Health Care Research Institute Research Articles

O.1.2-5 How to make physical activity part of daily life for elderly using the IPitup activity bench: CrossCare research

Abstract Purpose The main goal of IPitup is to lower the threshold to physical activity and to encourage people to become more active in public spaces. To do so IPitup (npo) offers a package that is built around the activity bench, an urban sitting furniture that provides a wide range of strength, balance and cardiovascular exercises. An app and training courses for coaches complete the offer. They provide the possibility to easily put into practice the WHO guidelines for physical activity. Within the CrossCare project, IPitup focussed specifically on prevention among elderly to allow them to remain physically active in their own living environment. Project description At first the market demand was mapped and stakeholders were identified. An extensive survey (n = 229) then provided insights into the movement patterns of the primary end-users and illustrated among others the interest in the existing IPitup package. 93% was found to be convinced of the importance of physical activity and 92% considered the activity bench suitable for use by elderly. Thanks to input of secondary and tertiary users and with the help of live tests and co-creation sessions, it became clear which adjustments should be made to the activity bench and the accompanying services. Input from elderly, caregivers, local residents, healthcare professionals and local governments made clear the importance of a comprehensive approach. Getting seniors to become more physically active requires more than just creating an movement-friendly environment (hardware). This only makes sense if sufficient attention goes to an adapted offer (software), which must be organized in a way that people get motivated to actively engage (orgware). In the end the concept was successfully implemented in various environments. Post-research practice suggested the project is replicable in other countries. Conclusions In elderly there is a clear acknowledgment and conviction about the importance of physical activity. Based on input from various stakeholders, specific adjustments were made to the activity bench and its supporting services. This seems to make the IPitup concept a valuable tool to lower the threshold for older people to become more active in daily life. Interreg project supported by four healthcare research institutes.

Situation analysis of research ethics governance in Pakistan.

Mapping of ethical governance structures is very useful in identifying strengths and weaknesses in order to uphold integrity and ensure standardization. However, reliable countrywide data about ethical review committees (ERCs) is unavailable in Pakistan. To evaluate the research ethics governance mechanisms at national level and at key healthcare institutions in Pakistan. This pilot mapping exercise used a mixed-methods approach, involving a cross-sectional survey of 19 key healthcare research institutions, and structured in-depth interviews with the chairs of the National Bioethics Committee and the Drug Regulatory Authority of Pakistan. Eighteen institutions responded to the ethics mapping survey. Twelve public sector ERCs had a permanent structure and 17 had formal terms of reference. Seven ERCs claimed accreditation, although no central accreditation agency exists in Pakistan. Eight ERCs were chaired by the heads of the institutions. There was no fixed tenure for the heads in 13 committees, and 14 committees allowed multiple terms. Six ERCs had follow-up mechanisms for ethical approvals, and 6 took punitive actions in response to any deviation from an approved protocol, or to a scientific misconduct. Two respondents recalled situations where applicants pressured committee members for favourable approvals. Survey respondents mentioned the lack of central research ethics guidelines as a weakness of the national governance system. Structured interviews revealed the need for formal training of committee members and capacity strengthening, particularly for administrative staff. There is a need to develop guidelines for local ethics governance in Pakistan, and ensure accreditation of ERCs through the National Bioethics Committee to uphold the integrity of the ethics governance structure.

In Memoriam: Richard H. Grimm, Jr, MD, MPH, PhD (August 22, 1946-September 8, 2022).

In Memoriam: Richard H. Grimm, Jr, MD, MPH, PhD (August 22, 1946-September 8, 2022).

214.5: Long-term Outcomes in Primary Simultaneous Kidney and Pancreas Recipients Under Steroid Avoidance in the United States

Background: Steroid avoidance in kidney transplantation has been proven non-inferior. Data on steroid avoidance in simultaneous pancreas-kidney (SPK) is scant. Methods: We utilized the Scientific Registry of Transplant Recipients (SRTR) between 2000 and 2020 we studied all primary crossmatch negative SPK recipients (N=5683) who received anti-thymocyte globulin for induction and were discharged alive on tacrolimus and mycophenolate with or without steroid maintenance. Recipients were grouped according to steroid use into two groups: steroid maintenance n=4191 and steroid avoidance n=1492. Kaplan-Meier curves with generated for Recipient and allografts survival according to steroid maintenance censored at 10 years. Predictors for recipient and grafts survival were examined using Cox proportional Hazards. Models were adjusted for age, BMI, ethnicity, diabetes type, HLA-antigen mismatches, cold ischemia time, transplant era, preemptive transplantation, and PDRI with the transplant center included as a random effect. Results: Steroid avoidance gained popularity over the years, accounting for over one fourth of the studied cohort. One-year acute rejection rates by steroid avoidance were comparable for kidney (8.6 vs. 9%, P= 0.783, however pancreas rejection rate was lower in the steroid avoidance group (7.9 vs. 10%. P=0.035). In the Kaplan-Meier analysis for the pancreas death-censored graft survival (DCGS), steroid avoidance was associated with better pancreas graft survival (log-rank p =0.006). The kidney DCGS did not vary between groups (log-rank p=0.233). In the multivariable models, steroid avoidance did not influence recipient (LLCI, aHR, ULCI) (0.94, 1.15,1.39), death-censored pancreas graft survival (0.75, 0.93, 1.16) or kidney (0.95, 1.18, 1.45) compared to recipients on steroid maintenance. Conclusion: After multivariable adjustment for recipient and grafts characteristics, steroid avoidance is associated with similar patient, pancreas and kidney grafts outcomes when compared with steroid maintenance in SPK recipients following r-ATG induction and tacrolimus plus mycophenolate maintenance. The data reported here have been supplied by the Hennepin Healthcare Research Institute (HHRI) as the contractor for the Scientific Registry of Transplant Recipients (SRTR). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy of or interpretation by the SRTR or the U.S. Government.

400.5: Outcomes After Declining a Donation After Cardiac Death (DCD) Liver for Transplant Candidates in the United States

Introduction: In the context of the deceased-donor liver shortage, donation after cardiac death (DCD) provides an opportunity to expand the donor pool, but DCD organs confer higher risk of biliary complications and graft loss. Patients and clinicians who are offered a DCD liver must choose whether to accept the higher risk or remain on the waitlist in hopes of a better offer. We explored outcomes of candidates who declined a DCD offer, and investigated the survival benefit accepting vs declining the offer of a DCD liver. In addition, we estimated the number of additional liver transplants that could be achieved if DCD livers were utilized at the same rate as livers from otherwise-comparable DBD donors. Methods: Using national registry data from the United States (SRTR) 2009-2020, we identified 1,564 candidates who accepted DCD offers (“acceptors”) and 16,981 candidates who declined the same DCD offers (“decliners”). We characterized outcomes of decliners using a competing risk framework. In addition, we compared patient survival of acceptors vs. decliners using Cox regression. We used Poisson regression to compare observed discard of DCD livers to the number of discards expected based on donor characteristics other than DCD. Results: Among DCD decliners, 50.9% died/dropped out from waitlist; only 43.1% were transplanted with a donation after brain death (DBD) liver. DCD acceptors had lower mortality compared to decliners at 10 years post-offer (35.4% vs. 48.9%, p<0.001) (Fiigure 1). After adjustment, DCD acceptors had 46% lower mortality risk compared to DCD decliners (aHR= 0.49 0.54 0.61). The survival benefit of DCD LT varied by MELD stratum. DCD acceptors and decliners with MELD 6-14 at offer had comparable risk of mortality (aHR= 0.56 0.89 1.42, p=0.6). DCD offer acceptors had 55%, 34% and 52% lower risk of mortality compared to DCD offer decliners within MELD strata 15-24 (aHR= 0.39 0.45 0.54, p<0.001), 25-34 (aHR= 0.55 0.66 0.79, p<0.001) and 35 or higher (aHR= 0.29 0.48 0.78, p=0.004), respectively (Figure 2). Out of 1005 recovered DCD livers, 298 were discarded in 2019. If DCD livers were utilized at the same rate as comparable DBD livers, we estimated that 235 (78.9%) of them would have been transplanted. Conclusions: Despite risk of biliary complications, DCD offer acceptance is associated with considerable long-term survival benefit for liver transplant candidates. Increased utilization of DCD livers should be encouraged. This work was supported by grant number K01DK101677 (Massie), 5T32DK007713-23 (Eagleson), and K24DK101828 (Segev) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The analyses described here are the responsibility of the authors alone and do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. The data reported here have been supplied by the Hennepin Healthcare Research Institute (HHRI) as the contractor for the Scientific Registry of Transplant Recipients (SRTR). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy of or interpretation by the SRTR or the U.S. Government.

Mapping spreading depolarisations after traumatic brain injury: a pilot clinical study protocol

IntroductionCortical spreading depolarisation (CSD) is characterised by a near-complete loss of the ionic membrane potential of cortical neurons and glia propagating across the cerebral cortex, which generates a transient suppression...

OPTN/SRTR 2020 Annual Data Report: COVID

OPTN/SRTR 2020 Annual Data Report: COVID

OPTN/SRTR 2020 Annual Data Report: Introduction

OPTN/SRTR 2020 Annual Data Report: Introduction

N,N-dimethyltryptamine and Amazonian ayahuasca plant medicine.

ObjectiveReports have indicated possible uses of ayahuasca for the treatment of conditions including depression, addictions, post‐traumatic stress disorder, anxiety and specific psychoneuroendocrine immune system pathologies. The article assesses potential ayahuasca and N,N‐dimethyltryptamine (DMT) integration with contemporary healthcare. The review also seeks to provide a summary of selected literature regarding the mechanisms of action of DMT and ayahuasca; and assess to what extent the state of research can explain reports of unusual phenomenology.DesignA narrative review.ResultsCompounds in ayahuasca have been found to bind to serotonergic receptors, glutaminergic receptors, sigma‐1 receptors, trace amine‐associated receptors, and modulate BDNF expression and the dopaminergic system. Subjective effects are associated with increased delta and theta oscillations in amygdala and hippocampal regions, decreased alpha wave activity in the default mode network, and stimulations of vision‐related brain regions particularly in the visual association cortex. Both biological processes and field of consciousness models have been proposed to explain subjective effects of DMT and ayahuasca, however, the evidence supporting the proposed models is not sufficient to make confident conclusions. Ayahuasca plant medicine and DMT represent potentially novel treatment modalities.ConclusionsFurther research is required to clarify the mechanisms of action and develop treatments which can be made available to the general public. Integration between healthcare research institutions and reputable practitioners in the Amazon is recommended.

COVID-19−Associated Decline in the Size of the End-Stage Kidney Disease Population in the United States

COVID-19−Associated Decline in the Size of the End-Stage Kidney Disease Population in the United States

Effect of alternative income assistance schedules on drug use and drug-related harm: a randomised controlled trial

SummaryBackgroundThe synchronised monthly disbursement of income assistance, whereby all recipients are paid on the same day, has been associated with increases in illicit drug use and serious associated harms. This phenomenon is often referred to as the cheque effect. Because payment variability can affect consumption patterns, this study aimed to assess whether these harms could be mitigated through a structural intervention that varied income assistance payment timing and frequency.MethodsThis randomised, parallel group trial was done in Vancouver, Canada, and enrolled recipients of income assistance whose drug use increased around payment days. The recipients were randomly assigned 1:2:2 to a control group that received monthly synchronised income assistance payments on government payment days, a staggered group in which participants received single desynchronised monthly income assistance payments, or a split and staggered group in which participants received desynchronised income assistance payments split into two instalments per month, 2 weeks apart, for six monthly payment cycles. Desynchronised payments in the intervention groups were made on individual payment days outside the week of the standard government schedules. Randomisation was through a pre-established stratified block procedure. Investigators and statisticians were masked to group allocation, but participants and front-line staff were not. Complete final results are reported after scheduled interim analyses and the resulting early stoppage of recruitment. Under intention-to-treat specifications, generalised linear mixed models were used to analyse the primary outcome, which was escalations in drug use, predefined as a 40% increase in at least one of: use frequency; use quantity; or number of substances used during the 3 days after government payments. Secondary analyses examined analogous drug use outcomes coinciding with individual payments as well as exposure to violence. This trial is registered with ClinicalTrials.gov, NCT02457949.FindingsBetween Oct 27, 2015, and Jan 2, 2019, 45 participants were enrolled to the control group, 72 to the staggered group, and 77 to the split and staggered group. Intention-to-treat analyses showed a significantly reduced likelihood of increased drug use coinciding with government payment days, relative to the control group, in the staggered (adjusted odds ratio 0·38, 95% CI 0·20–0·74; p=0·0044) and split and staggered (0·44, 0·23–0·83; p=0·012) groups. Findings were consistent in the secondary analyses of drug use coinciding with individual payment days (staggered group 0·50, 0·27–0·96, p=0·036; split and staggered group 0·49, 0·26–0·94, p=0·030). However, secondary outcome analyses of exposure to violence showed increased harm in the staggered group compared with the control group (2·71, 1·06–6·91, p=0·037). Additionally, 51 individuals had a severe or life-threatening adverse event and there were six deaths, none of which was directly attributed to study participation.InterpretationComplex results indicate the potential for modified income assistance payment schedules to mitigate escalations in drug use, provided measures to address unintended harms are also undertaken. Additional research is needed to clarify whether desynchronised schedules produce other unanticipated consequences and if additional measures could mitigate these harms.FundingCanadian Institutes of Health Research, Providence Health Care Research Institute, Peter Wall Institute for Advanced Research, Michael Smith Foundation for Health Research.

COVID-19 mortality among kidney transplant candidates is strongly associated with social determinants of health.

The COVID‐19 pandemic has affected all portions of the global population. However, many factors have been shown to be particularly associated with COVID‐19 mortality including demographic characteristics, behavior, comorbidities, and social conditions. Kidney transplant candidates may be particularly vulnerable to COVID‐19 as many are dialysis‐dependent and have comorbid conditions. We examined factors associated with COVID‐19 mortality among kidney transplant candidates from the National Scientific Registry of Transplant Recipients from March 1 to December 1, 2020. We evaluated crude rates and multivariable incident rate ratios (IRR) of COVID‐19 mortality. There were 131 659 candidates during the study period with 3534 all‐cause deaths and 384 denoted a COVID‐19 cause (5.00/1000 person years). Factors associated with increased COVID‐19 mortality included increased age, males, higher body mass index, and diabetes. In addition, Blacks (IRR = 1.96, 95% C.I.: 1.43–2.69) and Hispanics (IRR = 3.38, 95% C.I.: 2.46–4.66) had higher COVID‐19 mortality relative to Whites. Patients with lower educational attainment, high school or less (IRR = 1.93, 95% C.I.: 1.19–3.12, relative to post‐graduate), Medicaid insurance (IRR = 1.73, 95% C.I.: 1.26–2.39, relative to private), residence in most distressed neighborhoods (fifth quintile IRR = 1.93, 95% C.I.: 1.28–2.90, relative to first quintile), and most urban and most rural had higher adjusted rates of COVID‐19 mortality. Among kidney transplant candidates in the United States, social determinants of health in addition to demographic and clinical factors are significantly associated with COVID‐19 mortality.

Impact of the COVID-19 pandemic on commercial airlines in the United States and implications for the kidney transplant community.

Many deceased-donor and living-donor kidney transplants (KTs) rely on commercial airlines for transport. However, the coronavirus-19 pandemic has drastically impacted the commercial airline industry. To understand potential pandemic-related disruptions in the transportation network of kidneys across the United States, we used national flight data to compare scheduled flights during the pandemic vs 1-year earlier, focusing on Organ Procurement Organization (OPO) pairs between which kidneys historically most likely traveled by direct flight (High Volume by direct Air transport OPO Pairs, HVA-OPs). Across the United States, there were 39% fewer flights in April 2020 vs April 2019. Specific to the kidney transportation network, there were 65.1% fewer flights between HVA-OPs, with considerable OPO-level variation (interquartile range [IQR] 54.7%-75.3%; range 0%-100%). This translated to a drop in median number of flights between HVA-OPs from 112 flights/wk in April 2019 to 34 in April 2020 (P<.001), and a rise in wait time between scheduled flights from 1.5hours in April 2019 (IQR 0.76-3.3) to 4.9hours in April 2020 (IQR 2.6-11.2; P<.001). Fewer flights and longer wait times can impact logistics as well as cold ischemia time; our findings motivate an exploration of creative approaches to KT transport as the impact of this pandemic on the airline industry evolves.

Comparative effectiveness of buprenorphine-naloxone versus methadone for treatment of opioid use disorder: a population-based observational study protocol in British Columbia, Canada

IntroductionDespite a recent meta-analysis including 31 randomised controlled trials comparing methadone and buprenorphine for the treatment of opioid use disorder, important knowledge gaps remain regarding the long-term effectiveness of different...

P851Incidence and prognostic impact of acute infection among patients with type 1 and 2 myocardial infarction

Abstract Background The incidence and impact of acute infection among patients with type 1 (T1MI) and 2 myocardial infarction (T2MI) is not well known. Inflammation and increased procoagulant activity can lead to T1MI, whereas cytokine release can cause hemodynamic alterations affecting myocardial oxygen consumption and contribute to T2MI. Purpose Determine the incidence and prognostic impact of acute infection among patients with T1MI and T2MI. Methods Post-hoc analysis of UTROPIA (NCT02060760), a prospective, observational cohort study involving 1,640 consecutive emergency department patients with serial cardiac troponin (cTn) I measurements obtained on clinical indication. The incidence of acute infection, antibiotic use, and/or laboratory evidence of infection were examined among patients with T1MI and T2MI. 5-year cumulative survival curves were plotted using the Kaplan-Meier method, frequencies were compared via Chi-Square, and a multivariate cox-proportional hazards model was used to assess the impact of infection on mortality. Results Among 217 patients with acute MI (T1MI, n=77 and T2MI, n=140), acute infection occurred in 63 (29%) of patients. Acute infection was more common in patients with T2MI than T1MI (35% vs. 18%, p=0.009). The predominant source of infection was pneumonia (59%), followed by urinary tract infections (11%). Patients with T2MI were also more likely than T1MI to have sepsis (11% vs. 1%, p=0.012), bacteremia (30% vs. 18%, p=0.057), and antibiotic use (35% vs. 17%, p=0.005). At 5-years, patients with acute MI and acute infection had a higher mortality rate than patients without infection (49% vs. 25%, p=0.0006) (Figure). Among the 31 deaths in MI patients with acute infection, most deaths were non-cardiac (65%) and occurred in those with T2MI (77%). Following adjustment for age, sex, and comorbidities in a Cox proportional hazards model, acute infection was an independent predictor of death (hazard ratio: 2.2, 95% CI: 1.3–3.5, p=0.0016). Conclusion Acute infection occurs in almost a third of patients that are diagnosed with acute MI during the index hospitalization. Most infections are due to pneumonia and occur most often in patients classified as having T2MI. Acute infection is an independent risk factor for 5-year mortality, with nearly half of all patients with acute MI in whom concomitant acute infection is present during the index hospitalization dead at 5-years. Most deaths are non-cardiac and the vast majority occur in patients with T2MI. Acknowledgement/Funding Abbott Diagnostics and Hennepin Healthcare Research Institute (formerly MMRF)e

P3608Long-term mortality and mode of death among patients with type 1 and 2 myocardial infarction

Abstract Background Few studies address long-term outcomes among patients with type 2 myocardial infarction (T2MI). It has been suggested that patients with T2MI with concomitant stable ischemic heart disease are at higher-risk. Purpose Our goals were two-fold. First, to examine 5-year mortality rates and mode of death among patients with type 1 (T1MI) and T2MI. Second, to evaluate the prognostic impact of coronary artery disease (CAD) on long-term outcomes among patients with T2MI. Methods Post-hoc analysis of UTROPIA (NCT02060760), a prospective, observational cohort study involving 1,640 consecutive emergency department patients with serial cardiac troponin (cTn) I measurements obtained on clinical indication. 5-year death rates, including mode of death, were examined among patients with T1MI and T2MI. CAD was defined as the presence of any of the following: history of CAD, prior MI, prior coronary artery bypass graft surgery, prior percutaneous coronary intervention, prior coronary stenting, or documented CAD (≥50%) on index admission angiography. Results Among 1640 patients, acute MI was diagnosed in 217 patients, including 77 (4.7%) classified as T1MI and 140 (8.5%) as T2MI. At 5-years, 23% (n=18) of patients with T1MI had died, with 61% (n=11) categorized as cardiac deaths. For T2MI, 37% (n=52) had died at 5-years, with 36% (n=19) categorized as cardiac deaths. Patients with T2MI had a higher 5-year mortality than T1MI (37% vs 23%, p=0.038) (Figure, Panel A), with T2MI more likely than T1MI to die from non-cardiac causes (64% vs. 39%, p=0.04). CAD was present in 22% (n=31) of patients with T2MI and associated with worse outcomes (p=0.0496) (Figure, Panel B). Conclusion T2MI has worse long term outcomes than T1MI. The predominant mode of death among patients with T2MI is non-cardiac. However, approximately 40% of deaths are cardiac. Further, we confirm the presence of CAD identifies a subset of patients with T2MI at high-risk. Acknowledgement/Funding Abbott Diagnostics and Hennepin Healthcare Research Institute (formerly MMRF)

Geographic Variation in the Availability of Deceased Donor Kidneys per Wait-Listed Candidate in the United States

Geographic Variation in the Availability of Deceased Donor Kidneys per Wait-Listed Candidate in the United States

MicroRNA Modification of Coxsackievirus B3 Decreases Its Cardiotoxicity, While Retaining Oncolytic Potency Against Lung Cancer

Background: We recently discovered that coxsackievirus B3 (CVB3) is a potent oncolytic virus against KRAS-mutant (KRASmut) lung adenocarcinoma. Nevertheless, the evident cardiotoxicity restricts the use of wild-type (WT)-CVB3 for lung cancer therapy. The current study aims to genetically engineer the CVB3 genome to decrease its toxicity towards normal tissues and to extend our previous research to determine the safety and oncolytic efficacy of the modified CVB3 in treating TP53-and/or RB1-mutant small cell lung cancer (TP53mut/RB1mut SCLC). Methods: A microRNA-modified CVB3 (miR-CVB3) was generated via inserting multiple copies of tumor-suppressive miR-145 and miR-143 target sequences into the 5' untranslated region of the viral genome. The safety and effectiveness of the miR-CVB3 were then examined in cultured cells and using a TP53mut/RB1mut SCLC cell-derived xenograft model. Findings: In vitro experiments revealed that miR-CVB3 retained the ability to infect and lyse KRASmut lung adenocarcinoma and TP53mut/RB1mut SCLC cells, but with a markedly reduced cytotoxicity towards cardiomyocytes. In vivo study demonstrated that a single dose of miR-CVB3 via systemic administration resulted in a significant tumor regression. Most strikingly, mice treated with miR-CVB3 all survived the time-course of the experiment with greatly attenuated cardiotoxicities and decreased viral titers as compared to WT-CVB3-treated mice. Interpretation: We generated a recombinant CVB3 that was powerful in destroying both KRASmut lung adenocarcinoma and TP53mut/RB1mut SCLC, with a negligible toxicity towards normal tissues. Fundings: This work was supported by the BC Lung Association, Providence Health Care Research Institute and Vancouver Coastal Health Research Institute Innovation and Translational Research Award. Declaration of Interest: WWGJ is the Chief Scientific Officer at Virogin Biotech Ltd. HL (H Liu) and CSN are partially sponsored by Virogin Biotech Ltd. through MITACS Accelerate Program. No conflicts of interest were disclosed by others. Ethical Approval: The protocol was approved by the University Animal Care Committee (A18-0275).

Fungal adenoiditis and tonsillomycosis in children: features of diagnosis and therapy

The purpose of the work is to study the current state of the problem of diagnosing and treating fungal adenoiditis and tonsillomycosis in children. This article summarizes the literature data on the predisposing factors and characteristics of the occurrence of fungal infections of adenoid vegetations and tonsils in children. The works present modern approaches to the diagnosis and treatment of children with fungal adenoiditis and tonsillomycosis, depending on the selected genus and the type of fungus. Based on the conducted research, performed on the basis of "The Sverzhevskiy Otorhinolaryngology Healthcare Research Institute", we found that the incidence of fungal adenoiditis in children is 16.4%, and the incidence of tonsillomicosis in children with chronic tonsillitis is 21.5%. The most frequently detected strain in this pathology is C. albicans. In the presented study, a justification of the chosen treatment regimen was made on the basis of the data obtained during microbiological (bacteriological and mycological) studies.

PSEN1 and NUP98 as Diagnostic Biomarkers for Human Myocarditis

BackgroundMyocarditis, inflammation of the myocardium not associated with ischemia, is a spectrum of conditions causing considerable morbidity and mortality. The etiologies known to drive such inflammation are diverse and include autoimmunity and drug hypersensitivity, but are most commonly attributed to cardiotropic viral infections. Clinical symptoms are also variable, ranging from life threatening acute illness to chronic disease, while others never come to clinical attention. Moreover, these factors make the frequency of myocarditis difficult to ascertain, however, an estimated 9% of adult autopsies show myocarditis on histologic examination. Given the tools presently available, clinical, etiologic and hitstologic variability make diagnosis, and therefore treatment, exceedingly difficult. The current gold standard of diagnosis is inflammation shown on endomyocardial biopsy with (“active”) or without (“borderline”) myocyte damage. However, under these criteria, myocarditis diagnostic sensitivity is estimated as low as 30%. To improve upon this, we examined several markers implicated in the pathogenesis of viral myocarditis in animal models as possible adjunct diagnostic biomarkers in human myocarditis. PSEN1, a cellular protease implicated in heart failure and NUP98, a nuclear pore protein with inducible cardioprotective and antiviral gene transcription capabilities, have emerged as promising candidates.DesignTwo groups were examined for PSEN1 and NUP98 immunohistochemical (IHC) staining: a development set of 50 cases (18 lymphocytic active or healing myocarditis, 4 eosinophilic myocarditis, 4 idiopathic dilated cardiomyopathy, 3 hypertrophic cardiomyopathy, 4 sarcoidosis, 3 transplant rejection, 1 toxoplasmosis, 4 arrhythmogenic right ventricular cardiomyopathy (ARVC), 4 coronary artery disease (CAD) and 5 normal controls) and a validation set of all (62) cardiac biopsies performed at SPH from January 2015–June 2016, irrespective of diagnosis. Staining intensity was assessed by computer aided image analysis. Statistical analysis was performed using Mann Whitney U test and receiver operating characteristic (ROC) curves. All protocols were approved by the UBC/PHCRI Research Ethics Board.ResultsPSEN1 distinguished myocarditis from all other diagnoses in the development set (p=0.0001). NUP98 could distinguish inflammatory myocarditides as well as viral from non‐viral from most other diagnoses in the development set (p=0.001). ROC values comparing myocarditis to all other cardiomyopathies was 0.85 for PSEN1 and 0.80 for NUP98. These findings appear hold true in preliminary analyses of the validation set.ConclusionPSEN1 and NUP98 appear to be valuable biomarkers, particularly in combination, for improving sensitivity of endomyocardial biopsy for diagnosing myocarditis, and may provide greater ability to deduce etiologic information from such biopsies. Moreover, PSEN1 and NUP98 are detectable even in regions even without inflammation and in tissue long after initial insult. These insights will aid in personalization of treatment and significantly improve clinical outcomes.Support or Funding InformationThis research is funded by the Providence Health Care Research Institute and through donations made to the St. Paul's Hospital Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.