Search

Remodeling of the coronary arteries is a common feature in severe cases of Kawasaki disease (KD). This pathology is driven by the dysregulated proliferation of vascular fibroblasts, which can lead to coronary artery aneurysms, stenosis, and myocardial ischemia. We undertook this study to investigate whether inhibiting fibroblast proliferation might be an effective therapeutic strategy to prevent coronary artery remodeling in KD.We used a murine model of KD (induced by the injection of the Candida albicans water-soluble complex [CAWS]) and analyzed patient samples to evaluate potential antifibrotic therapies for KD.We identified the mechanistic target of rapamycin (mTOR) pathway as a potential therapeutic target in KD. The mTOR inhibitor rapamycin potently inhibited cardiac fibroblast proliferation in vitro, and vascular fibroblasts up-regulated mTOR kinase signaling in vivo in the CAWS mouse model of KD. We evaluated the in vivo efficacy of mTOR inhibition and found that the therapeutic administration of rapamycin reduced vascular fibrosis and intimal hyperplasia of the coronary arteries in CAWS-injected mice. Furthermore, the analysis of cardiac tissue from KD fatalities revealed that vascular fibroblasts localizing with inflamed coronary arteries up-regulate mTOR signaling, confirming that the mTOR pathway is active in human KD.Our findings demonstrate that mTOR signaling contributes to coronary artery remodeling in KD, and that targeting this pathway offers a potential therapeutic strategy to prevent or restrict this pathology in high-risk KD patients.

Lung transplantation is limited by a lack of suitable lung donors. In Australia, the national donation organisation (DonateLife) has taken a major role in optimising organ donor identification. However, the potential outside the DonateLife network hospitals remains uncertain. We aimed to create a prediction model for lung donation within the DonateLife network and estimate the untapped lung donors outside of the DonateLife network. We reviewed all deaths in the state of Victoria’s intensive care units using a prospectively collected population-based intensive care unit database linked to organ donation records. A logistic regression model derived using patient-level data was developed to characterise the lung donors within DonateLife network hospitals. Consequently, we estimated the expected number of lung donors in Victorian hospitals outside the DonateLife network and compared the actual number. Between 2014 and 2018, 291 lung donations occurred from 8043 intensive care unit deaths in DonateLife hospitals, while only three lung donations occurred from 1373 ICU deaths in non-DonateLife hospitals. Age, sex, postoperative admission, sepsis, neurological disease, trauma, chronic respiratory disease, lung oxygenation and serum creatinine were factors independently associated with lung donation. A highly discriminatory prediction model with area under the receiver operator characteristic curve of 0.91 was developed and accurately estimated the number of lung donors. Applying the model to non-DonateLife hospital data predicted only an additional five lung donors. This prediction model revealed few additional lung donor opportunities outside the DonateLife network, and the necessity of alternative and novel strategies for lung donation. A donor prediction model could provide a useful benchmarking tool to explore organ donation potential across different jurisdictions, hospitals and transplanting centres.

Although the use of donation after circulatory death (DCD) donors has increased lung transplant activity, 25-40% of intended DCD donors do not convert to actual donation because of no progression to asystole in the required time frame after withdrawal of cardiorespiratory support (WCRS). No studies have specifically focussed on DCD lung donor progression. This retrospective study reviewed intended DCD lung donors to make a prediction model of the likelihood of progression to death using logistic regression and classification and regression tree (CART). Between 2014 and 2018, 159 of 334 referred DCD donors were accepted, with 100 progressing to transplant, while 59 (37%) did not progress. In logistic regression, a length of ICU stay ≤ 5 days, severe infra-tentorial brain damage on imaging and use of vasopressin were related with the progression to actual donation. CART modelling of the likelihood of death within 90-minute post-WCRS provided prediction with a sensitivity of 1.00 and positive predictive value of 0.56 in the validation data set. In the nonprogressed DCD group, 26 died within 6 h post-WCRS. Referral received early after ICU admission, with nonspontaneous ventilatory mode, deep coma and severe infra-tentorial damage were relevant predictors. The CART model is useful to exclude DCD donor candidates with low probability of progression.

Recent studies have established that memory B cells, largely thought to be circulatory in the blood, can take up long-term residency in inflamed tissues, analogous to widely described tissue-resident T cells. The dynamics of recruitment and retention of memory B cells to tissues and their immunological purpose remains unclear. Here, we characterized tissue-resident memory B cells (B RM ) that are stably maintained in the lungs of mice after pulmonary influenza infection. Influenza - specific B RM were localized within inducible bronchus-associated lymphoid tissues (iBALTs) and displayed transcriptional signatures distinct from classical memory B cells in the blood or spleen while showing partial overlap with memory B cells in lung-draining lymph nodes. We identified lung-resident markers, including elevated expression of CXCR3, CCR6, and CD69, on hemagglutinin (HA)– and nucleoprotein (NP)–specific lung B RM . We found that CCR6 facilitates increased recruitment and/or retention of B RM in lungs and differentiation into antibody-secreting cells upon recall. Although expression of CXCR3 and CCR6 was comparable in total and influenza-specific memory B cells isolated across tissues of human donors, CD69 expression was higher in memory B cells from lung and draining lymph nodes of human organ donors relative to splenic and PBMC-derived populations, indicating that mechanisms underpinning B RM localization may be evolutionarily conserved. Last, we demonstrate that human memory B cells in lungs are transcriptionally distinct to populations in lung-draining lymph nodes or PBMCs. These data suggest that B RM may constitute a discrete component of B cell immunity, positioned at the lung mucosa for rapid humoral response against respiratory viral infections.

The spleen is a compartmentalized organ that serves as a blood filter and safeguard of systemic immune surveillance. Labyrinthine networks of fibroblastic stromal cells construct complex niches within the white pulp and red pulp that are important for tissue homeostasis and immune activation. However, the identity and roles of the global splenic fibroblastic stromal cells in homeostasis and immune responses are poorly defined. Here, we performed a cellular and molecular dissection of the splenic reticular stromal cell landscape. We found that white pulp fibroblastic reticular cells (FRCs) responded robustly during acute viral infection, but this program of gene regulation was suppressed during persistent viral infection. Single-cell transcriptomic analyses in mice revealed diverse fibroblast cell niches and unexpected heterogeneity among podoplanin-expressing cells that include glial, mesothelial, and adventitial cells in addition to FRCs. We found analogous fibroblastic stromal cell diversity in the human spleen. In addition, we identify the transcription factor SpiB as a critical regulator required to support white pulp FRC differentiation, homeostatic chemokine expression, and antiviral T cell responses. Together, our study provides a comprehensive map of fibroblastic stromal cell types in the spleen and defines roles for red and white pulp fibroblasts for splenic function and orchestration of immune responses.

We aimed to facilitate the donation of tissue samples for research by establishing a centralized system integrated in the organ donation program for collection, storage, and distribution of samples (the Australian Donation and Transplantation Biobank [ADTB]).Feasibility of a research biobank integrated within the deceased organ and tissue donation program was assessed. DonateLife Victoria sought consent for ADTB donation after consent was received for organ donation for transplantation from the donor's senior available next of kin. ADTB samples were collected during donation surgery and distributed fresh to researchers or stored for future research. The main outcome measures were ADTB donation rates, ADTB sample collection, ADTB sample use, and to identify ethical considerations.Over 2 y, samples were collected for the ADTB from 69 donors (28% of 249 donors). Samples were obtained from the spleen (n = 59, 86%), colon (n = 57, 83%), ileum (n = 56, 82%), duodenum (n = 55, 80%), blood (n = 55, 80%), bone marrow (n = 55, 80%), skin (n = 54, 78%), mesenteric lymph nodes (n = 56, 81%), liver (n = 21, 30%), lung (n = 29, 42%), and lung-draining lymph node (n = 29, 42%). Heart (n = 20), breast (n = 1), and lower urinary tract (n = 1) samples were obtained in the second year. Five hundred fifty-six samples were used in 19 ethics-approved research projects spanning the fields of immunology, microbiology, oncology, anatomy, physiology, and surgery.The integration of routine deceased donation and transplantation activities with a coordinated system for retrieval and allocation of donor samples for use in a range of research projects is feasible and valuable.

Supplemental Digital Content is available in the text., Background. Increased viral risk donors (IVRDs) with increased risk behaviors for blood-borne virus infection and negative nucleic acid testing have a low absolute risk of “window period” infection. Utilization and allocation of IVRD organs differ between jurisdictions. Methods. We examined the characteristics and utilization of deceased donor IVRD kidneys and recipient outcomes within a 2-y period (July 31, 2018–July 31, 2020) postimplementation of a new opt-in allocation pathway for preconsented recipients in Victoria, Australia. Results. Fifty-six kidneys from 31 IVRDs were utilized, comprising 13% of donors. Preconsent rate to accept IVRD kidneys increased to 41% of the waitlist in the 2 y postimplementation, and IVRDs having no kidneys utilized reduced to 0%. Compared with non-IVRD kidneys, kidney offer declines >10 per donor were less likely from IVRDs (3% vs 19%; P < 0.05). IVRDs were younger (median age 36 [IQR 30–44] vs 51 [35–60] y; P < 0.0001), with lower kidney donor profile index (25% [13–40%] vs 57% [29–75%]; P < 0.0001), and less hypertension (0% vs 22%; P < 0.01). Estimated glomerular filtration rate 3 mo post-transplant was superior (P < 0.01). Injecting drug use (61%) was the most common increased risk behavior. 29% of IVRDs were hepatitis C antibody positive but nucleic acid testing negative. No active infection was detected in any recipient post-transplant. Conclusions. The described opt-in system permits efficient allocation and utilization of kidneys from IVRDs, with superior quality and graft function. Education is crucial to facilitate informed consent and equity of access to this donor pool.

This article clarifies the role of donation physicians in the provision of high-quality end-of-life care in intensive care. We briefly address three points on which clarity is essential: the role and duties of a physician who is also a donation physician; the nature of the potential conflict(s) of interest that may arise when decision-making about EOL care is further complicated by the possibility of donation; and the importance of donation as a potential interest of people at the end of life.

Background In Australia, increased organ donation and subsequent lung transplantation (LTx) rates have followed enhanced donor identification, referral and management, as well as the introduction of a donation after circulatory death (DCD) pathway. However, the number of patients waiting for LTx still continues to exceed the number of lung donors and the search for further suitable donors is critical. Methods All 2014–2018 Victorian DonateLife hospital deaths after intensive care unit (ICU) admission were analysed retrospectively to quantify unrecognised lung donors using current criteria, as well as novel time-extended (90 mins–24 hrs post-withdrawal) DCD lung donors. Results Using standard lung donor eligibility criteria, we identified 473 potential lung donors and a further 122 time-extended DCD potential lung donors among 3,538 patients meeting general eligibility criteria. Detailed review of end-of-life discussions with patient families and the reasons why they were not offered donation revealed several categories of additional lung donors–traditional lung donors missed in current practice (n=2); hepatitis C infected lung donors potentially treatable with direct-acting antivirals (n=14), time-extended DCD lung donors (n=60); donor lungs potentially suitable for transplant with use of ex-vivo lung perfusion (EVLP) (n=7). Conclusion While the number of lung donor opportunities missed under existing DonateLife donor identification and management processes was limited, a time-extended DCD lung donation pathway could substantially expand the lung donor pool. The use of hepatitis C infected donors, and the possibility of EVLP to solve donor graft assessment or logistic issues, could also provide small additional lung donor opportunities.

Background Even in the extended-criteria era, the reasons for declining lung donors are not always clear. Furthermore, it has not been determined how many actual declined lungs would be retrieved by ex vivo lung perfusion (EVLP) beyond that already achieved in centers with an existing high utilization rate. Methods This retrospective study reviewed all lung donor referrals between 2014 and 2018, including detailed formal referrals and preliminary notifications. This study categorized reasons for lung donor non-acceptance and estimated how many declined grafts could have been theoretically retrievable by using EVLP. Results In total, 966 lung donor candidates were referred, including 313 transplanted donors, 336 declined donors after detailed referrals (group A) and 258 preliminary declined. In group A, the primary reasons for refusal were lung quality issues (49%), general medical issues (25%), and organization issues (26%), combined with secondary reasons in many cases. Main lung quality issues were an extensive smoking history, abnormal chest radiography, and underlying lung disease. Although 73 declined lung donors had indications for EVLP, the retrievable lungs decreased to only 30 cases after considering the details of all clinical contraindications and organizational issues. Nevertheless, 59 intended donation after circulatory death donors did not progress to death after withdrawal of cardiorespiratory support in the required timeframe, and EVLP may have an emerging additional role here. Conclusions Based on commonly cited criteria for EVLP indication, the number of EVLP retrievable lung donors represented only a small portion of declined donor lungs referred to our center from the state donation network.

End-of-life (EOL) care has become an integral part of intensive care medicine and includes the exploration of possibilities for deceased organ and tissue donation. Donation physicians are specialist doctors with expertise in EOL processes encompassing organ and tissue donation, who contribute significantly to improvements in organ and tissue donation services in many countries around the world. Donation physicians are usually also intensive care physicians, and thus they may be faced with the dual obligation of caring for dying patients and their families in the intensive care unit (ICU), whilst at the same time ensuring organ and tissue donation is considered according to best practice. This dual obligation poses specific ethical challenges that need to be carefully understood by clinicians, institutions and health care networks. These obligations are complementary and provide a unique skillset to care for dying patients and their families in the ICU. In this paper we review current controversies around EOL care in the ICU, including the use of palliative analgesia and sedation specifically with regards to withdrawal of cardiorespiratory support, the usefulness of the so-called doctrine of double effect to guide ethical decision-making, and the management of potential or perceived conflicts of interest in the context of dual professional roles.

BACKGROUND Donor smoking histories are common in the lung donor pool, which are known to adversely affect post–lung transplant (LTx) outcomes. However, no evidence is available about smoking status (current/former), cumulative dose effect, or the combined effect of tobacco with marijuana. METHODS We retrospectively reviewed our local state-based donation organization records and subsequent LTx recipient outcomes. The primary outcome was 3-year graft survival, with cause of death as secondary outcomes. Univariate and multivariate Cox regression analyses were used to explore smoking status or cumulative dose effect. RESULTS Between 2014 and 2018, 304 LTxs were performed: 133 (44%) LTxs were from never-smoker donors, 68 (22%) from former-smoker donors, and 103 (34%) from current-smoker donors. Of the current-smoker donors, 48% had a marijuana use history. There was no significant difference in early mortality, although recipients who received transplants from current-smoker donors had a lower 3-year graft survival than those who received transplants from never smokers. Multivariate modeling showed that current tobacco smoking (hazard ratio: 2.13, 95% CI: 1.13–3.99) and a more than 5-year weekly marijuana use (hazard ratio: 2.97, 95% CI: 1.29–6.87) were independent donor factors affecting graft survival. Chronic lung allograft dysfunction accounted for a higher proportion of the causes of death within 3 years after LTx where lungs from current/former smokers were utilized compared with those from never smokers (chronic lung allograft dysfunction-cause mortality: 11%, 7%, 0%, respectively). CONCLUSIONS More than 50% of LTx donors had smoking histories. Current tobacco use or more than 5-year weekly marijuana smoking history adversely affected 3-year graft survival. Our findings support the importance of obtaining a detailed donor tobacco and marijuana smoking history.

Background Although it is intense in health care resources, by facilitating assessment and reconditioning, ex vivo lung perfusion (EVLP) has the potential to expand the donor pool and improve lung transplant outcomes. However, inclusion criteria used in EVLP trials have not been validated. Methods This retrospective study from 2014 to 2018 reviewed our local state-based donation organization donor records as well as subsequent recipient outcomes to explore the relation between EVLP indications used in clinical trials and recipient outcomes. The primary outcome was primary graft dysfunction grade 3 at 24 hours, with 30-day mortality and posttransplant survival time as secondary outcomes, compared with univariate and multivariate analysis. Results From 705 lung donor referrals, 304 lung transplantations were performed (use rate of 42%); 212 of recipients (70%) met at least 1 of the commonly cited EVLP initiation criteria. There was no significant difference in primary graft dysfunction grade 3 or 30-day mortality between recipients with or without an EVLP indication (10.2% versus 7.8%, P = .51; and 2.4% versus 0%, P = .14, respectively). Multivariate analyses showed no significant relationship between commonly cited EVLP criteria and primary graft dysfunction grade 3 or survival time. Recipient outcomes were significantly associated with recipient diagnosis. Conclusions At least 1 commonly cited criterion for EVLP initiation was present in 70% of the transplanted donors, and yet it did not predict clinical results; acceptable outcomes were seen in both subgroups. To discover the true utility of EVLP beyond good clinical management and focus EVLP on otherwise unacceptable lungs, a reconsideration of EVLP inclusion criteria is required.

Purpose Although use of donation-after-circulatory-death (DCD) donors has significantly increased lung transplant (LTx) rates, 25-40% of intended DCD do not convert to actual donors due to non-progression to asystole in the required 90 minute time frame from withdrawal of cardio-respiratory support (WCRS). Predicting which intended DCD patient will progress remains problematic & impacts resourcing. Methods This retrospective study reviewed intended DCD lung donors referred between 2014-2018 to our program, to determine specific factors that may predict the likelihood of progression to death in ≤90mins. Donor demographics, relevant medical history, reason for WCRS, ICU hemodynamic/ventilation/admission data were compared between non-progresses and LTx DCD donor cohorts. Significant variables were included in multivariable logistic regression analysis and construction of a classification and regression tree (CART) prediction model. Results 159 of 334 referred DCD donors were accepted for LTx: 100 (63%) progressed to donation, 59 (37%) did not progress. Comparing non-progressed & LTx DCD donors, significant factors associated with death ≤90mins were: length of ICU stay ≤4 days, Glascow Coma Score=3, ventilation mode and severe infra-tentorial brain damage on imaging by CT/MRI . These factors were used to develop a CART predictive model for progression ≤90mins post-WCRS, which had a sensitivity of 0.95 and predictive value of 0.69 (Figure 1). Of the 59 who did not progress, 26 patients (44%) died within the subsequent 6 hours. Conclusion Intended DCD lung donors referred early after ICU admission, in a deep coma with severe infra-tentorial damage suggesting a significant neurological injury, are to most likely to progress within 90-minute post-WCRS. This CART prediction model is now being utilized prospectively to assist LTx team re decisions on potential DCD lung donor retrievals & resource allocation. Use of a time-extended DCD lung protocol up to 6 hours post WCRS, further expands the lung donor pool.

Deceased donation of kidneys for transplantation may occur through either brain death (BD) or donation after circulatory death (DCD) pathways with similar long-term benefit. Absolute contraindications to donation are few, and donors with chronic comorbidities such as hypertension and vascular disease frequently are considered. BD and its associated pathophysiology can affect graft function, necessitating careful supportive treatment in the intensive care unit (ICU), paying attention to the cardiovascular, endocrine, respiratory, and hematologic changes. Although maintenance of physiologic homeostasis appears logical, there is insufficient evidence to support a particular management algorithm over another. Nonetheless, hormonal supplementation frequently is used based on retrospective data showing increased graft use from donors treated with these agents in combination. DCD may be “controlled” (after withdrawal of ICU supports in anticipation of death), or “uncontrolled” (donation after a failed resuscitation attempt). In controlled DCD the principles of physiologic support and management before death are similar to other ICU patients, recognizing the specific ethical and legal considerations relating to antemortem interventions in these patients. In uncontrolled DCD the focus is on postmortem interventions, such as regional normothermic or hypothermic perfusion. Machine cold perfusion and ex vivo normothermic perfusion are additional strategies that are being evaluated to assess and preserve graft function in DCD donors.

Purpose Prophylactic laxative regimens may prevent constipation but may increase diarrhea and subsequent rectal tube insertion. Our aim was to compare three prophylactic laxative regimens on the rate of rectal tube insertion (primary outcome) and major constipation- or diarrhea-associated complications. Material and Methods We conducted a cluster-crossover trial. Three pods in a single ICU were each randomized to one of three regimens for four months with rolling cross-over. All mechanically-ventilated and enterally-fed adult patients received either regimen: A) one coloxyl with senna BD from day one; B) two coloxyl with senna +20 ml lactulose BD commencing on day 3; or C) two coloxyl with senna tablets +20 ml lactulose BD commencing on day 6. Results We enrolled 570 patients (A = 170, B = 205, C = 195) with similar baseline features. Overall, 53 (9.3%) patients received a rectal tube, and insertion rate was not statistically different between the three regimens (A = 12.9%, B = 7.8%, C = 7.7%; p = 0.15). The proportions of patients with other major constipation- or diarrhea-associated complications were similar, as were major patient-centred outcomes. Conclusion Earlier commencement of a prophylactic coloxyl-based laxative regimen (day 1 or 3) did not affect the rates of complications associated with constipation or diarrhea when compared to delayed introduction (day 6).

Purpose Ex-vivo lung perfusion (EVLP) is a complex, expensive assessment tool suggested to predict successful early graft function and therefore which ‘extended’ lungs should be used. Theoretic ‘graft at-risk’ criteria for EVLP initiation used in EVLP trials include: donor age >55yrs, PaO2/FIO2 (PF) 10 unit transfusion, DCD, expected graft ischemia time (GIT) >6hrs. Our centre routinely uses extended donor lungs without EVLP. Methods DonateLife records and clinical databases were combined, with univariate and multivariate analyses undertaken to clarify the relation between EVLP initiation criteria and lung-transplant (LTx) outcomes. Results 304 LTx were performed 2014 to 2018 from 704 donor referrals (=42% conversion rate, =11.3 LTx per million population, cf US = 7.0 LTx PMP). 69% of LTx performed had >1 criteria for EVLP assessment (25% = 2, 5.2% = >3 criteria). Table 1 outlines the incidence and effect of these criteria. A PF 6hrs had small effects on outcomes Conclusion At least 1 recommended criteria for EVLP initiation was present in the majority of our LTx. These did not predict early outcomes- with very acceptable results seen in all subgroups. However, the relevance of combination or extreme criteria in lungs not used is unknown. Based on this study, the true utility of EVLP to enhance LTx acceptability and success rates, beyond good clinical management alone, requires an RCT.

Purpose Donor tobacco and marijuana smoking are common in the lung donor pool, with both known to adversely affect post-lung transplant (LTx) outcomes. The intermediate survival outcomes and extent of the interactions of these smoking histories has not been described. Methods DonateLife records and clinical databases were combined, with univariate and multivariate analyses undertaken to clarify the relation between donor tobacco and/or marijuana history and LTx outcomes. Results Between 2014-2018, 304 LTx were performed from 296 donors, including: A) 140 (46%) donor never smokers; B) 114 (38%) tobacco-light smokers (= 20pk years) ± marijuana-light smokers; D) 20 (6.6%) marijuana-heavy smokers (= daily use or >5 yrs) + tobacco-light or heavy smokers (n=6 light marijuana only & n= 8 no data resulted not included) (Table 1). Donor smoking type, history and extent varied with donor age & gender. Smoking category adversely impacted 24hrPF ratio. Never smoker A) vs Combination D) were the only categories to show 3yr survival rate difference [P=0.02 by Log-rank (Figure 2), Hazard Ratio: 3.00 (95%CI: 1.17-7.69), P=0.02 by Cox Regression, adjusted for LTx type, diagnosis, and extended donor]. Conclusion A donor smoking history generally has only a small effect on early and later outcomes. Despite a significantly younger donor age, a combined heavy marijuana and tobacco usage history may have long term consequences that need to be balanced against the risk of no-transplant for an individual waiting list potential recipient.

Organ and tissue donation (OTD) rates in New Zealand are low compared to many countries. Young adults are 'tomorrow's donors', yet the attitudes and knowledge of this group to OTD have not been examined locally. Such information is relevant to ODT education and clinical engagement.A random sample of University of Otago students (25 years, permanent New Zealand resident) was surveyed to examine OTD knowledge and attitudes. This included general knowledge, OTD policy (opt-in, opt-out), donation by self, and donation by loved ones. Questions included yes-no, multiple choice, and Likert-type responses. Analyses by sex, demographic characteristics, supportive attitudes to ODT, and University of Otago student profile were performed.180 responses were gathered (mean age 20.1 years, 67% female, 68% New Zealand European); there were no age or response differences between sexes, participants were generally not representative of the University of Otago student profile. Outcomes indicated limited OTD knowledge, positive support for OTD, and willingness to engage in donation the decision-making process for loved ones. Differences between supportive and non-supportive OTD attitudes was seen for some questions.Findings highlight areas for strategic OTD public engagement and provide details relevant to guiding appropriate clinical interaction in facilitating decisions about OTD.