipient outcomes.

Melaleuca alternifolia concentrate (MAC) is a mixture predominantly composed of monoterpenoids and sesquiterpenes, refined from the essential oil of the tea tree by removing up to 99% of the more toxic, hydrophobic monoterpenes. MAC was examined here for its immunomodulatory effects on the human THP1 and murine RAW264.7 myeloid leukemic cell lines as models for macrophage-like cells. Firstly, MAC levels were determined that did not affect either the survival or proliferation of these cell lines in vitro. Next, the levels of lipopolysaccharide (LPS)-induced production of cytokines (IL-6, TNFα, IL-10, GM-CSF, IFNγ and IL-3) were examined from the myeloid cell lines using multiplex assays. Many of the LPS-inducible cytokines produced by either cell lines could be significantly inhibited by MAC. Closer examination of the mechanism of action of MAC showed that it inhibited the LPS-induced activation of IκB phosphorylation and nuclear factor (NF)-κB signalling and translocation, inhibiting iNOS protein expression and NO production. These results demonstrate that MAC exerts its immunomodulatory effects by inhibiting NF-κB signalling activation and levels of cytokine production by macrophage-like cell lines.

'Autoantigen complementarity' is a theory proposing that the initiator of an autoimmune response is not necessarily the autoantigen or its molecular mimic, but may instead be a peptide that is 'antisense/complementary' to the autoantigen. We investigated whether such complementary proteins play a role in the immunopathogenesis of autoimmune glomerulonephritis. Experimental autoimmune glomerulonephritis, a model of anti-glomerular basement membrane (GBM) disease, can be induced in Wistar Kyoto (WKY) rats by immunization with the α3 chain of type IV collagen. In this study, WKY rats were immunized with a complementary α3 peptide (c-α3-Gly) comprised of amino acids that 'complement' the well characterized epitope on α3(IV)NC1, pCol(24-38). Within 8 weeks post-immunization, these animals developed cresentic glomerulonephritis, similar to pCol(24-38)-immunized rats, while animals immunized with scrambled peptide were normal. Anti-idiotypic antibodies to epitopes from c-α3-Gly-immunized animals were shown to be specific for α3 protein, binding in a region containing sense pCol(24-38) sequence. Interestingly, anti-complementary α3 antibodies were identified in sera from patients with anti-GBM disease, suggesting a role for 'autoantigen complementarity' in immunopathogenesis of the human disease. This work supports the idea that autoimmune glomerulonephritis can be initiated through an immune response against a peptide that is anti-sense or complementary to the autoantigen. The implications of this discovery may be far reaching, and other autoimmune diseases could be due to responses to these once unsuspected 'complementary' antigens.

Background Delirium is relatively common after lung transplantation, although its prevalence and prognostic significance have not been systematically studied. The purpose of the present study was to examine pretransplant predictors of delirium and the short-term impact of delirium on clinical outcomes among lung transplant recipients. Methods Participants underwent pretransplant cognitive testing using the Repeatable Battery for the Assessment of Neuropsychological Status and the Trail Making Test. After transplant, delirium was assessed using the Confusion Assessment Method until discharge. Results Sixty-three patients were transplanted between March and November 2013, of which 23 (37%) developed delirium. Among transplanted patients, 48 patients completed pretransplant cognitive testing. Better pretransplant cognitive function was associated with lower risk of delirium (odds ratio, 0.69 [95% confidence interval 0.48, 0.99], P = .043); and demographic and clinical features including native disease ( P = .236), the Charlson comorbidity index ( P = .581), and the lung allocation score ( P = .871) were unrelated to risk of delirium, although there was a trend for women to experience delirium less frequently ( P = .071). The presence ( P = .006) and duration ( P = .027) of delirium were both associated with longer hospital stays. Conclusion Delirium occurs in more than one-third of patients after lung transplantation. Delirium was associated with poorer pretransplant cognitive functioning and longer hospital stays, after accounting for other medical and demographic factors.

As HLAs antibody detection technology has evolved, there is now detailed HLA antibody information available on prospective transplant recipients. Determining single antigen antibody specificity allows for a calculated panel reactive antibodies (cPRA) value, providing an estimate of the effective donor pool. For broadly sensitized lung transplant candidates (cPRA ≥ 80%), our center adopted a pretransplant multi-modal desensitization protocol in an effort to decrease the cPRA and expand the donor pool. This desensitization protocol included plasmapheresis, solumedrol, bortezomib and rituximab given in combination over 19 days followed by intravenous immunoglobulin. Eight of 18 candidates completed therapy with the primary reasons for early discontinuation being transplant (by avoiding unacceptable antigens) or thrombocytopenia. In a mixed-model analysis, there were no significant changes in PRA or cPRA changes over time with the protocol. A sub-analysis of the median fluorescence intensity (MFI) change indicated a small decline that was significant in antibodies with MFI 5000-10,000. Nine of 18 candidates subsequently had a transplant. Posttransplant survival in these nine recipients was comparable to other pretransplant-sensitized recipients who did not receive therapy. In summary, an aggressive multi-modal desensitization protocol does not significantly reduce pretransplant HLA antibodies in a broadly sensitized lung transplant candidate cohort.

Purpose There remains an urgent need to expand the donor pool for thoracic organ transplant recipients. Utilizing donors who are actively viremic with hepatitis C (HCV) is rapidly becoming standard practice, although no consensus exists regarding when to treat post-transplant, with which drug, and for how long. Cost remains an issue with direct acting antivirals (DAA). Hepatitis B (HBV) viremic donors are predicted to become more common. We designed and implemented a protocol to utilize HCV and HBV NAT+ donors. Methods We designed an open-label, ongoing safety and efficacy protocol to allow all transplant programs at our center, adult and pediatric, to enroll patients for whom there is an emergent need to expand the donor pool. Patients are consented and stratified into 2 groups: those who received NAT+ donors vs NAT- donor comparators. Patients are followed for a minimum of 12m post-transplant, with hepatitis viral loads measured at d5, 10 and 21 (and at clinical discretion thereafter). The primary end points are 3, 12month graft and patient survival. Secondary end points include viral cure rates, therapy associated adverse events, attributable hepatitis mortality, functional status, rejection rates and time to transplantation. HCV therapy of choice is started after discharge, or if needed urgently, begun inpatient and paid for by the hospital. HBV therapy is initiated at the time of transplantation. The protocol is monitored by a Data Safety Monitoring Board. Results 11 pts have enrolled to date and progressed to NAT+ transplant, including 8 adult heart transplants, 1 bilateral lung, 1 heart-lung and 1 lung-liver transplant. All have received HCV-viremic donors, within 1 month of consent. Median age is 56yrs (range 25-72). 3 recipients were HCV-viremic pre-transplant, 8 were HCV-naive. All 8 D+/R- pts became infected with HCV, 7 were actively viremic by day 5, one became viremic at d21. 9/9 patients are alive at 3months, with HCV therapy having been initiated in 6, and SVR12 achieved in 5 to date. So far we report 100% grafts survival, and no adverse events attributable to hepatitis. 1 patient required HCV therapy initiation in the hospital. Conclusion We present real world experience about the implementation of a protocol allowing HCV and HBV NAT+ donors to be used for thoracic and multivisceral transplants. Using a multidisciplinary approach, our protocol offers a means to expand the thoracic organ donor pool safely.

Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture's disease, can be induced in Wistar Kyoto (WKY) rats by immunization with the noncollagenous domain of the alpha 3 chain of type IV collagen, alpha3(IV)NC1. Recent studies have identified an immunodominant peptide, pCol (24-38), from the N-terminus of rat alpha3(IV)NC1; this peptide contains the major B- and T-cell epitopes in EAG and can induce crescentic nephritis. In this study, we investigated the mechanisms of mucosal tolerance in EAG by examining the effects of the nasal administration of this peptide after the onset of disease. A dose-dependent effect was observed: a dose of 300 microg had no effect, a dose of 1000 microg resulted in a moderate reduction in EAG severity, and a dose of 3000 microg produced a marked reduction in EAG severity accompanied by diminished antigen-specific, T-cell proliferative responses. These results demonstrate that mucosal tolerance in EAG can be induced by nasal administration of an immunodominant peptide from the N-terminus of alpha3(IV)NC1 and should be of value in designing new therapeutic strategies for patients with Goodpasture's disease and other autoimmune disorders.

Introduction Cystic fibrosis (CF) is an inherited disorder that presents in childhood as a multisystem disease. Pulmonary failure and pancreatic insufficiency, including CF-related diabetes (CFRD) and exocrine insufficiency, are significant causes of morbidity and mortality in these patients. In this report we have reviewed our experience with a simultaneous lung and pancreas transplantation in a patient with CF. Methods The recipient was a 25-year-old man with CF complicated by bronchiectasis with recurrent episodes of pneumonia, pancreatic exocrine insufficiency, and CFRD. He had normal hepatic and renal function. Surgical Technique The lung and pancreas allografts were procured from a single cadaveric donor. The double lung transplantation was performed through separate thoracic incisions. The pancreas transplantation was performed through a midline incision with systemic venous drainage and proximal enteric exocrine drainage. Results The recipient recovered well from his transplantation with early extubation. The pancreas allograft functioned well with normal blood glucose independent of insulin. As a result of the enteric drainage of the pancreas allograft, the patient no longer required supplemental pancreatic enzymes. His postoperative course was complicated by distal intestinal obstruction, a complex wound infection, and reversible leukoencephalopathy. At 1-year posttransplantation he remains free of supplemental oxygen, insulin, and pancreatic enzyme replacement. Conclusion Simultaneous lung and pancreas transplantation in a patient with CF was performed safely, providing the advantages of normalization of glucose and improved nutrition for a patient requiring lung transplantation.

Introduction Avoidance of previous donor mismatched HLA antigens is often considered for lung re-transplant due to concerns of potential HLA sensitization and memory responses. However, this approach may result in the exclusion of a large number of potential donors from consideration. Recently, we successfully performed a re-transplant with a history of multiple repeated mismatches. Patient/method A 30+ year old male with a past medical history of cystic fibrosis underwent two previous bilateral lung transplants in August 2004 and in November 2010. Both allografts failed due to CLAD/BOS that developed after respiratory viral infections. The patient also subsequently developed detectable class I and II HLA antibodies with a cPRA > 88% in May 2016. Among these antibodies, strong anti-A1, B7 and DQ2 were first donor HLA specific. The second donor shared an A3-B18-DR4 haplotype with the first donor but not the recipient. No HLA antibodies specific to this A3-B18-DR4 haplotype antigens or to any other mismatched HLA antigens of the second donor were detected. A third lung transplant became urgently necessary in October 2016. Adding his previous donors’ mismatched HLA antigens to the unacceptable HLA list resulted in a cPRA > 96%. Therefore, a personalized listing strategy was developed based on discussions between the HLA lab and the transplant program. Results A deceased donor became available in November 2016. The virtual crossmatch revealed that the donor had no unacceptable HLA antigens based on HLA antibody detection. However, this donor carried the A3-B18-DR4 haplotype which was a repeated mismatch haplotype of the previous two donors. Based on a risk and benefit assessment, this donor was accepted as the source of lungs for the third transplant. The patient received 5 plasmapheresis sessions post-transplant to prevent antibody mediated rejection. Frequent post-transplant HLA antibody monitoring has not detected development of donor specific antibodies to the third donor and the new allograft functions well. Conclusion Lung re-transplant can be performed with a cross of a repeated HLA mismatch provided that the recipient has no detectable HLA antibodies specific to the current donor. Our preliminary findings obtained from our study conducted on UNOS lung transplant data supports this conclusion. An assessment of risk and benefit of crossing the repeated mismatch HLA antigens should be done on a case-by-case basis.

The Space VLBI mission, VSOP, involves the participation of 15 countries with up to 40 radio telescopes spread across the Earth observing in close coordination with the 8 m radio telescope on board the Japanese spacecraft HALCA (Hirabayashi, 1998, and this Proceedings). This paper describes the contributions to the mission's success from Southern Hemisphere radio telescopes, facilities and Institutes.

We are using the VSOP spacecraft, HALCA, together with ground-based telescopes, to image six strong GPS sources with compact double structure. Space-ground baselines are needed to achieve the resolution to accurately measure component sizes at the frequency of the spectral peak, an essential requirement in distinguishing between free-free and synchrotron self absorption emission mechanisms. Many of the components of these sources are only just beginning to show signs of any internal structure on the longest Earth baselines and space VLBI is the only technique that permits investigation of their most compact structure at the frequency of the spectral peak.

On 27 July 1994 the Burst and Transient Source Experiment (BATSE) on the Compton Gamma Ray Observatory detected an outburst of high energy X-rays from a previously unknown source in the constellation Scorpius. This source was designated GRO J1655-40. Approximately 12 days after the start of the X-ray outburst, a strong outburst of radio emission occurred. Here we present very long baseline interferometry (VLBI) observations of GRO J1655-40 made with an array of telescopes in Australia, South Africa, and the western United States. These observations show that the radio source which appeared two weeks after the initial X-ray outburst consisted of two prominent components which separated with an apparent speed of 1.5 ± 0.4c. When the various possibilities for the geometry of the radio source are taken into account the apparent speed implies an intrinsic speed between 0.5c and 0.9c. Our results and those of other investigators imply a strong link between the accretion of material onto a highly compact object and the ejection of relativistic components of radio emission.

In our model of experimental autoimmune glomerulonephritis (EAG), BN rats given a single IM injection of homologous glomerular basement membrane (GBM) in FCA develop anti-GBM autoantibodies with focal glomerulonephritis. To investigate the role of lymphocytes in the induction of EAG, we examined the effects of antigen rechallenge and of adoptive cell transfer from donors with nephritis to naive recipients. Groups of animals were rechallenged with GBM in FCA following either low (non-nephritogenic) doses of GBM, or following resolution of EAG. This resulted in an enhanced anti-GBM antibody response in both groups, suggesting the presence of GBM specific T or B memory cells. To investigate this possibility, spleen cells from animals with EAG were transferred into lightly irradiated recipients. There was no significant rise in anti-GBM antibody levels after transfer. However, subsequent challenge with GBM in FCA resulted in an enhanced anti-GBM antibody response by 2 weeks when compared with recipients of normal spleen cells. Cells capable of priming for EAG developed by week 4 after immunization of donors and persisted in the recipients for at least 24 weeks. To investigate which cell type was responsible for this effect, we depleted or positively selected donor spleen cells prior to transfer, using Dynabeads coated with monoclonal antibodies to Th or B lymphocytes. Depletion of Th cells, but not B cells, reduced the enhanced anti-GBM antibody response of recipients challenged with GBM in FCA. Positively selected Th cells, but not B cells, resulted in an enhanced anti-GBM antibody response similar to that in positive controls. These results demonstrate the presence of immunological memory for the autoantigen and show that priming for EAG is mediated by Th lymphocytes.

As part of a larger study, medical practitioners working in Mamre, a 'coloured' village close to Cape Town, South Africa, were interviewed concerning their use of the term 'nerves' in interaction with their patients. Contrary to the initial perception of researchers and some clinicians, the term is not simply a folk category. It does, however, represent a medium through which psychosocial issues are discussed in the clinical encounter. Differences in the usage of the term by different practitioners seemed to indicate different attitudes towards patient care. The data are presented and discussed in the context of debates concerning the development of more accessible and responsive health services in a future South Africa, and the information gleaned has implications for future training of clinicians.

In the wake of the respective contentions put forward by Israel and the Palestinians in the context of 'Operation Cast Lead', this paper seeks to revisit the debates regarding Palestinian statehood that simmered in international legal circles following the 1988 Declaration of Independence, and the signing of the Oslo Accords in the mid-1990s. In considering the matter, a number of questions beg; not least regarding over which territory or territories the purported Palestinian state is constituted, who the representative authorities of that state are, how a ‘state’ is construed in international law, and for what purpose. The paper accordingly looks at the concepts of statehood and sovereignty in international law and considers their application in the Palestinian context.

Several innovative techniques have been described to overcome obstacles to surgically placed MCS systems in patients with palliated atrial switch procedures but have limited applicability during acute cardiovascular collapse. Among options available in the United States, only the TandemHeart provides sufficient cardiac output and decompresses the systemic ventricle. The recently approved Impella CP (4.0 liters/min; AbioMed Inc, Danvers, MA) may now be an option. However, the percutaneously placed Impella 2.5 does not provide adequate support, and the larger Impella 5.0 device requires surgical placement. Although extracorporeal membrane oxygenation provides circulatory support, it does not decompress the systemic ventricle. To perform a trans-baffle puncture, the needle is directed to the right and anterior (opposite of normal), and it can also be performed from the superior vena cava, which is normally extremely difficult. To gain insight into the complexity of the systemic and pulmonary venous baffles, which are complex, 3-dimensional intraatrial pathways, it helps to use the analogy of a pair of trousers. The systemic baffle is created by connecting the legs/limbs of the trouser to the superior and inferior vena cava and across the atrial septum to the mitral valve (Figure 2A). The right and left pulmonary veins join and wrap around the right side of the systemic venous baffle from posterior to anterior, creating the pulmonary venous baffle (Figure 2B and C). In conclusion, patients palliated with an atrial switch procedure can also benefit from rapid percutaneous MCS. Innovative adaptation of existing technology and collaborative teams are essential to provide cardiovascular care to adults who have received palliation for congenital heart disease.

Purpose Antibodies directed against human leukocyte antigens, particularly donor specific anti-HLA antibodies (DSAs), have been associated with the development of bronchiolitis obliterans syndrome and worse survival after lung transplant. Antibody depletion therapies have been successfully used to treat humoral rejection in kidney transplant recipients. We hypothesized that antibody directed therapies would alter circulating antibodies and improve survival in lung transplant recipients with evidence of allograft dysfunction and DSAs. Methods and Materials We developed a standard treatment that includes plasmapheresis, methylprednisolone, bortezomib, rituximab and IVIG. HLA antibodies were measured serially pre and post treatment with consideration for changes in the calculated panel reactive antibody (cPRA), a quantification of detectable anti-HLA antibodies. Primary endpoints were changes in cPRA class I and cPRA class II over time. Secondary endpoint was 1 year survival after starting therapy. Results Between 9/2010 and 2/2012, 9 LT recipients with DSA and allograft dysfunction received antibody directed therapy. Of the 411 HLA antibody tests reviewed, single antigen determination was available for 34 cPRA class I and for 69 cPRA class II values. Considering repeated measures overtime, there was a significant change in class I cPRA (p=0.01). There was no significant change in class II cPRA over time (p=0.88). One year unadjusted survival following antibody directed therapy was 61%. Conclusions Donor-specific HLA antibodies are associated with worse outcomes after lung transplantation and may be representative of antibody mediated rejection. The optimal treatment of DSAs is unknown. A protocol involving plasmapheresis and biological agents directed towards antibody depletion can effectively reduce class I cPRA but not class II cPRA. Additional studies are needed to determine if this approach improves allograft function or the poor survival associated with DSAs.

TAC BD then oral TAC, n 90,Aug 08-Jul 10; C) oral TAC BD, n 18 D) IV TAC BD 4hr bolus then oral TAC, n 62 (both Jul 10-Jul 11). SL TAC was specifically prepared by pharmacy to optimize buccal absorption. CSA/TAC trough levels at days 1-7, 14 and 28, acute rejection (AR ISHLT grade 2, day 90) and neurotoxicity/ nephrotoxicity events were analyzed. Target trough CSA/TAC levels were 250ng/ml & 8mcg/ml (HPLC) respectively. Results: Along with CSA/TAC all patients received immunosuppression as per institution protocol. Induction with ATG or Simulect was also similar per group (p-ns). There were no differences in recipient/donor demographics, ICU & total LOS between groups. Neurotoxicity nor significant nephrotoxicity were not apparent in any group. Despite extensive education, administration of SL TAC proved impractical with unacceptable trough level variability & poor efficacy.