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INTRODUCTION: Organs procured following brain stem death (BSD) are the main source of organ grafts for transplantation. However, BSD is associated with inflammatory responses that may damage the organ and affect both the quantity and quality of organs available for transplant. Therefore, we aimed to investigate plasma and bronchoalveolar lavage (BAL) pro-inflammatory cytokine profiles and cardiovascular physiology in a clinically relevant 6-hour ovine model of BSD. METHODS: Twelve healthy female sheep (37‒42 Kg) were anaesthetized and mechanically ventilated prior to undergoing BSD induction and then monitored for 6 hours. Plasma and BAL endothelin-1 and cytokines (IL-1β, 6, 8 and tumour necrosis factor alpha (TNF-α)) were assessed by ELISA. Differential white blood cell counts were performed. Cardiac function during BSD was also examined using echocardiography, and cardiac biomarkers (A-type natriuretic peptide and troponin I were measured in plasma. RESULTS: Plasma concentrations big ET-1, IL-6, IL-8, TNF-α and BAL IL-8 were significantly (p < 0.01) increased over baseline at 6 hours post-BSD. Increased numbers of neutrophils were observed in the whole blood (3.1×109 cells/L [95% confidence interval (CI) 2.06 - 4.14] vs. 6×109 cells/L [95%CI 3.92 - 7.97]; p < 0.01) and BAL (4.5×109 cells/L [95%CI 0.41 - 9.41] vs. 26 [95%CI 12.29 - 39.80]; p=0.03) after 6 hours of BSD induction vs baseline. A significant increase in ANP production (20.28 pM [95%CI 16.18 - 24.37] vs. 78.68 pM [95%CI 53.16 - 104.21];p < 0.0001) and cTnI release (0.039 ng/mL vs. 4.26 [95%CI 2.69 - 5.83] ng/mL; p < 0.0001), associated with a significant reduction in heart contractile function, were observed between baseline and 6 hours. CONCLUSIONS: BSD induced systemic pro-inflammatory responses, characterized by increased neutrophil infiltration and cytokine production in the circulation and BAL fluid, and associated with reduced heart contractile function in ovine model of BSD.

BackgroundThe Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies.MethodsUsing MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359).ResultsCompared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss.ConclusionsMany heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).

Objectives Short bowel syndrome (SBS) is a complex and rare condition (incidence 1200/ 100,000 live births) that requires a multidisciplinary team approach to management. In January 2019 the first European Reference Network on Rare and Inherited Congenital Anomalies (ERNICA) Intestinal Failure (IF) workshop was held. Several questions about the strategies used in managing IF associated with short bowel syndrome (SBS) were devised. The aim of our study was to collect data on the enteral feeding strategies adopted by the ERNICA centres. Methods A questionnaire (36 questions) about strategies used to introduce enteral nutrition post-operatively and start complementary food/solids in infants with SBS associated IF was developed and sent to 24 centres in 15 countries that participated in the ERNICA-IF workshop. The answers were collated and compared with the literature. Results There was 100% response rate. In infants enteral nutrition was introduced as soon as possible, ideally within 24-48 hours post-small intestinal surgical resection. In 10/24 centres, bolus feeding was used, in 9 continuous, and in 5 a combination of both. Twenty-three centres used mothers' own milk as the first choice of feed with extensively hydrolysed feed, amino acid based feed, donor human milk or standard preterm/term formula as second choice. Although twenty-two centres introduced complementary/solid food by 6 months of age, food choice varied greatly between centres and appeared to be culturally based. Conclusions There is diversity in post-surgical enteral feeding strategies among centres in Europe. Further multi-centre studies could help to increase evidence-based medicine and management on this topic.

Frailty has been defined as a state of increased vulnerability due to a decline in the reserve and function of multiple physiological systems. Initially conceived as a geriatric syndrome indicative of physiological aging, it is now apparent that frailty can also be observed as a manifestation of chronic disease states including heart failure. Estimates of the prevalence of frailty in heart failure vary according to the age of the study population and the frailty instrument used; however, multiple studies have identified frailty to be prevalent in patients with advanced heart failure including those who are referred for heart transplantation. Frailty is emerging as an independent predictor of mortality both before and after bridge-to-transplant ventricular assist device implantation and heart transplantation. Frailty is also predictive of prolonged hospitalization following these procedures. Heart failure-associated frailty is a dynamic state. While reversibility of frailty can be anticipated in younger heart failure patients, predicting the reversibility of frailty is more challenging in older patients who often have multiple comorbidities that may contribute to the frailty syndrome. Prehabilitation is a promising approach to both preventing and reversing frailty however more research is urgently needed to establish its effectiveness in mitigating the adverse impacts of frailty on postventricular assist device and posttransplant morbidity and mortality.

Background and Objectives: \ud Gastrectomy for gastric cancer is associated with significant infective postoperative complications. C-reactive protein (CRP) is a useful biomarker in the early detection of infective complications following major abdominal surgery. This single-centre retrospective study aimed to determine the relationship between postoperative CRP levels and development of postoperative infective complications after gastrectomy.\ud \ud Methods: \ud Daily postoperative CRP levels were analyzed to determine a CRP threshold associated with infective complications. ROC curve analysis was used to determine which postoperative day (POD) gave the optimal cutoff. Multivariate analysis was performed to determine significant factors associated with complications.\ud \ud Results: \ud One hundred and forty-four patients were included. A total of 61 patients (42%) had at least one infective complication. A CRP level of 220 mg/L was associated with the highest AUC (0.765) with a sensitivity of 70% and specificity of 76% (positive predictive value, 67%; negative predictive value, 78%). More patients with a CRP > 220 mg/L on POD 3 developed infective complications (67% vs. 21%, p

Low flow and suction alarms are provided to alert caregivers of changes in left ventricular assist device pump function but may be reset in clinical practice. We investigated the incidence and underlying causes of these alarms as well as their prognostic significance. HeartWare ventricular assist device patients (n = 113) were divided into quartiles based on their frequency of low flow and suction alarms. Survival and adverse events (thrombus, stroke, bleeding, and right heart failure) were compared between quartiles. Low flow alarms peaked in the first few months of pump support before dropping down to near negligible levels. Suction alarm frequency remained relatively constant throughout pump support. Although pump speeds (p < 0.001) and flow (p = 0.01) decreased over time, there was an increase in suction alarm frequency (p = 0.018), with no changes in low flow alarms. Patients with smaller body size (p = 0.016) and lower pump flows (p = 0.008) had higher frequencies of low flow alarms on multiple regression (p < 0.001). Patients with the highest low flow alarm frequency demonstrated poorer survival (p = 0.026). There was no relationship between suction alarm frequency and survival. There was also no relationship between either low flow or suction alarm frequency with strokes, gastrointestinal bleeds, pump thrombus, or right ventricular failure. Duration of alarm and intervention in response to the alarm was not assessed in this study. Further studies examining alarm duration and responses may inform future pump alarm algorithms.

OBJECTIVES: This study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT). BACKGROUND: Calcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs. METHODS: In this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (DeltaLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection. RESULTS: Forty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 +/- 3.5 mug/l vs. 8.6 +/- 2.8 mug/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 +/- 1.7 mug/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (DeltaLVM = -13.0 +/- 16.8 g vs. 2.1 +/- 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Delta circumferential strain = -2.9 +/- 2.8 vs. 2.1 +/- 2.3; p < 0.001; DeltaT1 mapping values = -32.7 +/- 51.3 ms vs. 26.3 +/- 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Delta mean arterial pressure = 4.2 +/- 18.8 mm Hg vs. 2.8 +/- 13.8 mm Hg; p = 0.77), renal function (Delta creatinine = 3.1 +/- 19.9 mumol/l vs. 9 +/- 21.8 mumol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups. CONCLUSIONS: The combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.

We present a case of recurrent isolated cardiac sarcoidosis, 3 years post-heart transplantation. The case highlights the scarcity of data on the utility of immunosuppression in cardiac sarcoidosis and, in particular, raises questions about the optimal immunosuppression regimen in transplant recipients. (Level of Difficulty: Advanced.), Graphical abstract

The ileo-anal pouch (IAP) has been the gold standard procedure for maintenance of bowel continuity after panproctocolectomy for ulcerative colitis, familial adenomatous polyposis or hereditary non-polyposis colorectal cancer. However, the IAP has an estimated failure rate of 13% at 10 years post-procedure (Tulchinsky et al., Ann Surg 238(2):229–34, 2003), which can result in pouch excision (P.E.). This systematic review aims to synthesise all the available studies reporting post-operative outcomes of P.E. and its impact on patient quality of life (QoL), when available, which have not previously been summarised. PubMed, Embase, Medline and the Cochrane library databases were searched with terms ‘Pouch AND excision’ OR ‘Pouch AND removal’ OR ‘Pouch AND remove’ OR ‘IAP AND excision’. All studies reporting post-operative morbidity, mortality or functional outcomes in patients who had P.E. were included. Studies with

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing the current coronavirus disease 2019 (COVID-19) pandemic, is not only highly infectious but can induce serious outcomes in vulnerable individuals including dental patients and dental health care personnel (DHCPs). Responses to COVID-19 have been published by the Centers for Disease Control and Prevention and the American Dental Association, but a more specific response is required for the safe practice of oral and maxillofacial radiology. We aim to review the current knowledge of how the disease threatens patients and DHCPs and how to determine which patients are likely to be SARS-CoV-2 infected; consider how the use of personal protective equipment and infection control measures based on current best practices and science can reduce the risk of disease transmission during radiologic procedures; and examine how intraoral radiography, with its potentially greater risk of spreading the disease, might be replaced by extraoral radiographic techniques for certain diagnostic tasks. This is complemented by a flowchart that can be displayed in all dental offices.

BACKGROUND Better tools are needed to diagnose and identify children at risk of clinical malnutrition. OBJECTIVES We aimed to compare body composition (BC) and malnutrition screening tools (MSTs) for detecting malnutrition on admission; and examine their ability to predict adverse clinical outcomes [increased length of stay (LOS) and complications] in complex pediatric patients. METHODS This was a prospective study in children 5-18 y old admitted to a tertiary pediatric hospital (n = 152). MSTs [Pediatric Yorkhill Malnutrition Score (PYMS), Screening Tool for the Assessment of Malnutrition in Pediatrics (STAMP), and Screening Tool for Risk of Impaired Nutritional Status and Growth (STRONGkids)] were completed on admission. Weight, height, and BC [fat mass (FM) and lean mass (LM) by DXA] were measured (n = 118). Anthropometry/BC and MSTs were compared with each other and with clinical outcomes. RESULTS Subjects were significantly shorter with low LM compared to reference data. Depending on the diagnostic criteria used, 3%-17% were classified as malnourished. Agreement between BC/anthropometric parameters and MSTs was poor. STAMP and STRONGkids identified children with low weight, LM, and height. PYMS, and to a lesser degree STRONGkids, identified children with increased LOS, as did LM compared with weight or height. Patients with complications had lower mean ± SD LM SD scores (-1.38 ± 1.03 compared with -0.74 ± 1.40, P

The aim was to investigate whether an intensive lifestyle intervention, with high volumes of exercise, improves beta cell function and to explore the role of low-grade inflammation and body weight. This was a randomised, assessor-blinded, controlled trial. Ninety-eight individuals with type 2 diabetes (duration

PURPOSE: There is increasing clinical utilization of hearts from the donation after circulatory death (DCD) pathway with the aim of expanding the donor pool and mitigating the ever-present discrepancy between the inadequate availability of good quality donor hearts and the rising number of patients with end-stage heart failure. METHODS: This article reviews the rationale, practice, logistical factors, and 5-year experience of DCD heart transplantation at St Vincent’s Hospital, Sydney. FINDINGS: Between July 2014 and July 2019, 69 DCD donor retrievals were undertaken resulting in 49 hearts being instrumented on an ex situ normothermic cardiac perfusion device. Seventeen (35%) of these hearts were declined and the remaining 32 (65%) were used for orthotopic DCD heart transplantation. At 5 years of follow-up, the 1-, 3-, and 5-year survival was 96%, 94%, and 94% for DCD hearts compared with 89%, 83%, and 82% respectively for donation after brain death (DBD) hearts (n.s). The immediate post-implant requirement for temporary extra-corporeal membrane oxygenation (ECMO) support for delayed graft function was 31% with no difference in rejection rates when compared with the contemporaneous cohort of patients transplanted with standard criteria DBD hearts. SUMMARY: DCD heart transplantation has become routine and incorporated into standard clinical practice by a handful of pioneering clinical transplant centres. The Australian experience demonstrates that excellent medium-term outcomes are achievable from the use of DCD hearts. These outcomes are consistent across the other centres and consequently favour a more rapid and wider uptake of heart transplantation using DCD donor hearts, which would otherwise be discarded.

BACKGROUND Frailty is a clinically recognized syndrome of decreased physiological reserve and a key contributor to suboptimal clinical outcomes in various lung disease groups. Interstitial lung disease (ILD) is fast approaching chronic obstructive pulmonary disease as the number one indication for lung transplantation worldwide. Our aim was to assess whether frailty is a predictor of mortality in patients with ILD referred for lung transplantation in an Australian cohort. METHODS Consecutive patients with ILD referred or on the waiting list for lung transplantation from May 2013 to December 2017 underwent frailty assessment using the modified Fried's frailty phenotype. Frailty was defined as a positive response to ≥3 of the following 5 components: weak grip strength, slowed walking speed, poor appetite, physical inactivity, and exhaustion. RESULTS One hundred patients (82 male:18 female; age, 59 ± 7 y; range, 30-70) underwent frailty assessment. Twenty-four of 100 (24%) were assessed as frail. Frailty was associated with anemia, hypoalbuminemia, low creatinine, and the use of supplemental oxygen (all P < 0.05). Frailty was independent of age, gender, measures of pulmonary dysfunction (PaO2, forced vital capacity percentage predicted, total lung capacity, total lung capacity percentage predicted, DLCO, or DLCO percentage predicted), cognitive impairment, or depression. Frailty and DLCO % predicted were independent predictors of increased all-cause mortality: 1-year actuarial survival was 86 ± 4% in the nonfrail group compared with 58 ± 10% for the frail group (P = 0.002). CONCLUSIONS Frailty is common among patients referred for lung transplant with a diagnosis of ILD and is associated with a marked increase in mortality.

BACKGROUND Frailty is prevalent in patients with heart failure (HF) and associated with increased morbidity and mortality. Hence, there has been increased interest in the reversibility of frailty following treatment with medication or surgery. This systematic review aimed to assess the reversibility of frailty in patients with HF before and after surgical interventions aimed at treating the underlying cause of HF. It also aimed to assess the efficacy of cardiac rehabilitation and prehabilitation in reversing or preventing frailty in patients with HF.Methods and Results:Searches of PubMed, MEDLINE and Academic Search Ultimate identified studies with HF patients undergoing interventions to reverse frailty. Titles, abstracts and full texts were screened for eligibility based on the PRISMA guidelines and using predefined inclusion/exclusion criteria in relation to participants, intervention, control, outcome and study design. In total, 14 studies were included: 3 assessed the effect of surgery, 7 assessed the effect of rehabilitation programs, 2 assessed the effect of a prehabilitation program and 2 assessed the effect of program interruptions on HF patients. CONCLUSIONS Overall, it was found that frailty is at least partially reversible and potentially preventable in patients with HF. Interruption of rehabilitation programs resulted in deterioration of the frailty status. Future research should focus on the role of prehabilitation in mitigating frailty prior to surgical intervention.

Aim Effective, high-quality patient handovers between the surgical team are essential for safe transfer of responsibility for patient care whilst ensuring continued patient-safety and supporting good clinical governance. Weekend handovers provide a particular challenge, with error potential, when patients are cared for by multiple different healthcare professionals. This project aimed to improve the documentation of the weekend handover for the surgical inpatients of a busy UK teaching hospital. Method Quality Improvement project performed within a single General Surgical department between August and October 2020. An initial casenote audit on 3 consecutive Fridays compared available handover information against RCS guidance. A comprehensive surgical weekend handover sticker was designed and all members of the surgical team educated in its use. Following sticker introduction, handover quality was similarly re-audited. **=p Results 138 inpatient records were evaluated in cycle 1 and 135 in cycle 2, with the proportion containing a weekend handover increased post-intervention (96 vs. 82%,p=0.0004). Handover quality improved following sticker introduction with more frequent documentation of: diagnosis (96 vs. 21%**); need for imaging review (94 vs. 29%**); intravenous fluid plan (84 vs. 21%**); blood test requirements (94 vs. 24%**); mode of nutrition (90 vs. 24%**); antibiotics (90 vs. 30%**); drug monitoring (90 vs. 1%**); discharge planning (94 vs. 44%**) and escalation plan (87 vs. 0%**). Conclusion Introduction of a sticker has significantly improved the quality of documented handover available to the responsible on-call team. Future work will assess sticker impact on quality of care and clinical outcomes.

Aims Appendicectomy is one of the commonest emergency General Surgical operations performed. However, there exists minimal published literature exploring whether there are differences between males and females undergoing appendicectomy. This study aimed to investigate the demographics, pre-operative investigation, intra-operative findings and clinical outcomes between both genders having an emergency appendicectomy. Methods A multicentre retrospective cohort study of all patients who had an emergency appendicectomy within four UK hospitals between September 2019 and November 2020. Electronic records were interrogated and patients dichotomised by gender and the results compared. Results 559 emergency appendicectomies (315 (56.4%) male and 244 (43.6%) female patients) were included. Males undergoing appendicectomy were younger (median age: 33 vs 41 years, p Conclusions This study demonstrates that differences exist between males and females who have emergency appendicectomy in terms of age, use of pre-operative imaging and operative approach, however, clinical outcomes are similar.

Global businesses responding to the demographic challenges of an ageing population have not only a vested interested but a moral responsibility in providing products and services that meet the needs of their clients and governmental foresight healthcare and ageing population panels have scoped trends, future scenarios and actions required. The ‘Ideal States’ cluster was formed between individuals in the two fields of design and clinical healthcare, both concerned with people-centric practices and in how to respond to healthcare and quality of life issues associated with an ageing population. Social scientists have investigated the patient’s perspective in healthcare for some years, primarily using qualitative methods but the concept of patient pathways, as a tool for facilitating improved healthcare delivery as a vital part of healthcare reform, appears to be a relatively recent one. Discovering the concept of the patient pathway was serendipitous, resulting in an appreciation of the potential value of pathway maps.

Background: Ischemia–reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH, which can reach as low as 6.0 to 6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly affects cardiac function. Methods: We used genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole-organ level. Human induced pluripotent stem cell–derived cardiomyocytes as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and postconditioning therapeutic agents. Results: Analysis of human complex trait genetics indicates that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using human induced pluripotent stem cell–derived cardiomyocytes in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacologic inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and 2 models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as preconditioning or postconditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no effect on cardiac ion channels regulating baseline electromechanical coupling and physiologic performance. Conclusions: Our data provide compelling evidence for a novel pharmacologic strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

Aim To assess whether this change of practice had an effect on the infection rate in hip fracture surgery. Method An audit was conducted to assess the re-operation rate on hip fracture patients over the three months of the initial “lockdown” (23rd March to 23rd May 2020) and compared to the 2 months immediately before and the same period in 2019. Cases were identified from the Theatre ORACLE system (GE Healthcare). Anonymised patient data was collected from the Electronic Patient Record (EPR) and paper case notes. Results During the pandemic period, a total of 45 patients underwent surgery for hip fractures with a median age 84 years (range 28-95 years). These represent similar cohorts to the periods immediately before lockdown and the previous year. The infection rate increased from 0% in the 2019 period to 2.5% prior to lockdown and 11.1% after the lockdown measures were implemented. All infections were in patients who received hemiarthroplasty. The rate of total hip replacement went down from 19.1% in 2019 to 10.0% just before the pandemic and just 4.4% during the pandemic Conclusions There was a marked increase in the number of re-operations for infection in patients who received hemiarthroplasty for hip fractures during the lockdown period.

BackgroundImmune defects in chronic pulmonary aspergillosis (CPA) are poorly characterized. We compared peripheral blood cytokine profiles in patients with CPA versus healthy controls and explored the relationship with disease severity.MethodsInterferon-gamma (IFNγ), interleukin (IL)-17, tumor necrosis factor-α, IL-6, IL-12, and IL-10 were measured after in vitro stimulation of whole blood with lipopolysaccharide (LPS), phytohemagglutinin, β-glucan, zymosan (ZYM), IL-12 or IL-18, and combinations. Clinical parameters and mortality were correlated with cytokine production.ResultsCytokine profiles were evaluated in 133 patients (57.1% male, mean age 61 years). In comparison to controls, patients with CPA had significantly reduced production of IFNγ in response to stimulation with β-glucan + IL-12 (312 vs 988 pg/mL), LPS + IL-12 (252 vs 1033 pg/mL), ZYM + IL-12 (996 vs 2347 pg/mL), and IL-18 + IL-12 (7193 vs 12 330 pg/mL). Age >60 (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.00–2.91; P = .05) and chronic obstructive pulmonary disease (HR, 1.69; 95% CI, 1.03–2.78; P = .039) were associated with worse survival, whereas high IFNγ production in response to beta-glucan + IL-12 stimulation (HR, 0.48; 95% CI, .25–0.92; P = .026) was associated with reduced mortality.ConclusionsPatients with CPA show impaired IFNγ production in peripheral blood in response to stimuli. Defective IFNγ production ability correlates with worse outcomes. Immunotherapy with IFNγ could be beneficial for patients showing impaired IFNγ production in CPA.

IntroductionThe effects of lifestyle interventions in persons with type 2 diabetes (T2D) on health-related quality of life (HRQoL) and subjective well-being are ambiguous, and no studies have explored the effect of exercise interventions that meet or exceed current recommended exercise levels. We investigated whether a 1-year intensive lifestyle intervention is superior in improving HRQoL compared with standard care in T2D persons.Research design and methodsWe performed secondary analyses of a previously conducted randomized controlled trial (April 2015 to August 2016). Persons with non-insulin-dependent T2D (duration ≤10 years) were randomized to 1-year supervised exercise and individualized dietary counseling (ie, ‘U-TURN’), or standard care. The primary HRQoL outcome was change in the 36-item Short Form Health Survey (SF-36) physical component score (PCS) from baseline to 12 months of follow-up, and a key secondary outcome was changes in the SF-36 mental component score (MCS).ResultsWe included 98 participants (U-TURN group=64, standard care group=34) with a mean age of 54.6 years (SD 8.9). Between-group analyses at 12-month follow-up showed SF-36 PCS change of 0.8 (95% CI −0.7 to 2.3) in the U-TURN group and deterioration of 2.4 (95% CI −4.6 to −0.1) in the standard care group (difference of 3.2, 95% CI 0.5 to 5.9, p=0.02) while no changes were detected in SF-36 MCS. At 12 months, 19 participants (30%) in the U-TURN group and 6 participants (18%) in the standard care group achieved clinically significant improvement in SF-36 PCS score (adjusted risk ratio 2.6, 95% CI 1.0 to 4.5 corresponding to number needed to treat of 4, 95% CI 1.6 to infinite).ConclusionIn persons with T2D diagnosed for less than 10 years, intensive lifestyle intervention improved the physical component of HRQoL, but not the mental component of HRQoL after 1 year, compared with standard care.Trial registration numberNCT02417012.

AIMS: Metformin may have clinical benefits in dialysis patients; however, its safety in this population is unknown. This systematic review evaluated the safety of metformin in dialysis patients. METHODS: MEDLINE, Embase, CENTRAL, PsycINFO and the Cochrane Library were searched for randomised controlled trials and observational studies evaluating metformin use in dialysis patients. Three authors reviewed the studies and extracted data. The primary outcomes were mortality, occurrence of lactic acidosis and myocardial infarction (MI) in patients taking metformin during dialysis treatment for ≥12 months (long term). Risk of bias was assessed using Risk Of Bias In Nonrandomised Studies of Interventions (ROBINS‐1). Overall quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Fifteen observational studies were eligible; 7 were prospective observational studies and 8 were case reports/case series. No randomised controlled trials were identified. The 7 prospective observational studies (n = 194) reported on cautious metformin use in patients undergoing maintenance dialysis. Only 3 provided long‐term follow‐up data. In 2 long‐term studies of metformin therapy (≤1000 mg/d) in patients undergoing peritoneal dialysis (PD), 1 reported 6 deaths (6/83; 7%) due to major cardiovascular events (3 MI) and the other reported no deaths (0/35). One long‐term study of metformin therapy (250 mg to 500 mg thrice weekly) in patients undergoing haemodialysis reported 4 deaths (4/61; 7%) due to major cardiovascular events (2 MI). These findings provide very low‐quality evidence as they come from small observational studies. CONCLUSION: The evidence regarding the safety of metformin in people undergoing dialysis is inconclusive. Appropriately designed randomised controlled trials are needed to resolve this uncertainty.

Background To determine whether parenteral plus enteral glutamine supplementation influences microbial invasion in surgical infants who require parenteral nutrition (PN). Methods An prospective double-blind randomized controlled trial studying surgical infants receiving PN for at least 5 days for congenital or acquired intestinal anomalies (2009-2012) was used. Infants were randomized to receive either glutamine supplementation (parenteral plus enteral; total 400 mg/kg/d) or isonitrogenous control. The primary end point was microbial invasion evaluated after 5 days of supplementation and defined as: (i) positive conventional blood culture, (ii) evidence of microbial DNA in blood (polymerase chain reaction), (iii) plasma endotoxin level ≥50 pg/mL, or (iv) plasma level of lipopolysaccharide binding protein ≥50 ng/mL. Data are given as median (range) and compared by logistic regression. Results Sixty infants were randomized and reached the primary end point. Twenty-five patients had intestinal obstruction, 19 had abdominal wall defects, and 13 had necrotizing enterocolitis. Thirty-six infants showed evidence of microbial invasion during the study, and 17 of these were not detected by conventional blood culture. There was no significant difference between the 2 groups in the primary outcome; evidence of microbial invasion after 5 days was found in 9/31 (control group) and 8/29 (glutamine group) (odds ratio 0.83 [0.24-2.86; P = 0.77]). Conclusion More than half of surgical infants requiring PN showed evidence of microbial invasion. Approximately half of this was not detectable by conventional blood cultures. Parenteral plus enteral glutamine supplementation had no effect on incidence of microbial invasion.

Aortic regurgitation (AR), mitral regurgitation (MR), and tricuspid regurgitation (TR) after continuous-flow left ventricular assist device (LVAD) are common and may increase with prolonged LVAD support. The aim of this study was to simulate severe valvular regurgitation (AR, MR, and TR) within a 4-elemental pulsatile mock circulatory loop (MCL) and observe their impact on isolated LVAD and biventricular assist device (BiVAD) with HeartWare HVAD. Aortic regurgitation, MR, and TR were achieved via the removal of one leaflet from bileaflet mechanical valve from the appropriate valves of the left or right ventricles. The impact of alteration of LVAD pump speed (LVAD 2200-4000 RPM, right ventricular assist device [RVAD] 2400 RPM) and altered LVAD preload (10-25 mm Hg) was assessed. With each of the regurgitant valve lesions, there was a decrease in isolated LVAD pump flow pulsatility. Isolated LVAD provided sufficient support in the setting of severe MR or TR compared with control, and flows were enhanced with BiVAD support. In severe AR, there was no benefit of BiVAD support over isolated LVAD, and actual loop flows remained low. High LVAD flows combined with low RVAD flows and dampened aortic pressures are good indicators of AR. The 4-elemental MCL successfully simulated several control and abnormal valvular conditions using various pump speeds. Current findings are consistent with conservative management of MR and TR in the setting of mechanical support, but emphasize the importance of the correction of AR.

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. To appraise published studies on the use of supplemental oxygen in chronic heart failure. Chronic breathlessness is a characterizing symptom of symptomatic heart failure resulting in substantial disability and healthcare utilization and is the primary reason for emergency room visits and hospitalizations. In spite of the variable evidence, oxygen therapy is commonly administered both acutely and chronically. Moreover, the role of oxygen therapy to relieve chronic breathlessness in heart failure is not well described, particularly in normoxemic or mild or intermittent hypoxemic states. In fact, several studies have shown the detrimental effects of oxygen therapy with normal oxygen saturation levels. A systematic review using PRISMA guidelines. Four databases PubMed, Embase, CINAHL, and Web of Science were systematically searched from January 2001 to January 2019 investigating the use of oxygen in heart failure. Duplicate articles were removed from the review. Titles and abstracts were screened for inclusion and exclusion criteria. The remaining full-text articles were reviewed and hand-searched for additional references. The quality of the full-text articles was assessed using standardized critical appraisal instruments by the Joanna Briggs Institute. A total of 11 studies, including three intervention and eight non-interventions studies, were included in this review from 1072 non-duplicated records retrieved. Sample size ranged from 4 to 5862. In spite of common usage, this review suggests that there are scant data available to justify the use of oxygen in individuals with non-hypoxemic chronic heart failure and chronic breathlessness.

Background Transplantation of hearts retrieved from donation after circulatory death (DCD) donors is an evolving clinical practice. Objectives The purpose of this study is to provide an update on the authors’ Australian clinical program and discuss lessons learned since performing the world’s first series of distantly procured DCD heart transplants. Methods The authors report their experience of 23 DCD heart transplants from 45 DCD donor referrals since 2014. Donor details were collected using electronic donor records (Donate Life, Australia) and all recipient details were collected from clinical notes and electronic databases at St. Vincent’s Hospital. Results Hearts were retrieved from 33 of 45 DCD donors. A total of 12 donors did not progress to circulatory arrest within the pre-specified timeframe. Eight hearts failed to meet viability criteria during normothermic machine perfusion, and 2 hearts were declined due to machine malfunction. A total of 23 hearts were transplanted between July 2014 and April 2018. All recipients had successful implantation, with mechanical circulatory support utilized in 9 cases. One case requiring extracorporeal membrane oxygenation subsequently died on the sixth post-operative day, representing a mortality of 4.4% over 4 years with a total follow-up period of 15,500 days for the entire cohort. All surviving recipients had normal cardiac function on echocardiogram and no evidence of acute rejection on discharge. All surviving patients remain in New York Heart Association functional class I with normal biventricular function. Conclusions DCD heart transplant outcomes are excellent. Despite a higher requirement for mechanical circulatory support for delayed graft function, primarily in recipients with ventricular assist device support, overall survival and rejection episodes are comparable to outcomes from contemporary brain-dead donors.

© 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ) Background: Chronic heart failure is a complex and multifaceted syndrome characterised by an unpredictable trajectory, high symptom burden and reduced quality of life. Although palliative care is recommended, patient, provider and system factors limit access. Aim: To examine the knowledge, attitudes and perspectives of health care professionals towards end of life care and palliative care for patients with chronic heart failure. Design: This is an integrative review. Data sources: CINAHL, Academic Search Complete and SCOPUS were searched. Specific inclusion criteria and search terms were used. The integrative review method entailed analysing data from primary articles using the constant comparison method and then synthesising data. Results: Twenty-six (26) articles were selected that explored health care professionals’ perspectives towards end of life care and palliative care. The categories that emerged were grouped into patient, provider and system issues. Most health care professionals involved in providing care to heart failure patients have misperceptions of palliative care, often confusing it with end of life and hospice care. This hinders patients’ access to palliative care as determining the end of life period in heart failure is difficult. Conclusions: Exploring health care professionals’ perspectives towards the delivery of end of life care and palliative care is important for understanding how their practice influences the delivery of palliative care for heart failure patients. Emphasis on increasing awareness of the principles of palliative care in the health care community, as well as addressing organisational issues will improve the care delivered to these patients.

BACKGROUND. Varicella-zoster virus (VZV) is under consideration as a promising recombinant viral vector to deliver foreign antigens including HIV. However, new vectors have come under increased scrutiny, since trials with adenovirus serotype 5–vectored (Ad5-vectored) HIV vaccine demonstrated increased HIV risk in individuals with pre-immunity to the vector that was thought to be associated with mucosal immune activation (IA). Therefore, given the prospect of developing an HIV/VZV chimeric vaccine, it is particularly important to define the impact of VZV vaccination on IA. METHODS. Healthy VZV-seropositive Kenyan women (n = 44) were immunized with high-dose live attenuated VZV vaccine, and we assessed the expression on CD4((+)) T cells isolated from blood, cervix, and rectum of IA markers including CD38 and HLA-DR and of markers of cell migration and tissue retention, as well as the concentration of genital and intestinal cytokines. A delayed-start group (n = 22) was used to control for natural variations in these parameters. RESULTS. Although immunogenic, VZV vaccination did not result in significant difference in the frequency of cervical activated (HLA-DR((+))CD38((+))) CD4((+)) T cells (median 1.61%, IQR 0.93%–2.76%) at 12 weeks after vaccination when compared with baseline (median 1.58%, IQR 0.75%–3.04%), the primary outcome for this study. VZV vaccination also had no measurable effect on any of the IA parameters at 4, 8, and 12 weeks after vaccination. CONCLUSION. This study provides the first evidence to our knowledge about the effects of VZV vaccination on human mucosal IA status and supports further evaluation of VZV as a potential vector for an HIV vaccine. TRIAL REGISTRATION. ClinicalTrials.gov NCT02514018. FUNDING. Primary support from the Canadian Institutes for Health Research (CIHR). For other sources, see Acknowledgments.

Objective:Ginsenosides, biologically active components of the root of Panax ginseng, have been reported to have therapeutic benefits in a number of disease states including psychiatric conditions such as major depressive disorder. Our objective was to determine if a standardised commercial ginseng extract, G115®, could reduce the signs of behavioural despair commonly observed in animal models of depression either alone or in combination with the selective serotonin reuptake inhibitor (SSRI) fluoxetine.Methods:Male Sprague-Dawley (SD) rats (N = 51) were divided into four groups: vehicle control, G115® ginseng root extract, fluoxetine and fluoxetine plus G115®. Rats were trained to voluntarily consume treatments twice daily for 14 days and were then tested in an open field (OF), elevated plus maze (EPM) and forced swim test (FST). Post-mortem hippocampal and prefrontal cortex tissue was analysed for expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) by western blot.Results:One-way Analysis of Variance revealed no significant group differences in the OF or plus-maze performance on any variable examined. In the FST, fluoxetine significantly reduced immobility time and increased latency to immobility. The effects of fluoxetine were further significantly potentiated by co-administration of G115®. Post-mortem tissue analysis revealed significant group differences in BDNF expression in the left hippocampus and left prefrontal cortex without any accompanying changes in TrkB expression.Conclusions:We conclude that oral G115® significantly potentiates the antidepressant-like effect of fluoxetine in the FST in the absence of potentially confounding effects on locomotion and anxiety.

BackgroundThe study aimed to determine whether the addition of cognitive impairment, depression, or both, to the assessment of physical frailty (PF) is associated with the risk of lung transplant (LTX) waitlist mortality.MethodsSince March 2013, all patients referred for LTX evaluation underwent PF assessment. Cognition was assessed using the Montreal Cognitive Assessment and depression assessed using the Depression in Medical Illness questionnaire. We assessed the association of 4 composite frailty measures: PF ≥3 of 5 = frail, cognitive frailty (CogF ≥ 3 of 6 = frail), depressive frailty (DepF ≥ 3 of 6 = frail), and combined frailty (ComF ≥ 3 of 7 = frail) with waitlist mortality.ResultsThe prevalence of PF was 78 (22%), CogF 100 (28%), DepF 105 (29%), and ComF 124 (34%). Waitlist survival in the non-PF group was 94% ± 2% versus 71% ± 7% in the PF group (p < 0.001). Cox proportional hazards regression analysis demonstrated that PF (Adjusted HR, 4.88; 95% CI, 2.06 - 11.56), mild cognitive impairment (Adjusted HR, 3.03; 95% CI, 1.05 - 8.78) and hypoalbuminemia (Adjusted HR, 0.89; 95% CI, 0.82 - 0.97) were independent predictors of waitlist mortality. There was no significant difference in the area under the curve of the 4 frailty measures.ConclusionsThe addition of cognitive function and depression variables to the PF assessment increased the number of patients classified as frail. However, the addition of these variables, does not strengthen the association with LTX waitlist mortality compared to the PF measure.

BACKGROUND The aim of this study was to validate our previous finding that frailty predicts early mortality in patients with advanced heart failure (AHF) and that including cognition in the frailty assessment enhances the prediction of mortality. METHODS Patients with AHF referred to our Transplant Unit between November 2015 and April 2020 underwent physical frailty assessment using the modified Fried physical frailty (PF) phenotype as well as cognitive assessment using the Montreal Cognitive Assessment (MOCA) to identify patients who were cognitively frail (CogF). We assessed the predictive value of the 2 frailty measures (PF ≥ 3 of 5 = frail; CogF ≥ 3 of 6 = frail) for pretransplant mortality. RESULTS 313 patients (233 male, 80 female; age 53 ± 13 years) were assessed. Of these, 224 patients (72%) were nonfrail and 89 (28%) were frail using the PF. The cognitive frailty assessment identified an additional 30 patients as frail: 119 (38%). Frail patients had significantly increased mortality as compared to nonfrail patients. Ventricular assist device and heart transplant-censored survival at 12 months was 92 ± 2 % for nonfrail and 69 ± 5% for frail patients (p < 0.0001) using the CogF instrument. CONCLUSIONS This study validates our previously published findings that frailty is prevalent in patients with advanced heart failure referred for heart transplantation. Physical frailty predicts early mortality. The addition of cognitive assessment to the physical assessment of frailty identifies an additional cohort of patients with a similarly poor prognosis.

Purpose Hemolysis is an important complication of ventricular assist device (VAD) therapy. Several studies have postulated that chronic hemolysis may be a cause of adverse outcomes in patients with VADs, but consistent definitions and clinical outcome data are lacking. Methods We conducted a single-center retrospective cohort study examining survival to transplantation in patients who underwent VAD implantation from 2010-2020. Baseline demographics, renal function, echocardiographic, and cardiac catheterization data for the first 12 months of VAD therapy or until transplantation were collected. Additionally, all available lactate dehydrogenase (LDH) values were collected over this time frame and means were calculated for each patient. Results VADs were implanted in 166 patients, 19% female and 87% left-sided devices. Patients with mean LDH above the upper limit of normal for our laboratory's LDH assay of 440 units/liter (U/L) were more likely to die prior to transplantation compared to those with mean LDH Conclusion Mean LDH above the normal range was an independent and significant predictor of mortality in patients with VADs awaiting transplantation at our center over the last decade. While concomitant severe liver or RV dysfunction can raise LDH, chronic hemolysis is an important potential etiology for our observations. Further work is needed to define chronic hemolysis and its impact on outcomes in patients with VADs.

Purpose The INTERHEART study previously used microarray assessment of 889 heart transplant biopsies to develop the Molecular Microscope Diagnostic System (MMDx) based on expression of rejection-associated transcripts (RATs). The present study reclassified the rejection-related states in an expanded set of 1320 prospectively collected biopsies from 645 patients from 13 centers. Methods Biopsies were classified by ensembles of classifiers and analyzed for left ventricular ejection fraction (LVEF) and survival. Results New algorithms identified 853 No rejection (NR), 179 ABMR, 76 TCMR, 13 Mixed, 161 possible ABMR (pABMR), and 38 possible TCMR (pTCMR). No rejection was subclassified as NR-Normal 462, NR-Minor 359, and NR-Early-injury 32 (Figure 1A). Compared to NR-Normal, NR-Minor biopsies had mild elevation of many inflammation transcripts (e.g. IFNG-inducible genes) and to a lesser extent parenchymal injury transcripts. NR-minor biopsies were often designated as TCMR1R by histology. In all NR biopsies, NR-Minor scores and histologic TCMR1R increased through the first year, peaking about one year, suggesting that Minor inflammation is a late response to injury, unrelated to rejection. LVEF was similar in NR-Normal and NR-Minor but depressed in TCMR and Early injury. In a 3-year post-biopsy survival analysis, NR-Minor and NR-Normal had similar survival. TCMR and Early-injury were associated with increased graft loss, but many losses were not related to rejection. Surprisingly, 76 hearts with ABMR (149 biopsies) and follow-up data had only 3 losses within 3 years post-biopsy (Figure 1B). Conclusion Many biopsies with molecular no rejection develop minor increases in rejection-related transcripts in the first year, often called TCMR1R by histology, with no apparent effects on function or survival. An unexpected finding was that molecular ABMR was associated with very few graft losses over three years. (ClinicalTrials.gov #NCT02670408).

Purpose Despite rapid progress in non-invasive techniques such as cMRI, endomyocardial biopsy (EMBx) remains the corner stone of the detection of rejection after cardiac transplantation. Since the first publications in the 1960’s, the technique has hardly changed. A typical heart transplanted patient will be exposed to 80-120mSv during the first four years after transplantation, 10-20% of this exposition resulting from EMBx. As the risk of malignancy is higher among transplant patients, efforts to reduce the exposition to ionizing energy are mandatory. Methods In order to reduce patient and personel exposition to radiation, a set of non-mandatory guidelines were introduced at our institution. This internal protocol is based on ECG guiding to reach the ventricular septum (SVS and VES), followed by a static fluoroscopy image to confirm adequate position. This is combined with a reduced amount of X-ray delivered to the patient by aggressive collimation and reduction of energy (A and KeV) applied to the vacuum chamber. Two months after the adoption of this technique, we conducted an audit of the practice to observe radiation exposure and complication rates in comparison with the preceding 2 months. Results 143 biopsies were observed before, and 154 biopsies after implementation of the guidelines. The median radiation dose decreased from 1.2mGy to 0.1mGy (p Conclusion A reduction of radiation exposition to radiation is achievable with minimal changes in the procedure, and without posing additional risks. Adoption of such radiation reduction policies could result in a long-term reduction of neoplasia in transplant patients and treating interventionalists.

Purpose Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy providing hemodynamic support to patients with advanced cardiorespiratory compromise. Following orthotopic heart transplantation (HTX), primary graft failure (PGF), especially wherein there is significant right ventricular dysfunction, can necessitate such intensive support to bridge to recovery or additional therapy. Marginal donors are used to increase the donor pool given the excess of candidates in most jurisdictions. Methods We conducted a single-center retrospective cohort study examining HTX from donation after brain death (DBD) donors that required post-operative ECMO for PGF from January 2008 - September 2020. Donor and recipient information were collected including demographics, renal function, echocardiographic measurements, biopsy data, and outcome measures. Marginal donor hearts were identified according to validated criteria including use of donor triiodothyronine (T3), donor left ventricular ejection fraction 60 years old, and donor ischemic time >6 hours or >4 hours if donor age >40 years old. Results Overall, 376 DBD HTX were performed, of which 126 involved marginal donor hearts (33.3%). ECMO was required in 81 (21.4%) of these patients, 42 (51.9%) of which involved marginal donor hearts. Thus, ECMO rates were 15.5% and 33.3% in non-marginal and marginal donor hearts, respectively. Overall, ECMO was successfully weaned in 75 (92.6%) and 62 (76.5%) survived their index HTX admission. Among patients who received non-marginal organs, 36 (92.3%) had ECMO weaned and 31 (79.5%) survived their index HTX admission versus 39 (92.9%) and 31 (73.8%) for these endpoints respectively among patients receiving marginal organs. Conclusion Our center's experience indicates that ECMO can provide satisfactory outcomes in HTX patients requiring advanced hemodynamic support post-operatively for PGF. Marginal donor hearts were more likely to require ECMO support post-operatively but had comparable and acceptable rates of index-admission survival compared to non-marginal cases. Further work is needed to evaluate outcome differences as efforts are made to expand the donor pool around the world.

Lifestyle interventions are pivotal for successful management of type 2 diabetes (T2D), however, the proportion of people with T2D adhering to physical activity advice has not been thoroughly studied. The purpose of this systematic review was to summarise the evidence on adherence to exercise or physical activity components in lifestyle interventions in those with T2D. We searched MEDLINE EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Scopus on 12 November 2019. Eligible studies enrolled adults with T2D and reported the proportion of adherence to lifestyle interventions as a primary or secondary outcome. We included 11 studies (nine randomised controlled trials (RCTs) enrolling 1717 patients and two nonrandomised studies enrolling 62 patients). Only one of the studies had low risk of bias. The proportion of participants adhering to physical activity varied from 32% to 100% with a median of 58%. Adherence was higher in interventions using supervised training and lowest in interventions using remote coaching and the adherence rate in observational studies was higher compared to RCTs (92% vs. 55%; p < 0.01). Study duration, risk of bias, or participants' sex, were not associated with adherence to physical activity. The proportion of those with T2D adhering to physical activity interventions for T2D varies widely and most of the included studies had a high risk of bias. These findings have important implications for planning and power analysis of future trials and when counselling patients about lifestyle interventions including physical activity or exercise components.

Hearts from older donors or procured via donation after circulatory death (DCD) can alleviate transplant waitlist; however, these hearts are particularly vulnerable to injury caused by warm ischemic times (WITs) inherent to DCD. This study investigates how the combination of increasing donor age and pharmacologic supplementation affects the ischemic tolerance and functional recovery of DCD hearts and how age impacts cardiac mitochondrial respiratory capacity and oxidative phosphorylation.MethodsWistar rats (12-, 18-, and 24-mo-old) were subjected to DCD with 20-min fixed WIT. Hearts were procured, instrumented onto a Langendorff perfusion circuit, flushed with Celsior preservation solution with or without supplementation (glyceryl trinitrate [GTN]/erythropoietin [EPO]/zoniporide [Z]) and perfused (Krebs-Henseleit buffer, 37°C Langendorff 30-min, working 30-min). Cardiac functional recovery of aortic flow (AF), coronary flow (CF), cardiac output (CO), and lactate dehydrogenase release were measured. Native heart tissue (3-, 12-, and 24-mo) were assessed for mitochondrial respiratory capacity.ResultsUnsupplemented 18- and 24-month DCD hearts showed a 6-fold decrease in AF recovery relative to unsupplemented 12-month DCD hearts. GTN/EPO/Z supplementation significantly increased AF and CO recovery of 18-month DCD hearts to levels comparable to supplemented 12-month hearts; however, GTN/EPO/Z did not improve 24-month DCD heart recovery. Compared to 12-month heart tissue, 24-month hearts exhibited significantly impaired mitochondrial oxygen flux at complex I, II, and uncoupled maximal respiration stage.ConclusionsReduced ischemic tolerance after DCD was associated with increasing age. Pharmacologic supplementation improves functional recovery of rat DCD hearts but only up to age 18 months, possibly attributed to a decline in mitochondrial respiratory capacity with increasing age.

Heart transplantation from donation after circulatory death (DCD) donors is a rapidly expanding practice. In this review, we describe the history and challenges of DCD heart transplantation and overview the procurement protocols and methods of limiting ischemic injury, current outcomes, and future directions. There are now at least three protocols that permit resuscitation and viability assessment of the DCD heart either in situ or ex situ. While the retrieval protocol for hearts from DCD donors will depend on local regulations, the outcomes of DCD heart transplant recipients reported to date are excellent regardless of the retrieval protocol and are comparable to the outcomes of heart transplant recipients from donation after brain death (DBD) donors. In the two centers with the largest published experience, DCD heart transplantation now accounts for one third of their heart transplant activity. With international trends indicating that there is an increasing utilisation of the DCD pathway, it is expected that DCD donors will become a major source of heart donation worldwide.

The persistent scarcity of donor allografts for transplantation has led to the acceptance of donors deemed ‘marginal’, due to factors such as older age, or indeed donor pathway. Ex situ organ perfusion or machine perfusion has evolved in the last decade as the primary technique utilised to facilitate the safe transplantation of such organs, traditionally often associated with higher rates of primary graft dysfunction, and subsequently, poor recipient outcomes. As well as having been demonstrated to permit the use of marginal brain dead donors with non-inferior outcomes, machine perfusion has also played a critical role in the development of heart transplant programs utilising donation after circulatory death donors. This represents a rapidly evolving area in heart transplantation, with over a decade of rigorous basic science research now translating into an increased quantity and quality of donor hearts for transplantation. Regardless of where future advances are made, current clinical experience and outcomes with marginal brain dead and donation after circulatory death donors has established ex situ perfusion and resuscitation of cardiac allografts as an invaluable tool in heart transplantation.

Schistosome infection is a major cause of global morbidity, particularly in sub-Saharan Africa. However, there is no effective vaccine for this major neglected tropical disease, and re-infection routinely occurs after chemotherapeutic treatment. Following invasion through the skin, larval schistosomula enter the circulatory system and migrate through the lung before maturing to adulthood in the mesenteric or urogenital vasculature. Eggs released from adult worms can become trapped in various tissues, with resultant inflammatory responses leading to hepato-splenic, intestinal, or urogenital disease – processes that have been extensively studied in recent years. In contrast, although lung pathology can occur in both the acute and chronic phases of schistosomiasis, the mechanisms underlying pulmonary disease are particularly poorly understood. In chronic infection, egg-mediated fibrosis and vascular destruction can lead to the formation of portosystemic shunts through which eggs can embolise to the lungs, where they can trigger granulomatous disease. Acute schistosomiasis, or Katayama syndrome, which is primarily evident in non-endemic individuals, occurs during pulmonary larval migration, maturation, and initial egg-production, often involving fever and a cough with an accompanying immune cell infiltrate into the lung. Importantly, lung migrating larvae are not just a cause of inflammation and pathology but are a key target for future vaccine design. However, vaccine efforts are hindered by a limited understanding of what constitutes a protective immune response to larvae. In this review, we explore the current understanding of pulmonary immune responses and inflammatory pathology in schistosomiasis, highlighting important unanswered questions and areas for future research.