David G Bowen’s research while affiliated with Royal Prince Alfred Hospital and other places

Background Access to liver transplantation (LT) is affected by geographic disparities. Higher waitlist mortality is observed in patients residing farther from LT centres, but the impact of distance on post‐LT outcomes is unclear. Aims To evaluate whether the distance LT recipients reside from their LT centre affects graft and patient outcomes. Methods We retrospectively studied consecutive adult patients who received deceased donor LT at a statewide LT referral centre, Royal Prince Alfred Hospital (RPAH), 2006–2021. The primary outcome was overall patient survival. Results A total of 973 patients who underwent LT during the study period were analysed. The median distance from patient residence to RPAH was 44.9 km (interquartile range 21.9–168.0). Of these, 64.2% lived ≤100 km from RPAH. Compared to patients living ≤100 km from RPAH, those living >100 km away were less likely to be male, have chronic hepatitis B as their cause of liver disease or have hepatocellular carcinoma as their primary indication for LT. Living >100 km from RPAH was associated with fewer face‐to‐face clinic visits in the first year after LT (10 vs 11 visits, P < 0.001) and fewer readmissions to RPAH (32.4% vs 67.6%, P < 0.001). Distance from RPAH, regional code and socioeconomic code did not affect long‐term graft or patient survival based on Kaplan–Meier survival analysis (log‐rank P > 0.1). Conclusion In our single‐centre Australian study, patients living farther from their LT centre had different demographics. Distance from the LT centre was not associated with long‐term inferior graft or patient survival after LT.

Background Post‐transplantation diabetes mellitus (PTDM) is common after solid organ transplantation. In the past decade, there has been increasing interest in the association between hypomagnesaemia and the development of PTDM. This systematic review aimed to investigate the current knowledge regarding the association between hypomagnesaemia and PTDM in adult liver and renal transplant recipients. Methods A literature search of five databases, Medline, Embase, ProQuest, Scopus and Google Scholar, as well as article reference lists, was performed. Eligible studies that focused on adult liver and renal transplant recipients without pretransplantation hyperglycaemia or diabetes were included. Other eligibility criteria included quantitative studies which reported magnesium concentrations, studies with at least 6 months of follow‐up, and studies published in English. The Newcastle–Ottawa Assessment Tool was used for the quality assessment. Results In total, 12 studies were included in the final analysis. Eleven focused on renal transplantation and one on liver transplantation. All studies were medium to high quality with eight out of 12 achieving the highest rating of nine. Eight studies found a negative association between either pretransplant or early post‐transplant serum magnesium concentration and the risk of PTDM, three studies found no association between these two variables, and one study found a positive association between the magnesium concentration at 8 weeks after transplantation and glycosylated haemoglobin A1C. Conclusions Further large‐scale prospective studies with at least 6 months of follow‐up are needed to confirm these findings, particularly in liver transplantation, to further clarify and explore the relationship between hypomagnesaemia and PTDM.

Background Acute allograft rejection is a well-known complication of liver transplantation (LT). The incidence, epidemiology and outcomes of acute rejection have not been well-described in Australia. Methods We retrospectively studied consecutive adults who underwent deceased-donor LT at a single centre between 2010-2020. Donor and recipient data at time of LT and recipient outcomes were collected from a prospective LT database. Liver biopsy reports were reviewed and only a graft’s first instance of biopsy-proven acute rejection was analysed. Results During the study period, 796 liver transplants were performed in 770 patients. Biopsy-proven rejection occurred in 34.9% of transplants. There were no significant changes in the incidence of rejection over time (linear trend p =0.11). The median time to first episode of rejection was 71 days post-LT: 2.2% hyperacute, 50.4% early (≤90 d) and 47.5% late rejection (>90 d). Independent risk factors for rejection were younger recipient age at transplant (aHR 0.98 per year increase, 95% CI 0.97-1.00, p =0.01), and ABO-incompatible grafts (aHR 2.55 vs. ABO-compatible, 95% CI 1.27-5.09, p <0.01) while simultaneous multiorgan transplants were protective (aHR 0.21 vs. LT only, 95% CI 0.08-0.58, p <0.01). Development of acute rejection (both early and late) was independently associated with significantly reduced graft (aHR 3.13, 95% CI 2.21-4.42, p <0.001) and patient survival (aHR 3.42, 95% CI 2.35-4.98, p <0.001). Conclusion In this 11-year Australian study, acute LT rejection occurred in 35%, with independent risk factors of younger recipient age and ABO-incompatible transplant while having a simultaneous multiorgan transplant was protective. Acute rejection was independently associated with reduced graft and patient survival after adjustment for other factors.

While CD4⁺ T cells are a prerequisite for CD8⁺ T cell-mediated protection against intracellular hepatotropic pathogens, the mechanisms facilitating the transfer of CD4-help to intrahepatic CD8⁺ T cells are unknown. Here, we developed an experimental system to investigate cognate CD4⁺ and CD8⁺ T cell responses to a model-antigen expressed de novo in hepatocytes and reveal that after initial priming, effector CD4⁺ and CD8⁺ T cells migrate into portal tracts and peri-central vein regions of the liver where they cluster with type-1 conventional dendritic cells. These dendritic cells are locally licensed by CD4⁺ T cells and expand the number of CD8⁺ T cells in situ, resulting in larger effector and memory CD8⁺ T cell pools. These findings reveal that CD4⁺ T cells promote intrahepatic immunity by amplifying the CD8⁺ T cell response via peripheral licensing of hepatic type-1 conventional dendritic cells and identify intrahepatic perivascular compartments specialized in facilitating effector T cell-dendritic cell interactions.

Background Research activities undertaken during University studies contribute to preparation of medical students for practice of evidence-based medicine. This study aimed to understand medical students’ experiences, perceived research skills development and satisfaction associated with completion of mandatory research projects. Methods An online survey was sent to five cohorts of students (n = 1375) from years 2017–2021 at the completion of their research projects. Univariate analysis was conducted to understand students’ perception of research skills development, followed by linear regression modeling to explore factors influencing satisfaction with their research project. Manifest content analysis employing a framework approach was used to analyse qualitative data from responses to open ended questions. Results Response rate was 42%, with 513 (89%) returned surveys being complete and included in analysis. Whilst 37% of students felt they had requisite research skills before undertaking the research project, 84% reported they had these skills after completing the project (χ² = 8.99, P = 0.02). Mean satisfaction score of the students was 5.0/10 (+/- 2.5, median = 6 (IQR = 3.0–7.0) with 59% of students reporting satisfaction scores higher than the average. Higher satisfaction scores were reported by those who perceived that: research methods and teaching was useful in preparing them for conducting research; the research project helped them acquire new skills; the project resulted in peer-reviewed publication; and, who felt supported by their supervisors. Responses to open ended questions offered important insights into student experience and emphasised the importance of supportive supervisors and the need for a dedicated research block in the busy medical program. Conclusions The majority of students reported positive outcomes from the mandatory research project. Student satisfaction can be improved by ensuring supportive research environments and high-quality supervision, and inclusion of dedicated research time in the medical curriculum.

Background and aim: Acute-on-chronic liver failure (ACLF) is distinct from acute decompensation (AD) of cirrhosis in its clinical presentation, pathophysiology, and prognosis. There are limited published Australian ACLF data. Methods: We performed a single-center retrospective cohort study of all adults with cirrhosis admitted with a decompensating event to a liver transplantation (LT) centre between 2015 and 2020. ACLF was defined using the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) definition while those who did not meet the definition were classified as AD. The primary outcome of interest was 90-day LT-free survival. Results: A total of 615 patients had 1039 admissions for a decompensating event. On their index admission, 34% (209/615) of patients were classified as ACLF. Median admission model for end-stage liver disease (MELD) and MELD-Na scores were higher in ACLF patients compared with AD (21 vs 17 and 25 vs 20 respectively, both P < 0.001). Both the presence and severity of ACLF (grade ≥ 2) significantly predicted worse LT-free survival compared with patients with AD. The EASL-CLIF ACLF score (CLIF-C ACLF), MELD and MELD-Na scores performed similarly in predicting 90-day mortality. Patients with index ACLF had a higher risk of 28-day mortality (28.1% vs 5.1%, P < 0.001) and shorter times to readmission compared with those with AD. Conclusion: ACLF complicates over a third of hospital admissions for cirrhosis with decompensating events and is associated with a high short-term mortality. The presence and grade of ACLF predicts 90-day mortality and should be identified as those at greatest risk of poor outcome without intervention such as LT.

Background: Immunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation-induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear. Methods: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg of nicotinamide or placebo twice daily for 12 months. Participants were examined for skin lesions by dermatologists at 3-month intervals for 12 months. The primary end point was the number of new keratinocyte cancers during the 12-month intervention period. Secondary end points included the numbers of squamous-cell and basal-cell carcinomas during the 12-month intervention period, the number of actinic keratoses until 6 months after randomization, safety, and quality of life. Results: A total of 158 participants were enrolled, with 79 assigned to the nicotinamide group and 79 to the placebo group. The trial was stopped early owing to poor recruitment. At 12 months, there were 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group (rate ratio, 1.0; 95% confidence interval, 0.8 to 1.3; P = 0.96). No significant between-group differences in squamous-cell and basal-cell carcinoma counts, actinic keratosis counts, or quality-of-life scores were observed. Adverse events and changes in blood or urine laboratory variables were similar in the two groups. Conclusions: In this 12-month, placebo-controlled trial, oral nicotinamide therapy did not lead to lower numbers of keratinocyte cancers or actinic keratoses in immunosuppressed solid-organ transplant recipients. (Funded by the National Health and Medical Research Council; ONTRANS Australian New Zealand Clinical Trials Registry number, ACTRN12617000599370.).