Objective Oxidant stress pathway activation during ischemia reperfusion injury may contribute to the development of primary graft dysfunction (PGD) after lung transplantation. We hypothesized that ...oxidant stress gene variation in recipients and donors is associated with PGD. Methods Donors and recipients from the Lung Transplant Outcomes Group (LTOG) cohort were genotyped using the Illumina IBC chip filtered for oxidant stress pathway genes. Single nucleotide polymorphisms (SNPs) grouped into SNP sets based on haplotype blocks within 49 oxidant stress genes selected from gene ontology pathways and literature review were tested for PGD association using a sequencing kernel association test. Analyses were adjusted for clinical confounding variables and population stratification. Results Three hundred ninety-two donors and 1038 recipients met genetic quality control standards. Thirty percent of patients developed grade 3 PGD within 72 hours. Donor NADPH oxidase 3 ( NOX3 ) was associated with PGD ( P = .01) with 5 individual significant loci ( P values between .006 and .03). In recipients, variation in glutathione peroxidase ( GPX1 ) and NRF-2 ( NFE2L2 ) was significantly associated with PGD ( P = .01 for both). The GPX1 association included 3 individual loci ( P values between .006 and .049) and the NFE2L2 association included 2 loci ( P = .03 and .05). Significant epistatic effects influencing PGD susceptibility were evident between 3 different donor blocks of NOX3 and recipient NFE2L2 ( P = .026, P = .017, and P = .031). Conclusions Our study has prioritized GPX1 , NOX3 , and NFE2L2 genes for future research in PGD pathogenesis, and highlights a donor-recipient interaction of NOX3 and NFE2L2 that increases the risk of PGD.
The lung microbiome in lung transplantation McGinniss, John E; Whiteside, Samantha A; Simon-Soro, Aurea ...
The Journal of heart and lung transplantation,
08/2021, Letnik:
40, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Culture-independent study of the lower respiratory tract after lung transplantation has enabled an understanding of the microbiome - that is, the collection of bacteria, fungi, and viruses, and their ...respective gene complement - in this niche. The lung has unique features as a microbial environment, with balanced entry from the upper respiratory tract, clearance, and local replication. There are many pressures impacting the microbiome after transplantation, including donor allograft factors, recipient host factors such as underlying disease and ongoing exposure to the microbe-rich upper respiratory tract, and transplantation-related immunosuppression, antimicrobials, and postsurgical changes. To date, we understand that the lung microbiome after transplant is dysbiotic; that is, it has higher biomass and altered composition compared to a healthy lung. Emerging data suggest that specific microbiome features may be linked to host responses, both immune and non-immune, and clinical outcomes such as chronic lung allograft dysfunction (CLAD), but many questions remain. The goal of this review is to put into context our burgeoning understanding of the lung microbiome in the postlung transplant patient, the interactions between microbiome and host, the role the microbiome may play in post-transplant complications, and critical outstanding research questions.
Endobronchial stents are increasingly used to treat airway complications in multiple conditions including lung transplantation but little is known about the biofilms that form on these devices. We ...applied deep sequencing to profile luminal biofilms of 46 endobronchial stents removed from 20 subjects primarily with lung transplantation-associated airway compromise. Microbial communities were analyzed by bacterial 16S rRNA and fungal ITS marker gene sequencing. Corynebacterium was the most common bacterial taxa across biofilm communities. Clustering analysis revealed three bacterial biofilm types: one low diversity and dominated by Corynebacterium; another was polymicrobial and characterized by Staphylococcus; and the third was polymicrobial and associated with Pseudomonas, Streptococcus, and Prevotella. Biofilm type was significantly correlated with stent material: covered metal with the Staphylococcus-type biofilm, silicone with the Corynebacterium-dominated biofilm, and uncovered metal with the polymicrobial biofilm. Subjects with sequential stents had frequent transitions between community types. Fungal analysis found Candida was most prevalent, Aspergillus was common and highly enriched in two of three stents associated with airway anastomotic dehiscence, and fungal taxa not typically considered pathogens were highly enriched in some stents. Thus, molecular analysis revealed a complex and dynamic endobronchial stent biofilm with three bacterial types that associate with stent material, a central role for Corynebacterium, and that both expected and unexpected fungi inhabit this unique niche. The current work provides a foundation for studies to investigate the relationship between stent biofilm composition and clinical outcomes, mechanisms of biofilm establishment, and strategies for improved stent technology and use in airway compromise.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The gamma-aminobutyric acid A (GABAA) receptor is an important mediator of cellular signaling in the globus pallidus (GP) and might be implicated in the pathophysiology of Parkinson disease (PD). The ...goal of the present study was to characterize GABAA receptor subunit expression in the normal and parkinsonian human GP.
Postmortem brain specimens were obtained from 8 patients with pathological evidence of PD at autopsy and from 4 patients without such evidence. These tissues were exposed to primary antibodies directed against the α1 and α3 subunits of the GABAA receptor and were visualized and quantified using fluorescence microscopy.
No differences were found in the pallidal neuronal density in the control versus PD tissues. Projection neurons strongly expressed the α1, α3, and β2 GABAA receptor subunits. After normalizing the immunofluorescence intensities in the GP to those in the adjacent structures, no significant differences were found in GABAA receptor subunit expression in the GP between the PD specimens and the control specimens.
Compensatory changes in GABAA receptor α1 and α3 subunit expression in response to PD-related signaling abnormalities in the GP did not occur in our PD cohort.
Primary graft dysfunction (PGD) is a risk factor for chronic lung allograft dysfunction (CLAD). However, the association between PGD and degree of allograft injury remains poorly defined. In this ...study, we leverage a novel biomarker for allograft injury, percentage donor-derived cell-free DNA (%ddcfDNA), to study the association between PGD, degree of allograft injury, and the development of CLAD.
This prospective cohort study recruited 99 lung transplant recipients and collected plasma samples on days 1, 3, and 7 for %ddcfDNA measurements. Clinical data on day 3 was used to adjudicate for PGD. %ddcfDNA levels were compared between PGD grades. In PGD patients, %ddcfDNA was compared between those who developed CLAD and those who did not.
On posttransplant day 3, %ddcfDNA was higher in PGD than in non-PGD patients (median IQR: 12.2% 8.2, 22.0 vs 8.5% 5.6, 13.2 p = 0.01). %ddcfDNA correlated with the severity grade of PGD (r = 0.24, p = 0.02). Within the PGD group, higher levels of %ddcfDNA correlated with increased risk of developing CLAD (log OR(SE) 1.38 (0.53), p = 0.009). PGD patients who developed CLAD showed ∼2-times higher %ddcfDNA levels than patients who did not develop CLAD (median IQR: 22.4% 11.8, 27.6 vs 9.9% 6.7, 14.9, p = 0.007).
PGD patients demonstrated increased early posttransplant allograft injury, as measured by %ddcfDNA, in comparison to non-PGD patients, and these high %ddcfDNA levels were associated with subsequent development of CLAD. This study suggests that %ddcfDNA identifies PGD patients at greater risk of CLAD than PGD alone.
Tacrolimus exhibits unpredictable pharmacokinetics (PKs) after lung transplant, partly explained by cytochrome P450 (CYP)–enzyme polymorphisms. However, whether exposure variability during the ...immediate postoperative period affects outcomes is unknown, and pharmacogenetic dosing may be limited by residual PK variability. We estimated adjusted associations between early postoperative tacrolimus concentrations and acute kidney injury (AKI) and acute cellular rejection (ACR), and identified clinical and pharmacogenetic factors that explain postoperative tacrolimus concentration variability in 484 lung transplant patients. Increasing tacrolimus concentration was associated with higher AKI risk (hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.20–1.96 per 5‐mg/dL); and increasing AKI severity (odds ratio 1.29; 95% CI 1.04–1.60 per 5‐mg/dL), but not ACR (HR 1.02; 95% CI 0.73–1.42). A model with clinical and pharmacogenetic factors explained 42% of concentration variance compared with 19% for pharmacogenetic factors only. Early tacrolimus exposure was independently associated with AKI after lung transplantation, but not ACR. Clinical factors accounted for substantial residual tacrolimus concentration variability not explained by CYP‐enzyme polymorphisms.
•A small proportion (13%) of CF lung transplant recipients have been prescribed ETI.•Most recipients were prescribed ETI for sinus disease or GI symptoms.•Many (30–40%) CF lung transplant recipients ...stopped ETI due to side effects.•Hemoglobin and hemoglobin A1c may improve with ETI use after transplant.
Cystic fibrosis (CF) lung transplant (LT) recipients may warrant treatment with elexacaftor/tezacaftor/ivacaftor (ETI) to improve extrapulmonary manifestations of CF. Our objectives were to identify reasons for prescribing ETI after LT and evaluate changes in body mass index (BMI), hemoglobin A1c, hemoglobin, and liver enzymes.
This was an electronic health record-based cohort study, October 2019-September 2020, at 14 CF LT Consortium sites in North America. The study included CF LT recipients prescribed ETI after transplant. Differences in BMI, A1c, and hemoglobin were assessed with paired t-tests.
There were 94 patients prescribed ETI; indications included sinus disease (68%), GI symptoms (39%), or low BMI (19%). Prescriptions were written by CF physicians (34%), LT physicians (27%), or physicians who practice both CF and LT (39%). Forty patients (42%) stopped ETI at a median of 56 days IQR 26, 139 after start/prescription date. ETI was not associated with a significant change in BMI (0.2 kg/m2, 95% CI -0.1, 0.6, p = 0.150), but was associated with decreased A1c (0.4%, 95% CI 0.2, 0.7, p = 0.003), and increased hemoglobin for patients with anemia (0.6 g/dL, 95% CI 0.2, 1.0, p = 0.007). Three people (3%) stopped ETI due to elevated transaminases.
ETI is rarely prescribed for non-pulmonary indications after LT for CF. Further study is needed to determine the risks and benefits of ETI in the CF lung transplant population given the potential for drug interactions, side effects leading to discontinuation of ETI, and the possible mechanisms for ETI to positively impact long-term post-transplant outcomes.
Interictal epileptiform discharges have been shown to propagate from focal epileptogenic sources as travelling waves or through more rapid white matter conduction. We hypothesize that both modes of ...propagation are necessary to explain interictal discharge timing delays. We propose a method that, for the first time, incorporates both propagation modes to identify unique potential sources of interictal activity. We retrospectively analysed 38 focal epilepsy patients who underwent intracranial EEG recordings and diffusion-weighted imaging for epilepsy surgery evaluation. Interictal discharges were detected and localized to the most likely source based on relative delays in time of arrival across electrodes, incorporating travelling waves and white matter propagation. We assessed the influence of white matter propagation on distance of spread, timing and clinical interpretation of interictal activity. To evaluate accuracy, we compared our source localization results to earliest spiking regions to predict seizure outcomes. White matter propagation helps to explain the timing delays observed in interictal discharge sequences, underlying rapid and distant propagation. Sources identified based on differences in time of receipt of interictal discharges are often distinct from the leading electrode location. Receipt of activity propagating rapidly via white matter can occur earlier than more local activity propagating via slower cortical travelling waves. In our cohort, our source localization approach was more accurate in predicting seizure outcomes than the leading electrode location. Inclusion of white matter in addition to travelling wave propagation in our model of discharge spread did not improve overall accuracy but allowed for identification of unique and at times distant potential sources of activity, particularly in patients with persistent postoperative seizures. Since distant white matter propagation can occur more rapidly than local travelling wave propagation, combined modes of propagation within an interictal discharge sequence can decouple the commonly assumed relationship between spike timing and distance from the source. Our findings thus highlight the clinical importance of recognizing the presence of dual modes of propagation during interictal discharges, as this may be a cause of clinical mislocalization.
Sleep disruption, a common symptom among patients requiring cardiovascular surgery, is a potential risk factor for the development of postoperative delirium. Postoperative delirium is a disorder of ...acute disturbances in cognition associated with prolonged hospitalization, cognitive decline, and mortality.
The aim of this study was to evaluate the feasibility and acceptability of using polysomnography (PSG) to capture sleep in patients with scheduled cardiothoracic surgery.
Wireless limited PSG assessed sleep at baseline (presurgery at home), postoperatively in the intensive care unit, and at home post hospital discharge. Primary outcomes were quality and completeness of PSG signals, and acceptability by participants and nursing staff.
Among 15 patients, PSG data were of high quality, and mean percentage of unscorable data was 5.5% ± 11.1%, 3.7% ± 5.4%, and 3.7% ± 8.4% for baseline, intensive care unit, and posthospitalization measurements, respectively. Nurses and patients found the PSG monitor acceptable.
Wireless, limited PSG to capture sleep across the surgical continuum was feasible, and data were of high quality. Authors of future studies will evaluate associations of sleep indices and development of postoperative delirium in this high-risk population.
Primary graft dysfunction (PGD) is the principal cause of early morbidity and mortality after lung transplantation. The lung microbiome has been implicated in later transplantation outcomes but has ...not been investigated in PGD.
To define the peritransplant bacterial lung microbiome and relationship to host response and PGD.
This was a single-center prospective cohort study. Airway lavage samples from donor lungs before organ procurement and recipient allografts immediately after implantation underwent bacterial 16S ribosomal ribonucleic acid gene sequencing. Recipient allograft samples were analyzed for cytokines by multiplex array and pepsin by ELISA.
We enrolled 139 transplant subjects and obtained donor lung (
= 109) and recipient allograft (
= 136) samples. Severe PGD (persistent grade 3) developed in 15 subjects over the first 72 hours, and 40 remained without PGD (persistent grade 0). The microbiome of donor lungs differed from healthy lungs, and recipient allograft microbiomes differed from donor lungs. Development of severe PGD was associated with enrichment in the immediate postimplantation lung of oropharyngeal anaerobic taxa, particularly
. Elevated pepsin, a gastric biomarker, and a hyperinflammatory cytokine profile were present in recipient allografts in severe PGD and strongly correlated with microbiome composition. Together, immediate postimplantation allograft
/
ratio, pepsin, and indicator cytokines were associated with development of severe PGD during the 72-hour post-transplantation period (area under the curve = 0.81).
Lung allografts that develop PGD have a microbiome enriched in anaerobic oropharyngeal taxa, elevated gastric pepsin, and hyperinflammatory phenotype. These findings suggest a possible role for peritransplant aspiration in PGD, a potentially actionable mechanism that warrants further investigation.
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