Organ preservation solutions: linking pharmacology to survival for the donor organ pathway

PURPOSE OF REVIEW: To provide an understanding of the scientific principles, which underpinned the development of organ preservation solutions, and to bring into context new strategies and challenges for solution development against the background of changing preservation technologies and expanded criteria donor access. RECENT FINDINGS: Improvements in organ preservation solutions continue to be made with new pharmacological approaches. New solutions have been developed for dynamic perfusion preservation and are now in clinical application. Principles defining organ preservation solution pharmacology are being applied for cold chain logistics in tissue engineering and regenerative medicine. SUMMARY: Organ preservation solutions support the donor organ pathway. The solution compositions allow additives and pharmacological agents to be delivered direct to the target organ to mitigate preservation injury. Changing preservation strategies provide further challenges and opportunities to improve organ preservation solutions

New Insights on the Role of TRP Channels in Calcium Signalling and Immunomodulation: Review of Pathways and Implications for Clinical Practice

Calcium is the most abundant mineral in the human body and is central to many physiological processes, including immune system activation and maintenance. Studies continue to reveal the intricacies of calcium signalling within the immune system. Perhaps the most well-understood mechanism of calcium influx into cells is store-operated calcium entry (SOCE), which occurs via calcium release-activated channels (CRACs). SOCE is central to the activation of immune system cells; however, more recent studies have demonstrated the crucial role of other calcium channels, including transient receptor potential (TRP) channels. In this review, we describe the expression and function of TRP channels within the immune system and outline associations with murine models of disease and human conditions. Therefore, highlighting the importance of TRP channels in disease and reviewing potential. The TRP channel family is significant, and its members have a continually growing number of cellular processes. Within the immune system, TRP channels are involved in a diverse range of functions including T and B cell receptor signalling and activation, antigen presentation by dendritic cells, neutrophil and macrophage bactericidal activity, and mast cell degranulation. Not surprisingly, these channels have been linked to many pathological conditions such as inflammatory bowel disease, chronic fatigue syndrome and myalgic encephalomyelitis, atherosclerosis, hypertension and atopy

Role of circulating exosomal biomarkers and their diagnostic accuracy in pancreatic cancer

Background and Aim: New biomarkers have the potential to facilitate early diagnosis of pancreatic cancer (PC). Circulating exosomes are cell-derived protein complexes containing RNA that can be used as indicators of cancer development. The aim of this review is to evaluate the current literature involving PC patient groups for highly accurate exosomal biomarkers. Methods: The literature search followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight-hundred and seventy-five studies were identified across various databases (Ovid MEDLINE, Embase, and Cochrane) published between 2009 and 2020. Nine studies fulfilled the inclusion criteria: human PC patients, diagnosis as outcome of interest, serum biomarker of exosomal content, reporting of diagnostic values, and disease progress. Area under the curve (AUC) of the exosomal biomarker was compared against that of CA19-9. Results: Nine papers were reviewed for relevant outcomes based on the inclusion criteria. These studies involved 565 participants (331 PC, 234 controls; male/female ratio 1.21; mean age 64.1). Tumor staging was reported in all studies, with 45.6% of PC patients diagnosed with early-stage PC (T1–2). The mRNA panel (ARG1, CD63, CK18, Erbb3, GAPDH, H3F3A, KRAS, ODC1) and GPC 1 reported the highest performing sensitivity and specificity at 100% each. The microRNA panel (miR-10b, miR-21, miR-30c, miR-181a, and miR-let7a), mRNA panel (ARG1, CD63, CK18, Erbb3, GAPDH, H3F3A, KRAS, ODC1), and GPC 1 showed a perfect AUC of 1.0. Five studies compared the AUC of the exosomal biomarker against CA19-9, each being superior to that of CA19-9. Conclusion: The potential of exosomal biomarkers remains promising in PC diagnosis. Standardization of future studies will allow for larger comparative analyses and overcoming contrasting findings

Systematic review of the role of high intensity focused ultrasound (HIFU) in treating malignant lesions of the hepatobiliary system

BACKGROUND: High Intensity Focused Ultrasound (HIFU) is an emerging non-invasive, targeted treatment of malignancy. The aim of this review was to assess the efficacy, safety and optimal technical parameters of HIFU to treat malignant lesions of the hepatobiliary system. METHODS: A systematic search of the English literature was performed until March 2020, interrogating Pubmed, Embase and Cochrane Library databases. The following key-words were input in various combinations: 'HIFU', 'High intensity focussed ultrasound', 'Hepatobiliary', 'Liver', 'Cancer' and 'Carcinoma'. Extracted content included: Application type, Exposure parameters, Patient demographics, and Treatment outcomes. RESULTS: Twenty-four articles reported on the clinical use of HIFU in 940 individuals to treat malignant liver lesions. Twenty-one studies detailed the use of HIFU to treat hepatocellular carcinoma only. Mean tumour size was 5.1 cm. Across all studies, HIFU resulted in complete tumour ablation in 55% of patients. Data on technical parameters and the procedural structure was very heterogeneous. Ten studies (n = 537 (57%) patients) described the use of HIFU alongside other modalities including TACE, RFA and PEI; 66% of which resulted in complete tumour ablation. Most common complications were skin burns (15%), local pain (5%) and fever (2%). CONCLUSION: HIFU has demonstrated benefit as a treatment modality for malignant lesions of the hepatobiliary system. Combining HIFU with other ablative therapies, particularly TACE, increases the efficacy without increasing complications. Future human clinical studies are required to determine the optimal treatment parameters, better define outcomes and explore the risks and benefits of combination therapies

Pesticide Consumption in Greenhouses; a Case Study of Kashan Region

Aims: In regard to increasing greenhouse area in Iran followed by increased use of pesticides and contaminated crops, this study aimed to determine the frequency and types of consumed pesticides in Kashan region, Iran, greenhouses. Instrument & Methods: In this descriptive study in 2011-2012, samples was entered by census method. At the first step, a list of greenhouses was obtained from agricultural organization, 39 active greenhouses were detected, thereafter the questionnaires have been completed in detail by direct interview; obtained data were analyzed in SPSS 23 by descriptive statistics. Findings: 87.1 of greenhouses used chemical methods for controlling pest and diseases of products and 43.5 used non-chemical methods. The most frequent used chemical pesticides were Deltamethrin (37.9) and Permethrin (28.3) as pyrethroid insecticides, Diazinon (23.1) as an organophosphate insecticide and Carbendazim (23.2) as a fungicides. Conclusion: 87.1 of the greenhouses’ owners of Kashan region, Iran, use chemical pesticide for pest control

The integration of rapid qualitative research in clinical trials: reflections from the ward-based goal-directed fluid therapy (GDFT) in acute pancreatitis feasibility trial

Background: There has been an increase in the integration of qualitative studies in randomised controlled trials. The purpose of this article is to reflect on our experience of carrying out a rapid qualitative study during a feasibility trial of goal-directed fluid therapy (GDFT) in patients with acute pancreatitis, including our sharing of emerging findings and the use of these findings by the trial team. / Methods: The study was designed as a rapid feedback evaluation and combined interviews with staff and patients who took part in the trial. / Findings: The rapid qualitative study pointed to common problems in trial recruitment among multiple sites, where lack of engagement of clinical teams across sites might impact negatively on patient recruitment. The article describes how the use of rapid feedback loops can be used as the trial is ongoing to inform changes in implementation. It also covers the potential challenges of working rapidly and collaborative with the trial team. / Conclusions: Rapid feedback evaluations can be used to generate findings across all stages of trial design and delivery. Additional research is required to explore the implementation of this research design in other settings and trial designs

Ultrasound Histotripsy on a Viable Perfused Whole Porcine Liver: Histological Aspects, Including 3D Reconstruction of the Histotripsy Site

Non-invasive therapeutic-focused ultrasound (US) can be used for the mechanical dissociation of tissue and is described as histotripsy. We have performed US histotripsy in viable perfused ex vivo porcine livers as a step in the development of a novel approach to hepatocyte cell transplantation. The histotripsy nidus was created with a 2 MHz single-element focused US transducer, producing 50 pulses of 10 ms duration, with peak positive and negative pressure values of P+ = 77.7 MPa and P- = -13.7 MPaat focus, respectively, and a duty cycle of 1%. Here, we present the histological analysis, including 3D reconstruction of histotripsy sites. Five whole porcine livers were retrieved fresh from the abattoir using human transplant retrieval and cold static preservation techniques and were then perfused using an organ preservation circuit. Whilst under perfusion, histotripsy was performed to randomly selected sites on the live. Fifteen lesional sites were formalin-fixed and paraffin-embedded. Sections were stained with Haematoxylin and Eosin and picro-Sirius red, and they were also stained for reticulin. Additionally, two lesion sites were used for 3D reconstruction. The core of the typical lesion consisted of eosinophilic material associated with reticulin loss, collagen damage including loss of birefringence to fibrous septa, and perilesional portal tracts, including large portal vein branches, but intact peri-lesional hepatic plates. The 3D reconstruction of two histotripsy sites was successful and confirmed the feasibility of this approach to investigate the effects of histotripsy on tissue in detail

Ward based goal directed fluid therapy (GDFT) in acute pancreatitis (GAP) trial: A feasibility randomised controlled trial

Background: Goal-directed fluid therapy (GDFT) reduces complications in patients undergoing major general surgery. There are no reports of cardiac output evaluation being used to optimise the fluid administration for patients with acute pancreatitis (AP) in a general surgery ward. / Method: 50 patients with AP were randomised to either ward-based GDFT (n = 25) with intravenous (IV) fluids administered based on stroke volume optimisation protocol or standard care (SC) (n = 25), but with blinded cardiac output evaluation, for 48-h following hospital admission. Primary outcome was feasibility. / Results: 50 of 116 eligible patients (43.1%) were recruited over 20 months demonstrating feasibility. 36 (72%) completed the 48-h of GDFT; 10 (20%) discharged within 48-h and 4 withdrawals (3 GDFT, 1 SC). Baseline characteristics were similar with only 3 participants having severe disease (6%, 1 GDFT, 2 SC). Similar volumes of IV fluids were administered in both groups (GDFT 5465 (1839) ml, SC 5211 (1745) ml). GDFT group had a lower heart rate, blood pressure and respiratory rate and improved oxygen saturations. GDFT was not associated with any harms. There was no evidence of difference in complications of AP (GDFT 24%, SC 32%) or in the duration of stay in intensive care (GDFT 0 (0), SC 0.7 (3) days). Length of hospital stay was 5 (2.9) days in GDFT and 6.3 (7.6) in SC groups. / Conclusion: Ward-based GDFT is feasible and shows a signal of possible efficacy in AP in this early-stage study. A larger multi-site RCT is required to confirm clinical and cost effectiveness

Ward-based Goal-Directed Fluid Therapy (GDFT) in Acute Pancreatitis (GAP) trial: study protocol for a feasibility randomised controlled trial

IntroductionAcute pancreatitis is an inflammatory disease of the pancreas with high risk of developing multiorgan failure and death. There are no effective pharmacological interventions used in current clinical practice. Maintaining fluid and electrolyte balance is the mainstay of supportive management. Goal-directed fluid therapy (GDFT) has been shown to decrease morbidity and mortality in surgical conditions with systemic inflammatory response. There is currently no randomised controlled trial (RCT) investigating the role of GDFT based on cardiac output parameters in patients with acute pancreatitis in the ward setting. A feasibility trial was designed to determine patient and clinician support for recruitment into an RCT of ward-based GDFT in acute pancreatitis, adherence to a GDFT protocol, safety, participant withdrawal, and to determine appropriate endpoints for a subsequent larger trial to evaluate efficacy.Methods and analysisThe GDFT in Acute Pancreatitis trial is a prospective two-centre feasibility RCT. Eligible adults admitted with new onset of acute pancreatitis will be enrolled and randomised into ward-based GDFT (n=25) or standard fluid therapy (n=25) within 6 hours from the diagnosis and continuing for the following 48 hours. Cardiac output parameters will be monitored with a non-invasive device (Cheetah NICOM; Cheetah Medical). The intervention group will consist of a protocolised GDFT approach consisting of stroke volume optimisation with crystalloid fluid boluses, while the control group will receive standard care fluid therapy as advised by the clinical team. The primary endpoint is feasibility. Secondary endpoints will include safety of the intervention, complications, mortality, admission to intensive care unit, cost and quality of life.Ethics and disseminationEthics approval was granted by the London Central Research Ethics Committee (17/LO/1235, project ID: 221872). The results of this trial will be presented to international conference with interest in general surgery and acute care and published in a peer-reviewed journal.Trial registration numberISRCTN36077283.</jats:sec

Warm versus cold cardioplegia in cardiac surgery: A meta-analysis with trial sequential analysis.

ObjectiveThis meta-analysis aimed to compare clinical outcomes of warm and cold cardioplegia in cardiac surgeries in adult patients, with trial sequential analysis (TSA) used to determine the conclusiveness of the results.MethodsElectronic searches were performed on PubMed, Medline, Scopus, EMBASE, and Cochrane library to identify all studies that compared warm and cold cardioplegia in cardiac surgeries. Primary end points were in-hospital or 30-day mortality, myocardial infarction, low cardiac output syndrome, intra-aortic balloon pump use, stroke, and new atrial fibrillation. Secondary end points were acute kidney injury, hospital length of stay, and intensive care unit length of stay. Prespecified subgroup analyses were performed for (1) studies published since publication of Fan and colleagues in 2010, (2) randomized controlled studies, (3) studies with low risk of bias, (4) coronary artery bypass graft surgeries, and (5) studies with cold blood versus those with cold crystalloid cardioplegia. TSA was performed to determine conclusiveness of the results, using on all outcomes without significant heterogeneity from studies of low risk of bias.ResultsNo significant differences were found between post-operative rates of mortality, myocardial infarction, low cardiac output syndrome, intra-aortic balloon pump use, stroke, new atrial fibrillation, and acute kidney injury between warm and cold cardioplegia. TSA concluded that current evidence was sufficient to rule out a 20% relative risk reduction in these outcomes.ConclusionsConcerning safety outcomes, current evidence suggests that the choice between warm and cold cardioplegia remains in the surgeon's preference