From Haphazard to a Sustainable Normothermic Regional Perfusion Service: A Blueprint for the Introduction of Novel Perfusion Technologies.

Normothermic Regional Perfusion (NRP) has shown encouraging clinical results. However, translation from an experimental to routine procedure poses several challenges. Herein we describe a model that led to the implementation of NRP into standard clinical practice in our centre following an iterative process of refinement incorporating training, staffing and operative techniques. Using this approach we achieved a four-fold increase in trained surgical staff and a 6-fold increase in competent senior organ preservation practitioners in 12 months, covering 93% of the retrieval calls. We now routinely provide NRP throughout the UK and attended 186 NRP retrievals from which 225 kidneys, 26 pancreases and 61 livers have been transplanted, including 5 that were initially declined by all UK transplant centres. The 61 DCD(NRP) liver transplants undertaken exhibited no primary non-function or ischaemic cholangiopathy with up to 8 years of follow-up. This approach also enabled successful implementation of ex situ normothermic liver perfusion which together with NRP contributed 37.5% of liver transplant activity in 2021. Perfusion technologies (in situ and ex situ) are now supported by a team of Advanced Perfusion and Organ Preservation Specialists. The introduction of novel perfusion technologies into routine clinical practice presents significant challenges but can be greatly facilitated by developing a specific role of Advanced Perfusion and Organ Preservation Specialist supported by a robust education, training and recruitment programme.

SARS-CoV-2 infection and early mortality of waitlisted and solid organ transplant recipients in England: A national cohort study.

Patients waitlisted for and recipients of solid organ transplants (SOT) are perceived to have a higher risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and death; however, definitive epidemiological evidence is lacking. In a comprehensive national cohort study enabled by linkage of the UK transplant registry and Public Health England and NHS Digital Tracing services, we examined the incidence of laboratory-confirmed SARS-CoV-2 infection and subsequent mortality in patients on the active waiting list for a deceased donor SOT and recipients with a functioning SOT as of February 1, 2020 with follow-up to May 20, 2020. Univariate and multivariable techniques were used to compare differences between groups and to control for case-mix. One hundred ninety-seven (3.8%) of the 5184 waitlisted patients and 597 (1.3%) of the 46 789 SOT recipients tested positive for SARS-CoV-2. Mortality after testing positive for SARS-CoV-2 was 10.2% (20/197) for waitlisted patients and 25.8% (154/597) for SOT recipients. Increasing recipient age was the only variable independently associated with death after positive SARS-CoV-2 test. Of the 1004 transplants performed in 2020, 41 (4.1%) recipients have tested positive for SARS-CoV-2 with 8 (0.8%) deaths reported by May 20. These data provide evidence to support decisions on the risks and benefits of SOT during the coronavirus disease 2019 pandemic.

Lessons from a pilot for uncontrolled donation after circulatory death in the ED in the UK.

Worldwide there is a shortage of available organs for patients requiring transplants. However, some countries such as France, Italy and Spain have had greater success by allowing donations from patients with unexpected and unrecoverable circulatory arrest who arrive in the ED. Significant advances in the surgical approach to organ recovery from donation after circulatory death (DCD) led to the establishment of a pilot programme for uncontrolled DCD in the ED of the Royal Infirmary of Edinburgh. This paper describes the programme and discusses the lessons learnt.

In situ normothermic perfusion of livers in controlled circulatory death donation may prevent ischemic cholangiopathy and improve graft survival.

Livers from controlled donation after circulatory death (DCD) donors suffer a higher incidence of nonfunction, poor function, and ischemic cholangiopathy. In situ normothermic regional perfusion (NRP) restores a blood supply to the abdominal organs after death using an extracorporeal circulation for a limited period before organ recovery. We undertook a retrospective analysis to evaluate whether NRP was associated with improved outcomes of livers from DCD donors. NRP was performed on 70 DCD donors from whom 43 livers were transplanted. These were compared with 187 non-NRP DCD donor livers transplanted at the same two UK centers in the same period. The use of NRP was associated with a reduction in early allograft dysfunction (12% for NRP vs. 32% for non-NRP livers, P = .0076), 30-day graft loss (2% NRP livers vs. 12% non-NRP livers, P = .0559), freedom from ischemic cholangiopathy (0% vs. 27% for non-NRP livers, P < .0001), and fewer anastomotic strictures (7% vs. 27% non-NRP, P = .0041). After adjusting for other factors in a multivariable analysis, NRP remained significantly associated with freedom from ischemic cholangiopathy (P < .0001). These data suggest that NRP during organ recovery from DCD donors leads to superior liver outcomes compared to conventional organ recovery.

Improving the management of urinary incontinence.

Urinary incontinence (UI) is the complaint of any involuntary loss of urine and is a common condition that is likely to be under-reported. In the UK, the prevalence is estimated to be 17-40%, and rates are higher in the elderly. UI is more common in women than men. Its frequency increases with age, parity, high BMI, and associated comorbidities. The common types are stress UI, overactive bladder (OAB) or urge UI, and mixed UI a combination of the two. In stress UI there is involuntary loss of urine that occurs in association with an increase in intra-abdominal pressure. OAB is caused by overactivity of the detrusor muscle. This may be idiopathic or secondary to lesions affecting the motor or sensory pathways to the muscle. The history should include the circumstances in which the incontinence occurs, the duration and how it affects the patient's quality of life. The initial assessment should include enquiring for symptoms of urinary tract infection and carrying out a urine dipstick test. Abdominal examination should exclude a large pelvic-abdominal mass and a palpable bladder post micturition. Vulval-vaginal examination should assess for atrophic vaginitis and prolapse, masses and pelvic floor muscle contraction. Involving a skilled continence nurse or dedicated pelvic physiotherapist will improve care and can reduce referrals to secondary care. When conservative measures for OAB are unsuccessful, the next step is pharmacological treatment. Referral to secondary care should be offered when the response to two drugs has not been satisfactory. For stress UI, referral is indicated after failure of pelvic floor muscle training.

Does Time to Asystole in Donors After Circulatory Death Impact Recipient Outcome in Liver Transplantation?

BACKGROUND: The agonal phase can vary following treatment withdrawal in donor after circulatory death (DCD). There is little evidence to support when procurement teams should stand down in relation to donor time to death (TTD). We assessed what impact TTD had on outcomes following DCD liver transplantation. METHODS: Data were extracted from the UK Transplant Registry on DCD liver transplant recipients from 2006 to 2021. TTD was the time from withdrawal of life-sustaining treatment to asystole, and functional warm ischemia time was the time from donor systolic blood pressure and/or oxygen saturation falling below 50 mm Hg and 70%, respectively, to aortic perfusion. The primary endpoint was 1-y graft survival. Potential predictors were fitted into Cox proportional hazards models. Adjusted restricted cubic spline models were generated to further delineate the relationship between TTD and outcome. RESULTS: One thousand five hundred fifty-eight recipients of a DCD liver graft were included. Median TTD in the entire cohort was 13 min (interquartile range, 9-17 min). Restricted cubic splines revealed that the risk of graft loss was significantly greater when TTD ≤14 min. After 14 min, there was no impact on graft loss. Prolonged hepatectomy time was significantly associated with graft loss (hazard ratio, 1.87; 95% confidence interval, 1.23-2.83; P = 0.003); however, functional warm ischemia time had no impact (hazard ratio, 1.00; 95% confidence interval, 0.44-2.27; P > 0.9). CONCLUSIONS: A very short TTD was associated with increased risk of graft loss, possibly because of such donors being more unstable and/or experiencing brain stem death as well as circulatory death. Expanding the stand down times may increase the utilization of donor livers without significantly impairing graft outcome.

Improved Organ Utilization and Better Transplant Outcomes With In Situ Normothermic Regional Perfusion in Controlled Donation After Circulatory Death.

BACKGROUND: . We evaluated whether the use of normothermic regional perfusion (NRP) was associated with increased organ recovery and improved transplant outcomes from controlled donation after circulatory death (cDCD). METHODS: . This is a retrospective analysis of UK adult cDCD donors' where at least 1 abdominal organ was accepted for transplantation between January 1, 2011, and December 31, 2019. RESULTS: . A mean of 3.3 organs was transplanted when NRP was used compared with 2.6 organs per donor when NRP was not used. When adjusting for organ-specific donor risk profiles, the use of NRP increased the odds of all abdominal organs being transplanted by 3-fold for liver ( P < 0.0001; 95% confidence interval [CI], 2.20-4.29), 1.5-fold for kidney ( P = 0.12; 95% CI, 0.87-2.58), and 1.6-fold for pancreas ( P = 0.0611; 95% CI, 0.98-2.64). Twelve-mo liver transplant survival was superior for recipients of a cDCD NRP graft with a 51% lower risk-adjusted hazard of transplant failure (HR = 0.494). In risk-adjusted analyses, NRP kidneys had a 35% lower chance of developing delayed graft function than non-NRP kidneys (odds ratio, 0.65; 95% CI, 0.465-0.901)' and the expected 12-mo estimated glomerular filtration rate was 6.3 mL/min/1.73 m 2 better if abdominal NRP was used ( P < 0.0001). CONCLUSIONS: . The use of NRP during DCD organ recovery leads to increased organ utilization and improved transplant outcomes compared with conventional organ recovery.

A national pilot of donation after circulatory death (DCD) heart transplantation within the United Kingdom.

BACKGROUND: The United Kingdom (UK) was one of the first countries to pioneer heart transplantation from donation after circulatory death (DCD) donors. To facilitate equity of access to DCD hearts by all UK heart transplant centers and expand the retrieval zone nationwide, a Joint Innovation Fund (JIF) pilot was provided by NHS Blood and Transplant (NHSBT) and NHS England (NHSE). The activity and outcomes of this national DCD heart pilot program are reported. METHODS: This is a national multi-center, retrospective cohort study examining early outcomes of DCD heart transplants performed across 7 heart transplant centers, adult and pediatric, throughout the UK. Hearts were retrieved using the direct procurement and perfusion (DPP) technique by 3 specialist retrieval teams trained in ex-situ normothermic machine perfusion. Outcomes were compared against DCD heart transplants before the national pilot era and against contemporaneous donation after brain death (DBD) heart transplants, and analyzed using Kaplan-Meier analysis, chi-square test, and Wilcoxon's rank-sum. RESULTS: From September 7, 2020 to February 28, 2022, 215 potential DCD hearts were offered of which 98 (46%) were accepted and attended. There were 77 potential donors (36%) which proceeded to death within 2 hours, with 57 (27%) donor hearts successfully retrieved and perfused ex situ and 50 (23%) DCD hearts going on to be transplanted. During this same period, 179 DBD hearts were transplanted. Overall, there was no difference in the 30-day survival rate between DCD and DBD (94% vs 93%) or 90 day survival (90% vs 90%) respectively. There was a higher rate of ECMO use post-DCD heart transplants compared to DBD (40% vs 16%, p = 0.0006), and DCD hearts in the pre pilot era, (17%, p = 0.002). There was no difference in length of ICU stay (9 DCD vs 8 days DBD, p = 0.13) nor hospital stay (28 DCD vs 27 DBD days, p = 0.46). CONCLUSION: During this pilot study, 3 specialist retrieval teams were able to retrieve DCD hearts nationally for all 7 UK heart transplant centers. DCD donors increased overall heart transplantation in the UK by 28% with equivalent early posttransplant survival compared with DBD donors.

Which patients should be offered caesarean section?

Caesarean section (CS) rates have steadily risen from 10% of all deliveries in the 1980s to a current figure of around 23.8%. Approximately 75% of CS are emergency procedures and only 25% are elective planned deliveries. When deciding whether to offer CS, it is important to consider the psychological implications for the patient as well as the physical and mental sequelae in future pregnancies. Clinicians should provide pregnant women with evidence-based information and support. Information should include details about the true indication(s) for the CS and what it implies, including its risks and benefits. The updated NICE guideline does not advocate CS in uncomplicated pregnancies. However, it supports CS on maternal request when attempts to empower the mother to have a vaginal birth have not been successful. CS on maternal request only represented 1.4% of all CS in 2001. CS may reduce perineal and abdominal pain during birth and 3 days postpartum. It may also reduce injury to the vagina, early postpartum haemorrhage and obstetric shock. The following patients should be offered a planned elective CS: singleton breech presentation at term, after external cephalic version has failed, has been declined or is contraindicated; multiple pregnancies when the first twin is not cephalic; placenta praevia, minor or major, (close to or covering the os); HIV-positive women who are not on any antiretroviral therapy, have a high viral load or co-infection with hepatitis C irrespective of viral load; and women with primary genital herpes simplex virus infection occurring in the third trimester.

Kidney Transplantation From Deceased Donors With Vaccine-induced Immune Thrombocytopenia and Thrombosis: An Updated Analysis of the UK Experience.

BACKGROUND: The emergence and attendant mortality of vaccine-induced immune thrombocytopenia and thrombosis (VITT) as a consequence of vaccination against severe acute respiratory syndrome coronavirus 2 have resulted in some patients with VITT being considered as deceased organ donors. Outcomes after kidney transplantation in this context are poorly described. Because the disease seems to be mediated by antiplatelet factor 4 antibodies, there is a theoretical risk of transmission via passenger leukocytes within the allograft. METHODS: We analyzed the experience of kidney transplantation from donors with VITT in the United Kingdom between January and June 2021. We followed-up all recipients of kidney-only transplants from donors with VITT to detect major postoperative complications or features of disease transmission and assess graft survival and function. RESULTS: There were 16 kidney donors and 30 single kidney transplant recipients in our study period. Of 11 preimplantation biopsies, 4 showed widespread glomerular microthrombi. After a median of 5 mo, patient and graft survival were 97% and 90%, respectively. The median 3-mo estimated glomerular filtration rate was 51 mL/min/1.73 m 2 . Two recipients had detectable antiplatelet factor 4 antibodies but no evidence of clinical disease after transplantation. Major hemorrhagic complications occurred in 3 recipients, all of whom had independent risk factors for bleeding, resulting in the loss of 2 grafts. The involvement of VITT could not be completely excluded in one of these cases. CONCLUSIONS: The UK experience to date shows that favorable outcomes are possible after kidney transplantation from donors with VITT but highlights the need for ongoing vigilance for donor-related complications in these patients.

Portal venous endothelium in developing human liver contains haematopoietic and epithelial progenitor cells.

Future treatments for chronic liver disease are likely to involve manipulation of liver progenitor cells (LPCs). In the human, data characterising the regenerative response is limited and the origin of adult LPCs is unknown. However, these remain critical factors in the design of cell-based liver therapies. The developing human liver provides an ideal model to study cell lineage derivation from progenitors and to understand how foetal haematopoiesis and liver development might explain the nature of the adult LPC population. In 1st trimester human liver, portal venous endothelium (PVE) expressed adult LPC markers and markers of haematopoietic progenitor cells (HPCs) shared with haemogenic endothelium found in the embryonic dorsal aorta. Sorted PVE cells were able to generate hepatoblast-like cells co-expressing CK18 and CK19 in addition to Dlk/pref-1, E-cadherin, albumin and fibrinogen in vitro. Furthermore, PVE cells could initiate haematopoiesis. These data suggest that PVE shares phenotypical and functional similarities both with adult LPCs and embryonic haemogenic endothelium. This indicates that a temporal relationship might exist between progenitor cells in foetal liver development and adult liver regeneration, which may involve progeny of PVE.

Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling.

Human embryonic stem cells (hESCs) are a valuable source of pluripotential primary cells. To date, however, their homogeneous cellular differentiation to specific cell types in vitro has proven difficult. Wnt signaling has been shown to play important roles in coordinating development, and we demonstrate that Wnt3a is differentially expressed at critical stages of human liver development in vivo. The essential role of Wnt3a in hepatocyte differentiation from hESCs is paralleled by our in vitro model, demonstrating the importance of a physiologic approach to cellular differentiation. Our studies provide compelling evidence that Wnt3a signaling is important for coordinated hepatocellular function in vitro and in vivo. In addition, we demonstrate that Wnt3a facilitates clonal plating of hESCs exhibiting functional hepatic differentiation. These studies represent an important step toward the use of hESC-derived hepatocytes in high-throughput metabolic analysis of human liver function.

GPs should be vigilant for pelvic inflammatory disease.

Pelvic inflammatory disease (PID) typically results from ascending infection through the endocervix, from the lower to the upper genital tract. This leads to inflammation of the endometrium, uterus, fallopian tubes, adnexal structures or pelvic peritoneum. PID accounts for one in 60 GP consultations by women under 45. The long-term effects of PID include chronic pelvic pain, subfertility and ectopic pregnancy. The most common cause of PID is sexually transmitted infection. Patients with PID may be asymptomatic or may present with a spectrum of symptoms including: lower abdominal pain (typically bilateral, sometimes radiating to the legs, abnormal vaginal or cervical discharge (often purulent), dysuria, deep dyspareunia and abnormal vaginal bleeding (postcoital, intermenstrual and breakthrough). A general, abdominal and pelvic examination should be performed. Outpatient therapy is considered to be as effective as inpatient treatment for patients with clinically mild to moderate PID. Most clinical trial data support the use of IM cefoxitin, however, as this drug is not readily available in the U.K. ceftriaxone has been deemed a suitable alternative. Metronidazole is usually included in most outpatient regimens to cover for the presence of anaerobes. The duration of outpatient treatment is usually 14 days. Patients should be told to avoid any form of sexual intercourse until they, and their partner(s) have completed their full course of treatment.

Exploring the use of high and low demand simulation for human performance assessment during multiorgan retrieval with the joint scrub practitioner.

Introduction: The National Organ Retrieval Service (NORS) 2015 review recommended a Joint Scrub Practitioner for abdominal and cardiac teams during combined organ retrieval. To evaluate the feasibility of this role, and to understand the functional implications, this study explores the use of simulation and provides a novel and comprehensive approach to assess individual and team performance in simulated multiorgan retrievals. Methods: Two high-fidelity simulations were conducted in an operating theatre with porcine organs, en bloc, placed in a mannequin. For donation after brainstem death (DBD) simulation, an anaesthetic machine provided simulated physiological output. Retrievals following donation after circulatory death (DCD) began with rapid arrival in theatre of the mannequin. Cardiothoracic (lead surgeon) and abdominal (lead and assistant surgeons; joint scrub practitioner, n=9) teams combined for the retrievals. Data collected before, during and after simulations used self-report and expert observers to assess: attitudinal expectations, mental readiness, mental effort, non-technical skills, teamwork, task workload and social validation perceptions. Results: Attitudinal changes regarding feasibility of a joint scrub practitioner for DBD and DCD are displayed in the main body. There were no significant differences in mental readiness prior to simulations nor in mental effort indicated afterwards; however, variance was noted between simulations for individual team members. Non-technical skills were slightly lower in DCD than in DBD. Global ratings of teamwork were significantly (p<0.05) lower in DCD than in DBD. Measures of attitude indicated less support for the proposed joint scrub practitioner role for DCD than for DBD. Discussion: The paper posits that the joint scrub practitioner role in DCD multiorgan retrieval may bring serious and unanticipated challenges. Further work to determine the feasibility of the NORS recommendation is required. Measures of team performance and individual psychological response can inform organ retrieval feasibility considerations nationally and internationally.

The Vanguard Study: Human Performance Evaluation of UK National Organ Retrieval Service Teams Utilizing a Single Scrub Practitioner in Multiorgan Retrieval.

BACKGROUND: The National Organ Retrieval Service (NORS) 2015 review recommended a single scrub practitioner provide support simultaneously to abdominal and cardiothoracic teams in UK multiorgan retrieval. Previously, this model had been used only by the combined abdominal and cardiac team in Scotland. This study reports the impact on performance as part of the Vanguard project, which utilized the single scrub practitioner role with 5 NORS teams, to determine applicability United Kingdom wide. METHODS: Participants comprised members of abdominal (n = 56) and cardiothoracic (n = 54) teams attending UK thoraco-abdominal retrievals. Data were collected by validated psychometric scales to assess individual workload, anxiety, confidence, demands/coping resources, and teamwork. Additional data were collected through open comments and quantitative data describing context and outcome of retrieval. RESULTS: Abdominal and cardiothoracic teams showed different responses when using single (Vanguard) or dual scrub practitioners (Standard). Vanguard configuration was associated with significantly higher anxiety for abdominal but not cardiothoracic teams. Perceived workload increased for abdominal teams during Vanguard but decreased for cardiothoracic teams. Scrub practitioners reported elevated anxiety and decreased confidence in retrievals using Vanguard configuration. CONCLUSIONS: This is the first large study examining human performance during organ retrieval in the United Kingdom. Despite previous regional success, this study showed a significant negative impact of the single scrub practitioner when extrapolated widely to UK teams. As a result of this study, NORS declined to implement the single scrub model. These data support the use of human performance analysis as an essential part of successful development in organ retrieval practice.

Liver development, regeneration, and carcinogenesis.

The identification of putative liver stem cells has brought closer the previously separate fields of liver development, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bioartificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers.

Side population cells in developing human liver are primarily haematopoietic progenitor cells.

Side population (SP) cells have recently been identified in a number of tissues although their phenotype and functional abilities are poorly understood. Surface marker characterisation and functional assessment of developing liver SP cells might allow for their isolation and manipulation using clinically relevant techniques. It was hypothesised that SP cells are present early during human liver development and contribute to haematopoietic and epithelial lineage generation. Whilst the SP population remained positive for CD34 during the 1st and 2nd trimester, 1st trimester SP cells were more highly enriched for haematopoietic and epithelial progenitor activity than those from the 2nd trimester in vitro. Marker expression and functional similarities indicate that SP cells in developing human liver may share a temporal relationship with oval/progenitor cells, responsible for liver regeneration after massive or chronic hepatic injury. Furthermore, modification of SP integrin expression during development suggests a potential adaptive interaction with niche components such as fibronectin. Improved understanding of developing human liver SP cells will contribute to the generation of novel cell-based therapies for liver disease.