Hydrographic shifts in coastal waters reflect climate-driven changes in hydrological regimes across Northwestern Patagonia.

Climate-driven changes in freshwater inputs have been shown to affect the structure and function of coastal ecosystems. We evaluated changes in the influence of river runoff on coastal systems of Northwestern Patagonia (NWP) over recent decades (1993-2021) by combined analysis of long-term streamflow time series, hydrological simulation, satellite-derived and reanalysis data on sea surface conditions (temperature, turbidity, and salinity). Significant decreases in minimum streamflow across a zone spanning six major river basins were evident at weekly, monthly, and seasonal scales. These changes have been most pronounced in mixed-regime northern basins (e.g., Puelo River) but appear to be progressing southward to rivers characterised by a nival regime. In the adjacent two-layer inner sea, reduced freshwater input corresponds with a shallower halocline and increased surface temperatures across northern Patagonia. Our results underscore the rapidly evolving influence of rivers on adjacent estuarine and coastal waters in NWP. We highlight the need for cross-ecosystem observation, forecasting, mitigation and adaptation strategies in a changing climate, together with corresponding adaptive basin management of systems that supply runoff to the coastal marine waters.

Tall Bornean forests experience higher canopy disturbance rates than those in the eastern Amazon or Guiana shield.

The future of tropical forests hinges on the balance between disturbance rates, which are expected to increase with climate change, and tree growth. Whereas tree growth is a slow process, disturbance events occur sporadically and tend to be short-lived. This difference challenges forest monitoring to achieve sufficient resolution to capture tree growth, while covering the necessary scale to characterize disturbance rates. Airborne LiDAR time series can address this challenge by measuring landscape scale changes in canopy height at 1 m resolution. In this study, we present a robust framework for analysing disturbance and recovery processes in LiDAR time series data. We apply this framework to 8000 ha of old-growth tropical forests over a 4-5-year time frame, comparing growth and disturbance rates between Borneo, the eastern Amazon and the Guiana shield. Our findings reveal that disturbance was balanced by growth in eastern Amazonia and the Guiana shield, resulting in a relatively stable mean canopy height. In contrast, tall Bornean forests experienced a decrease in canopy height due to numerous small-scale (<0.1 ha) disturbance events outweighing the gains due to growth. Within sites, we found that disturbance rates were weakly related to topography, but significantly increased with maximum canopy height. This could be because taller trees were particularly vulnerable to disturbance agents such as drought, wind and lightning. Consequently, we anticipate that tall forests, which contain substantial carbon stocks, will be disproportionately affected by the increasing severity of extreme weather events driven by climate change.

Temporal trends and outcomes of acute ischaemic strokes in patients hospitalised for percutaneous coronary intervention.

BACKGROUND: Acute ischaemic stroke (AIS) after percutaneous coronary intervention (PCI) is a rare, but debilitating, complication. However, contemporary data from real-world unselected patients are scarce. AIMS: We aimed to explore the temporal trends, outcomes and variables associated with AIS as well as in-hospital all-cause mortality in a nationwide cohort. METHODS: A retrospective analysis of healthcare records from 2006-2021 was implemented. Patients were stratified according to the occurrence of AIS in the setting of PCI. The temporal trends of AIS were analysed. A stepwise regression model was used to identify variables associated with AIS and in-hospital all-cause mortality. RESULTS: A total of 4,910,430 PCIs were included for the current analysis. AIS occurred in 4,098 cases (0.08%). An incremental increase in the incidence of AIS after PCI from 0.03% to 0.14% per year was observed from 2006-2021. The strongest associations with AIS after PCI included carotid artery disease, medical history of stroke, atrial fibrillation, presentation with an ST-segment elevation myocardial infarction (STEMI) or non-STEMI and coronary thrombectomy. For patients with AIS, a higher in-hospital all-cause mortality (18.11% vs 3.29%; p<0.001) was documented. With regard to all-cause mortality, the strongest correlations in the stroke cohort were found for cardiogenic shock, dialysis and clinical presentation with a STEMI. CONCLUSIONS: In an unselected nationwide cohort of patients hospitalised for PCI, a gradual increase in AIS incidence was noted. We identified several variables associated with AIS as well as with in-hospital mortality. Hereby, clinicians might identify the patient population at risk for a peri-interventional AIS as well as those at risk for an adverse in-hospital outcome after PCI.

[Labor migrants are not safe on Dutch workplaces]. / Arbeidsmigranten niet veilig op Nederlandse werkvloer.

OBJECTIVE: In recent years, several international studies have been published, that describe a relationship between country of origin and the occurrence of work-related injury. Since we regularly treat migrant workers in our hospital after work-related injury, we wanted to gain more insight into the characteristics of this group. DESIGN: Descriptive retrospective cohort study. METHOD: Patients were identified from the Dutch Nationwide Trauma Registration (LTR). Patients that were included in the study were admitted and treated in our hospital after a work-related injury from 2017 to 2021. Additional information regarding patient characteristics and outcomes were retrieved from our electronic hospital information system. RESULTS: 14,9% of the 397 patients were found to have an injury with an Injury Severity Score (ISS) of 16 or higher. The most common mechanism of injury was a fall from height (ISS≤15: 26.0%, ISS≥16: 57.6%). In the study population, 15,4% had a non-Dutch origin. The majority consisted of employees with an Eastern European nationality (70,5%), mainly from Poland. Within this group relatively more often patients were encountered that had no valid insurance (14% of patients with an Eastern European origin) or were intoxicated (19% of patients with Eastern European origin). CONCLUSION: A relatively large part of our patient population consisted of migrant workers. We did not observe large differences in mechanism of injury, severity of injury and outcome between native patients and migrant workers. We did observe a relatively high frequency of insurance problems and intoxications among migrant workers.

scTab: Scaling cross-tissue single-cell annotation models.

Identifying cellular identities is a key use case in single-cell transcriptomics. While machine learning has been leveraged to automate cell annotation predictions for some time, there has been little progress in scaling neural networks to large data sets and in constructing models that generalize well across diverse tissues. Here, we propose scTab, an automated cell type prediction model specific to tabular data, and train it using a novel data augmentation scheme across a large corpus of single-cell RNA-seq observations (22.2 million cells). In this context, we show that cross-tissue annotation requires nonlinear models and that the performance of scTab scales both in terms of training dataset size and model size. Additionally, we show that the proposed data augmentation schema improves model generalization. In summary, we introduce a de novo cell type prediction model for single-cell RNA-seq data that can be trained across a large-scale collection of curated datasets and demonstrate the benefits of using deep learning methods in this paradigm.

Transformers in single-cell omics: a review and new perspectives.

Recent efforts to construct reference maps of cellular phenotypes have expanded the volume and diversity of single-cell omics data, providing an unprecedented resource for studying cell properties. Despite the availability of rich datasets and their continued growth, current single-cell models are unable to fully capitalize on the information they contain. Transformers have become the architecture of choice for foundation models in other domains owing to their ability to generalize to heterogeneous, large-scale datasets. Thus, the question arises of whether transformers could set off a similar shift in the field of single-cell modeling. Here we first describe the transformer architecture and its single-cell adaptations and then present a comprehensive review of the existing applications of transformers in single-cell analysis and critically discuss their future potential for single-cell biology. By studying limitations and technical challenges, we aim to provide a structured outlook for future research directions at the intersection of machine learning and single-cell biology.

Medication improves velocity, reaction time, and movement time but not amplitude or error during memory-guided reaching in Parkinson's disease.

The motor impairments experienced by people with Parkinson's disease (PD) are exacerbated during memory-guided movements. Despite this, the effect of antiparkinson medication on memory-guided movements has not been elucidated. We evaluated the effect of antiparkinson medication on motor control during a memory-guided reaching task with short and long retention delays in participants with PD and compared performance to age-matched healthy control (HC) participants. Thirty-two participants with PD completed the motor section of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) and performed a memory-guided reaching task with two retention delays (0.5 s and 5 s) while on and off medication. Thirteen HC participants completed the MDS-UPDRS III and performed the memory-guided reaching task. In the task, medication increased movement velocity, decreased movement time, and decreased reaction time toward what was seen in the HC. However, movement amplitude and reaching error were unaffected by medication. Shorter retention delays increased movement velocity and amplitude, decreased movement time, and decreased error, but increased reaction times in the participants with PD and HC. Together, these results imply that antiparkinson medication is more effective at altering the neurophysiological mechanisms controlling movement velocity and reaction time compared with other aspects of movement control.

The Use of Augmented Reality as an Educational Tool in Minimally Invasive Transforaminal Lumbar Interbody Fusion.

BACKGROUND AND OBJECTIVES: One of the major challenges in training neurosurgical and orthopedic residents the technique for minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is the lack of visualization of surgical landmarks (pedicle, pars, lamina). This is due to the limited access to the bony spine through a tubular retractor, in addition to a smaller working corridor or patient-specific factors such as bony overgrowth, disk space collapse, and listhesis. These factors increase the possibility for surgical error and prolonged surgery time. With augmented reality (AR), relevant surgical anatomy can be projected directly into the user's field of view through the microscope. The purpose of this study was to assess the utility, accuracy, efficiency, and precision of AR-guided MIS-TLIF and to determine its impact in spine surgery training. METHODS: At 2 centers, 12 neurosurgical residents performed a one-level MIS-TLIF on a high-fidelity lumbar spine simulation model with and without AR projection into the microscope. For the MIS-TLIF procedures with AR, surgical landmarks were highlighted in different colors on preoperative image data. These landmarks were visualized in the spinal navigation application on the navigation monitor and in the microscope to confirm the relevant anatomy. Postprocedural surveys (National Aeronautics and Space Administration Task Load Index) were given to the residents. RESULTS: Twelve residents were included in this trial. AR-guided procedures had a consistent impact on resident anatomical orientation and workload experience. Procedures performed without AR had a significantly higher mental demand (P = .003) than with AR. Residents reported to a significantly higher rate that it was harder work for them to accomplish their level of performance without AR (P = .019). CONCLUSION: AR can bring a meaningful value in MIS teaching and training to confirm relevant anatomy in situations where the surgeon will have less direct visual access. AR used in surgical simulation can also speed the learning curve.

Small data methods in omics: the power of one.

Over the last decade, biology has begun utilizing 'big data' approaches, resulting in large, comprehensive atlases in modalities ranging from transcriptomics to neural connectomics. However, these approaches must be complemented and integrated with 'small data' approaches to efficiently utilize data from individual labs. Integration of smaller datasets with major reference atlases is critical to provide context to individual experiments, and approaches toward integration of large and small data have been a major focus in many fields in recent years. Here we discuss progress in integration of small data with consortium-sized atlases across multiple modalities, and its potential applications. We then examine promising future directions for utilizing the power of small data to maximize the information garnered from small-scale experiments. We envision that, in the near future, international consortia comprising many laboratories will work together to collaboratively build reference atlases and foundation models using small data methods.

Inverse set estimation and inversion of simultaneous confidence intervals.

Motivated by the questions of risk assessment in climatology (temperature change in North America) and medicine (impact of statin usage and coronavirus disease 2019 on hospitalized patients), we address the problem of estimating the set in the domain of a function whose image equals a predefined subset of the real line. Existing methods require strict assumptions. We generalize the estimation of such sets to dense and nondense domains with protection against inflated Type I error in exploratory data analysis. This is achieved by proving that confidence sets of multiple upper, lower, or interval sets can be simultaneously constructed with the desired confidence nonasymptotically through inverting simultaneous confidence intervals. Nonparametric bootstrap algorithm and code are provided.

Evaluation of OCT biomarker changes in treatment-naive neovascular AMD using a deep semantic segmentation algorithm.

OBJECTIVES: To determine real-life quantitative changes in OCT biomarkers in a large set of treatment naive patients in a real-life setting undergoing anti-VEGF therapy. For this purpose, we devised a novel deep learning based semantic segmentation algorithm providing the first benchmark results for automatic segmentation of 11 OCT features including biomarkers for neovascular age-related macular degeneration (nAMD). METHODS: Training of a Deep U-net based semantic segmentation ensemble algorithm for state-of-the-art semantic segmentation performance which was used to analyze OCT features prior to, after 3 and 12 months of anti-VEGF therapy. RESULTS: High F1 scores of almost 1.0 for neurosensory retina and subretinal fluid on a separate hold-out test set with unseen patients. The algorithm performed worse for subretinal hyperreflective material and fibrovascular PED, on par with drusenoid PED, and better in segmenting fibrosis. In the evaluation of treatment naive OCT scans, significant changes occurred for intraretinal fluid (mean: 0.03 µm3 to 0.01 µm3, p < 0.001), subretinal fluid (0.08 µm3 to 0.01 µm3, p < 0.001), subretinal hyperreflective material (0.02 µm3 to 0.01 µm3, p < 0.001), fibrovascular PED (0.12 µm3 to 0.09 µm3, p = 0.02) and central retinal thickness C0 (225.78 µm3 to 169.40 µm3). The amounts of intraretinal fluid, fibrovascular PED, and ERM were predictive of poor outcome. CONCLUSIONS: The segmentation algorithm allows efficient volumetric analysis of OCT scans. Anti-VEGF provokes most potent changes in the first 3 months while a gradual loss of RPE hints at a progressing decline of visual acuity. Additional research is required to understand how these accurate OCT predictions can be leveraged for a personalized therapy regimen.

Biological and structural investigation of tetrahydro-ß-carboline-based selective HDAC6 inhibitors with improved stability.

Our previously reported HDAC6 inhibitor (HDAC6i) Marbostat-100 (4) has provided many arguments for further clinical evaluation. By the substitution of the acidic hydrogen of 4 for different carbon residues, we were able to generate an all-carbon stereocenter, which significantly improves the hydrolytic stability of the inhibitor. Further asymmetric synthesis has shown that the (S)-configured inhibitors preferentially bind to HDAC6. This led to the highly selective and potent methyl-substituted derivative S-29b, which elicited a long-lasting tubulin hyperacetylation in MV4-11 cells. Finally, a crystal structure of the HDAC6/S-29b complex provided mechanistic explanation for the high potency and stereoselectivity of synthesized compound series.

Impact of Lipoprotein(a) Level on Low-Density Lipoprotein Cholesterol- or Apolipoprotein B-Related Risk of Coronary Heart Disease.

BACKGROUND: Conventional low-density lipoprotein cholesterol (LDL-C) quantification includes cholesterol attributable to lipoprotein(a) (Lp(a)-C) due to their overlapping densities. OBJECTIVES: The purposes of this study were to compare the association between LDL-C and LDL-C corrected for Lp(a)-C (LDLLp(a)corr) with incident coronary heart disease (CHD) in the general population and to investigate whether concomitant Lp(a) values influence the association of LDL-C or apolipoprotein B (apoB) with coronary events. METHODS: Among 68,748 CHD-free subjects at baseline LDLLp(a)corr was calculated as "LDL-C-Lp(a)-C," where Lp(a)-C was 30% or 17.3% of total Lp(a) mass. Fine and Gray competing risk-adjusted models were applied for the association between the outcome incident CHD and: 1) LDL-C and LDLLp(a)corr in the total sample; and 2) LDL-C and apoB after stratification by Lp(a) mass (≥/<90th percentile). RESULTS: Similar risk estimates for incident CHD were found for LDL-C and LDL-CLp(a)corr30 or LDL-CLp(a)corr17.3 (subdistribution HR with 95% CI) were 2.73 (95% CI: 2.34-3.20) vs 2.51 (95% CI: 2.15-2.93) vs 2.64 (95% CI: 2.26-3.10), respectively (top vs bottom fifth; fully adjusted models). Categorization by Lp(a) mass resulted in higher subdistribution HRs for uncorrected LDL-C and incident CHD at Lp(a) ≥90th percentile (4.38 [95% CI: 2.08-9.22]) vs 2.60 [95% CI: 2.21-3.07]) at Lp(a) <90th percentile (top vs bottom fifth; Pinteraction0.39). In contrast, apoB risk estimates were lower in subjects with higher Lp(a) mass (2.43 [95% CI: 1.34-4.40]) than in Lp(a) <90th percentile (3.34 [95% CI: 2.78-4.01]) (Pinteraction0.49). CONCLUSIONS: Correction of LDL-C for its Lp(a)-C content provided no meaningful information on CHD-risk estimation at the population level. Simple categorization of Lp(a) mass (≥/<90th percentile) influenced the association between LDL-C or apoB with future CHD mostly at higher Lp(a) levels.

Aberrant hippocampal Ca2+ microwaves following synapsin-dependent adeno-associated viral expression of Ca2+ indicators.

Genetically encoded calcium indicators (GECIs) such as GCaMP are invaluable tools in neuroscience to monitor neuronal activity using optical imaging. The viral transduction of GECIs is commonly used to target expression to specific brain regions, can be conveniently used with any mouse strain of interest without the need for prior crossing with a GECI mouse line, and avoids potential hazards due to the chronic expression of GECIs during development. A key requirement for monitoring neuronal activity with an indicator is that the indicator itself minimally affects activity. Here, using common adeno-associated viral (AAV) transduction procedures, we describe spatially confined aberrant Ca2+ microwaves slowly travelling through the hippocampus following expression of GCaMP6, GCaMP7, or R-CaMP1.07 driven by the synapsin promoter with AAV-dependent gene transfer in a titre-dependent fashion. Ca2+ microwaves developed in hippocampal CA1 and CA3, but not dentate gyrus nor neocortex, were typically first observed at 4 wk after viral transduction, and persisted up to at least 8 wk. The phenomenon was robust and observed across laboratories with various experimenters and setups. Our results indicate that aberrant hippocampal Ca2+ microwaves depend on the promoter and viral titre of the GECI, density of expression, as well as the targeted brain region. We used an alternative viral transduction method of GCaMP which avoids this artefact. The results show that commonly used Ca2+-indicator AAV transduction procedures can produce artefactual Ca2+ responses. Our aim is to raise awareness in the field of these artefactual transduction-induced Ca2+ microwaves, and we provide a potential solution.

Panpipes: a pipeline for multiomic single-cell and spatial transcriptomic data analysis.

Single-cell multiomic analysis of the epigenome, transcriptome, and proteome allows for comprehensive characterization of the molecular circuitry that underpins cell identity and state. However, the holistic interpretation of such datasets presents a challenge given a paucity of approaches for systematic, joint evaluation of different modalities. Here, we present Panpipes, a set of computational workflows designed to automate multimodal single-cell and spatial transcriptomic analyses by incorporating widely-used Python-based tools to perform quality control, preprocessing, integration, clustering, and reference mapping at scale. Panpipes allows reliable and customizable analysis and evaluation of individual and integrated modalities, thereby empowering decision-making before downstream investigations.

Wits Transplant Unit Annual Report 2022: Adult and paediatric liver transplantation.

In 2022, the Wits Transplant Unit performed 57 liver transplants: 33/57 adult (58%) and 24/57 paediatric (42%) recipients. At the beginning of 2022, 28 candidates were on the adult waitlist. Forty-six candidates were added to the waitlist during the year. Sixty-five percent of waitlisted candidate were transplanted. Adult candidates remained on the waitlist for longer than previous years, with 52% of them waitlisted for less than one year before undergoing liver transplantation. There was a decrease in adult pretransplant mortality to 9% in 2021 from 25% in 2020. The most common aetiology in waitlist candidates was alcoholic steatohepatitis (ASH)/non-alcoholic steatohepatitis (NASH) (36%) and in recipients cholestatic (primary sclerosing cholangitis (PSC) and primary biliary sclerosis (PBC)) (40%). Most adult recipients received a deceased donor graft (79%). Unadjusted recipient one- and three-year survivals were 75% (95% confidence interval (CI) 65 - 83) and 74% (95% CI 65 - 81), respectively. In the paediatric population, the most common aetiologies for both pretransplant candidates and transplant recipients remained cholestatic disease and acute liver failure. There was a decrease in paediatric pretransplant mortality from 27% in 2017 to 6% in 2021. Unlike the adult cohort, most paediatric recipients received a living donor graft (79%). Unadjusted one-year and three-year survival rates were 85% (95% CI 75 - 92) and 68% (95% CI 56 - 77), respectively.

A retrospective analysis of outcomes and complications of living- and deceased-donor split-liver transplantation in Johannesburg, South Africa.

BACKGROUND: South African transplant centres are faced with significant challenges in meeting the need for liver transplantation, owing to the low and ever-decreasing number of deceased-donor organs. To increase organ utility, deceased-donor split-liver transplant (DDSLT) and living-donor liver transplant (LDLT) programmes were initiated in the Wits Transplant Unit. OBJECTIVE: To evaluate outcomes of the LDLT and DDSLT programmes. METHODS: A retrospective analysis of de-identified recipient and donor variables from all adult and paediatric DDSLTs and LDLTs conducted between 2013 and 2021 was performed. Comparison of categorical study variables between graft types was done with the χ2 test. Continuous variables were compared by means of the independent samples t-test. Cox proportional hazards regression was performed to examine the effect of graft type on recipient and graft survival. All comparisons were made unadjusted, and adjusted for recipient age, recipient ethnicity, donor sex, and graft-weight-to-recipient-weight ratio (GWRWR) (for the paediatric cohort); and for donor age and GWRWR (for the adult cohort). RESULTS: A total of 181 paediatric and 48 adult liver transplants have been performed since the inception of the two programmes. Chronic liver failure, specifically intra- and extrahepatic cholestatic disease, was our main indication for liver transplantation in both cohorts. There were no significant differences between the DDSLTs and LDLTs in respect of pre- or post-discharge intervention, in-hospital mortality, length of stay, and recipient or graft survival within both the paediatric and adult groups. Our overall 1- and 3-year survival estimates (95% confidence intervals) were 77% (70% - 83%) and 71% (64% - 78%) for the paediatric cohort, and 77% (62% - 87%) and 66% (50% - 78%) for the adult cohort, respectively. CONCLUSION: The results of this study demonstrate comparable outcomes between DDSLT and LDLT, indicating that both methods are effective approaches to optimise organ utilisation for liver transplantation within our setting.

ABO-incompatible liver transplantation - exploring utilitarian solutions to restricted access and organ shortages: A single-centre experience from Johannesburg, South Africa.

BACKGROUND: Liver transplantation is the definitive management for severe acute liver failure refractory to supportive management, and end- stage chronic liver failure. Owing to a shortage of deceased liver donors, South Africa requires innovative techniques to broaden the donor pool. OBJECTIVES: This study evaluated the outcomes of the Wits Transplant Unit ABO-incompatible liver transplant (ABOi-LT) programme. METHODS: This retrospective record review compared all adult and paediatric patients receiving ABO-compatible (ABOc) and ABO-incompatible (ABOi) liver transplants from January 2014 to December 2021 with a minimum one-year follow-up. Primary outcomes were recipient and graft survival and secondary outcomes included vascular, enteric and biliary complications, relook surgery, acute cellular rejection (ACR) and lenghth of hospital stay. Cox proportional hazards regression was performed to examine the effect of ABO-compatibility group on recipient and graft survival. The relationship between the ABO-compatibility group and categorical outcomes was assessed by binomial regression. RESULTS: During the study period, 532 liver transplants were performed; 44/532 (8%) were ABOi of which 14/44 (32%) were paediatric and 30/44 (68%) adult recipients. Within the pediatric group, the proportion of transplants performed for acute liver failure was significantly higher in the ABOi group (7/14; 50%) compared with the ABOc group (33/207; 16%) (p=0.005). Comparable recipient and graft survival estimates were noted: one-, three- and five-year recipient survival in the ABOi group was 77% (95% confidence interval (CI) 44 - 92), 58% (95% CI 17 - 84) and 58% (95% CI 17 - 84) respectively. There were significantly increased relative risks of relook surgery for the ABOi group compared with the ABOc group, both overall (relative risk (RR) 1.74; 95% CI 1.10 - 2.75) and at 90 days (RR 2.28; 95% CI 1.27 - 4.11); and also, for pre-discharge bloodstream infection (BSI), (RR 1.84; 95% CI 1.11 - 3.06). In adults, there were significantly more acute indications for liver transplantation in the ABOi (10/30; 33%) compared with the ABOc group (26/281; 9%) (p=0.0007) with the most common cause being drug or toxin ingestion (16/36; 44%). For the ABOi group, recipient survival estimates (95% CI) at 1, 3 and 5 years were 71% (50 - 84), 63% (41 - 78) and 58% (37 - 75) which, as noted with complication rates, were similar between ABO groups. CONCLUSION: This study confirms ABOi-LT as a feasible option to increase the liver donor pool in this organ-depleted setting as recipient survival and complication rates were similar between ABO-compatibility groups.

The paediatric liver transplant experience in Johannesburg, South Africa: A broad overview and update.

BACKGROUND: The Wits Transplant Unit performed its first paediatric liver transplant in 2005. Initial experiences from the unit were published in 2012 and 2014. Since then, significant progress has been made in capacity-building the unit, improving outcomes and enhancing service delivery. This paper presents a broad overview and update of the unit's 17-year experience.   Methods: We conducted a retrospective review of all paediatric liver transplants performed in Johannesburg from 1 January 2005 to 31 December 2021 with a minimum one-year follow-up. Data were accessed from the Wits Donald Gordon Medical Centre Paediatric Liver Transplant Research Database (University of the Witwatersrand Human Research Ethics approval: M190749). The following data were collected: donor and recipient sociodemographic and clinical characteristics, details of transplant procedures, donor grafts and recipient outcomes (post-operative complications, graft and recipient survival).   Results: A total of 270 transplants were performed during the review period. Two thirds of recipients (n=180, 67%) were younger than 5 years at time of transplant and half (n=135, 50%) received a living donor graft. The most common indication for liver transplant was biliary atresia, followed by acute liver failure. Unadjusted recipient survival was 80% (95% CI: 75-85%) at one year, and 68% (95% CI: 59-75%) at five years. Waiting list mortality decreased from 27.3% in 2017 to 5.9% in 2021. One hundred and fifty-four (57.0%) recipients experienced at least one type of intervention requiring surgical complication - the most common being biliary in nature (n = 91; 33.7%).   Conclusion: Over last seventeen years, a sustainable paediatric liver transplantation service has been established in Johannesburg. Living donor, split and ABO incompatible liver transplants have been incorporated in response to the severe organ shortage in South Africa. However, our outcomes can be improved. Additionally, a national transplant initiative to coordinate timeous referrals and expand access to liver transplantation for children with severe acute and chronic liver failure is advised.

Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patients.

BACKGROUND: In the paediatric liver transplant programme in Johannesburg, South Africa (SA), tacrolimus is the calcineurin inhibitor of choice, comprising an essential component of the immunosuppression regimen. It is characterised by a narrow therapeutic index and wide interpatient variability, necessitating therapeutic drug monitoring of whole-blood concentrations. Pharmacogenetic research, although not representative of SA population groups, suggests that single-nucleotide polymorphisms within the cytochrome P450 3A5 (CYP3A5) gene contribute to the variability in tacrolimus dosing requirements. The rs776746 polymorphism, CYP3A5*3, results in a splice defect and a non-functional enzyme. Clinically, to reach the same tacrolimus concentration-to-dose ratio (CDR), expressors (CYP3A5*1/*1 and *1/*3) require a higher tacrolimus dose than non-expressors (*3/*3). OBJECTIVES: To compare the pharmacokinetics of tacrolimus in paediatric liver transplant recipients with their donors' CYP3A5 genotypes, considering both donor and recipient characteristics. METHODS: Blood samples from 46 living liver donors were collected, their genomic DNA was extracted, and their CYP3A5 genotype was established (polymerase chain reaction and restriction fragment length polymorphism analysis, validated by Sanger sequencing). The relationship of donor and recipient characteristics with the mean tacrolimus CDR was analysed using a general linear model. Non- confounding significant variables were included in a multiple regression model. RESULTS: The study showed that all expressor donors genotyped as CYP3A5*1/*1 were of black African self-reported race and ethnicity. During the first 15 days post-transplant, we found that children who received grafts from donor CYP3A5 expressors (CYP3A5*1/*1 and *1/*3) had significantly lower mean tacrolimus CDRs compared with those who received grafts from donor CYP3A5 non-expressors (*3/*3); the recipients of CYP3A5 expressor grafts therefore require higher doses of oral tacrolimus to achieve the same therapeutic target range. In addition, graft-to-recipient weight ratio and the CYP3A5 donor genotypes were independent factors that significantly (p<0.05) affected mean tacrolimus CDRs in recipients. CONCLUSION: In this study, we showed that all CYP3A5*1 homozygote donors were of black African self-reported race and ethnicity, and tacrolimus CDRs in paediatric living-donor liver transplant recipients were significantly affected by donor graft size and donor CYP3A5 genotypes. Information from this study may inform the development of an Afrocentric tacrolimus precision-medicine algorithm to optimise recipient safety and graft outcomes.