Advances in targeted liquid chromatography-tandem mass spectrometry methods for endocannabinoid and N-acylethanolamine quantification in biological matrices: A systematic review.

Liquid chromatography paired with tandem mass spectrometry (LC-MS/MS) is the gold standard in measurement of endocannabinoid concentrations in biomatrices. We conducted a systematic review of literature to identify advances in targeted LC-MS/MS methods in the period 2017-2024. We found that LC-MS/MS methods for endocannabinoid quantification are relatively consistent both across time and across biomatrices. Recent advances have primarily been in three areas: (1) sample preparation techniques, specific to the chosen biomatrix; (2) the range of biomatrices tested, recently favoring blood matrices; and (3) the breadth of endocannabinoid and endocannabinoid-like analytes incorporated into assays. This review provides a summary of the recent literature and a guide for researchers looking to establish the best methods for quantifying endocannabinoids in a range of biomatrices.

Differences in Right Heart Function After Pulmonary Valve Replacement in Patients With Pulmonary Valve Stenosis Versus Tetralogy of Fallot.

BACKGROUND: There are limited data about the impact of timing of pulmonary valve replacement (PVR) on right heart reverse remodeling in patients with pulmonary regurgitation following intervention for isolated pulmonary valve stenosis (PS). This study compared differences in postprocedural right heart reverse remodeling after early versus late PVR (defined as PVR before versus after attainment of the conservative consensus criteria proposed by Bokma et al, 2018) in patients with prior intervention for PS, using patients with tetralogy of Fallot as the reference group. METHOD AND RESULTS: Right atrial reservoir strain and right ventricular free wall strain was measured at baseline, 1 and 3 years after PVR. There were 114 patients with PS (early PVR, 87 [76%]; late PVR, 27 [24%]) and 291 patients with tetralogy of Fallot (early PVR, 197 [67%]; late PVR, 96 [33%]). The PS group had greater improvement in right atrial reservoir strain at 1 year (12%±4% versus 8%±4%; P<0.001) and 3 years (15%±6% versus 9%±6%; P<0.001), and a greater improvement in right ventricular free wall strain at 1 year (12%±4% versus 7%±3%, P=0.008) and 3-years (16%±6% versus 12%±5%; P=0.01) after PVR compared with the tetralogy of Fallot group. There was no difference in right heart reverse remodeling between patients who underwent early versus later PVR within the PS group. In contrast, late PVR was associated with less right heart reverse remodeling within the tetralogy of Fallot group. CONCLUSIONS: These data suggest that patients with palliated PS presenting pulmonary regurgitation have a more benign clinical course, and hence delaying PVR in this population may be appropriate.

Adult Congenital Heart Disease Transplantation: Does Univentricle Physiology Impact Early Mortality?

BACKGROUND: With congenital heart disease patients increasingly living into adulthood, there is a growing population of adult congenital heart disease (ACHD) patients suffering from heart failure. Limited data exist evaluating heart transplant in this population. METHODS: Retrospective review was performed of ACHD patients undergoing heart transplantation 11/1990-1/2023. Kaplan-Meier, cumulative incidence accounting for competing risk of death, and subgroup analyses comparing those with biventricular (BiV) and univentricular (UniV) physiology were performed. Data are presented as median (interquartile range) or counts (%). RESULTS: 77 patients with a median age of 36 years (27, 45) were identified, including 57 (74%) BiV and 20 (26%) UniV. Preoperatively, UniV patients were more likely to have cirrhosis (9/20 [45.0%] vs 4/57 [7.0%], p<0.001) and protein losing enteropathy (4/20 [20.0%] vs 1/57 [1.8%], p=0.015). Multiorgan transplantation was performed in 23 patients (30%) and more frequently in UniV patients (10 [50%] vs. 13[23%], p=0.04). Operative mortality was 6.5%, 2/20 (10%) among UniV and 2/57 (4%) among BiV patients, p=0.276. Median clinical follow-up was 6.0 (1.4, 13.1) years. Survival tended to be lower among UniV patients compared to BiV patients, particularly within the first year (p=0.09), but was similar for survivors beyond one year. At 5 years, incidence of rejection was 28% (17%, 38%) and coronary allograft vasculopathy was 16% (7%, 24%). CONCLUSIONS: Underlying liver disease and need for heart/liver transplantation were significantly higher among UniV patients. Survival tended to be lower among UniV, particularly within the first year, but was similar for survivors beyond one year.

Increased whole-brain functional heterogeneity in psychosis during rest and task.

Past work has shown that people with schizophrenia exhibit more cross-subject heterogeneity in their functional connectivity patterns. However, it remains unclear whether specific brain networks are implicated, whether common confounds could explain the results, or whether task activations might also be more heterogeneous. Unambiguously establishing the existence and extent of functional heterogeneity constitutes a first step toward understanding why it emerges and what it means clinically. METHODS: We first leveraged data from the HCP Early Psychosis project. Functional connectivity (FC) was extracted from 718 parcels via principal components regression. Networks were defined via a brain network partition (Ji et al., 2019). We also examined an independent data set with controls, later-stage schizophrenia patients, and ADHD patients during rest and during a working memory task. We quantified heterogeneity by averaging the Pearson correlation distance of each subject's FC or task activity pattern to that of every other subject of the same cohort. RESULTS: Affective and non-affective early psychosis patients exhibited more cross-subject whole-brain heterogeneity than healthy controls (ps < 0.001, Hedges' g > 0.74). Increased heterogeneity could be found in up to seven networks. In-scanner motion, medication, nicotine, and comorbidities could not explain the results. Later-stage schizophrenia patients exhibited heterogeneous connectivity patterns and task activations compared to ADHD and control subjects. Interestingly, individual connection weights, parcel-wise task activations, and network averages thereof were not more variable in patients, suggesting that heterogeneity becomes most obvious over large-scale patterns. CONCLUSION: Whole-brain cross-subject functional heterogeneity characterizes psychosis during rest and task. Developmental and pathophysiological consequences are discussed.

Sex Differences in Outcomes of Adults With Isolated Coarctation of the Aorta.

Background: Data are limited about the effect (or lack thereof) of sex on clinical outcomes in adults with coarctation of the aorta (COA). The purpose of this study was to compare atherosclerotic cardiovascular disease (ASCVD) risk profile, blood pressure (BP) data, echocardiographic indices, and mortality between men and women with COA. Methods: Retrospective study of adults with COA, and no associated left-sided obstructive lesions, who received care at Mayo Clinic (2003-2022). ASCVD risk profile was assessed as the prevalence of hypertension, hyperlipidemia, type 2 diabetes, obesity, smoking history, and coronary artery disease. A 24-hour BP monitor was used to assess daytime and nighttime BP and calculate nocturnal dipping. Results: Of 621 patients with isolated COA, 375 (60%) were men, and 246 (40%) were women. Women had similar ASCVD risk profile and daytime BP as men. However, women had less nocturnal dipping (7 ± 5 mm Hg vs 16 ± 7 mm Hg, P < 0.001), higher pulmonary artery mean pressure (23 mm Hg [interquartile range: 16-31] vs 20 mm Hg [interquartile range: 15-28], P = 0.04), and higher pulmonary vascular resistance index (3.41 ± 1.14 WU · m2 vs 3.02 ± 0.76 WU · m2, P = 0.006). Female sex was associated with all-cause mortality (adjusted hazard ratio 1.26, 95% confidence interval 1.04-1.94) and cardiovascular mortality (adjusted hazard ratio 1.38, 95% confidence interval 1.09-2.18). Conclusions: Women had a higher risk of both cardiovascular mortality and all-cause mortality compared to the risks in men. This difference may be related to the higher-than-expected ASCVD risk factors, abnormal nocturnal blood pressure, and pulmonary hypertension observed in women in this cohort. Further studies are required to identify optimal measures to address these risk factors.

Contexte: Il existe peu de données sur l'issue clinique en fonction du sexe chez les adultes présentant une coarctation de l'aorte (CoA). Le but de cette étude consistait donc à comparer le profil de risque de maladie cardiovasculaire athéroscléreuse (MCVAS), les données relatives à la pression artérielle (PA), les indices échocardiographiques et le taux de mortalité chez des hommes et des femmes présentant une CoA. Méthodologie: Il s'agissait d'une étude rétrospective réalisée chez des adultes présentant une CoA en l'absence de lésions obstructives gauches, soignés à la clinique Mayo entre 2003 et 2022. Le profil de risque de MCVAS a été évalué en fonction de la prévalence de l'hypertension, de l'hyperlipidémie, du diabète de type 2, de l'obésité, des antécédents tabagiques et de la coronaropathie. Une surveillance sur 24 heures a été utilisée pour évaluer la PA diurne et nocturne, en plus de calculer la chute nocturne de la PA. Résultats: Parmi les 621 patients présentant une CoA isolée, 375 (60 %) étaient des hommes et 246 (40 %) étaient des femmes. Les femmes présentaient une PA diurne et un profil de risque de MCVAS semblables aux hommes. Elles présentaient néanmoins une chute nocturne de la PA moins prononcée (7 ± 5 mmHg vs 16 ± 7 mmHg, p < 0,001), une pression artérielle pulmonaire moyenne plus haute (23 mmHg [max.-min. : 16-31] vs 20 mmHg [max.-min. : 15-28], p = 0,04) et un indice de résistance vasculaire pulmonaire plus élevé (3,41 ± 1,14 UW · m2 vs 3,02 ± 0,76 UW · m2, p = 0,006). Le sexe féminin a été associé à un plus fort taux de mortalité toutes causes confondues (rapport de risques ajusté : 1,26; intervalle de confiance à 95 % : 1,04-1,94) et de mortalité cardiovasculaire (rapport de risques ajusté : 1,38; intervalle de confiance à 95 % : 1,09-2,18). Conclusions: Les femmes sont exposées à un risque de mortalité cardiovasculaire et de mortalité toutes causes confondues plus élevé que les hommes. Cette différence pourrait être attribuable au rôle plus important que prévu joué par les facteurs de risque de MCVAS ainsi qu'à la pression artérielle nocturne anormale et à l'hypertension pulmonaire chez les femmes de cette cohorte. D'autres études sont nécessaires pour savoir quels seraient les paramètres optimaux qui permettraient d'évaluer ces facteurs de risque.

Cell type-specific network analysis in Diversity Outbred mice identifies genes potentially responsible for human bone mineral density GWAS associations.

Genome-wide association studies (GWASs) have identified many sources of genetic variation associated with bone mineral density (BMD), a clinical predictor of fracture risk and osteoporosis. Aside from the identification of causal genes, other difficult challenges to informing GWAS include characterizing the roles of predicted causal genes in disease and providing additional functional context, such as the cell type predictions or biological pathways in which causal genes operate. Leveraging single-cell transcriptomics (scRNA-seq) can assist in informing BMD GWAS by linking disease-associated variants to genes and providing a cell type context for which these causal genes drive disease. Here, we use large-scale scRNA-seq data from bone marrow-derived stromal cells cultured under osteogenic conditions (BMSC-OBs) from Diversity Outbred (DO) mice to generate cell type-specific networks and contextualize BMD GWAS-implicated genes. Using trajectories inferred from the scRNA-seq data, we identify networks enriched with genes that exhibit the most dynamic changes in expression across trajectories. We discover 21 network driver genes, which are likely to be causal for human BMD GWAS associations that colocalize with expression/splicing quantitative trait loci (eQTL/sQTL). These driver genes, including Fgfrl1 and Tpx2, along with their associated networks, are predicted to be novel regulators of BMD via their roles in the differentiation of mesenchymal lineage cells. In this work, we showcase the use of single-cell transcriptomics from mouse bone-relevant cells to inform human BMD GWAS and prioritize genetic targets with potential causal roles in the development of osteoporosis.

Use of the 445-nm Blue Laser for Management of Early Glottic Carcinoma: Preliminary 1-Year Results.

OBJECTIVE: To analyze oncological efficacy and voice outcomes of the 445-nm blue laser (BL) in the treatment of early glottic carcinoma and compare results with the 532-nm potassium-titanyl-phosphate (KTP) laser. STUDY DESIGN: Single institution, retrospective chart review. METHODS: All patients who underwent microlaryngoscopic KTP or BL laser excision of early glottic carcinoma from 2018 to the present day with at least 1-year follow-up were included. Primary and recurrent disease, including radiation and surgical failures, were included. Demographic data, voice outcomes and oncologic outcomes were compared between the two laser groups. RESULTS: Forty-nine patients met the inclusion criteria for the BL group and 88 for the KTP group, with average follow-up of 635 and 1236 days, respectively. Oncologic outcomes were not significantly different, with disease-specific survival rates of 95.9% for BL and 100% for KTP (p = 0.13), organ preservation rates of 98.0% for BL and 95.6% for KTP (p = 0.39), and local control rates of 93.9% for BL and 92.1% for KTP (p = 0.81). Both BL and KTP groups showed significant improvement in CAPE-V (p = 0.04, 0.006 respectively) and VHI-10 scores (p = 0.003, <0.00001) following surgery. CONCLUSIONS: Photoangiolytic removal of early glottic carcinoma with BL appears to be equally safe and effective as with KTP laser at minimum one-year follow-up, and with excellent voice outcomes. Additional study will be warranted over time to assess long-term outcomes in BL patients. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Mesostriatal Dopaminergic Circuit Dysfunction in Schizophrenia: A Multimodal Neuromelanin-sensitive MRI and [18F]-DOPA PET Study.

BACKGROUND: Striatal hyperdopaminergia is implicated in the pathoetiology of schizophrenia, but how this relates to dopaminergic midbrain activity is unclear. Neuromelanin-sensitive MRI (NM-MRI) provides a marker of long-term dopamine function. We examined if midbrain NM-MRI contrast-to-noise ratio (NM-CNR) was higher in people with schizophrenia relative to controls and if this correlated with dopamine synthesis capacity. METHODS: N=154 participants (n=74 individuals with schizophrenia and n=80 healthy controls) underwent NM-MRI of the substantia nigra and ventral tegmental area (SN-VTA). A subset of the schizophrenia group (n=38) also received [18F]-DOPA PET to measure dopamine synthesis capacity (Kicer) in the SN-VTA and striatum. RESULTS: SN-VTA NM-CNR was significantly higher in patients with schizophrenia relative to controls (effect size=0.38, p=0.019). This effect was greatest for voxels in the medial and ventral SN-VTA. In patients, SN-VTA Kicer positively correlated with SN-VTA NM-CNR (r=0.44, p=0.005) and striatal Kicer (r=0.71, p<0.001). Voxelwise analysis demonstrated that SN-VTA NM-CNR was positively associated with striatal Kicer (r=0.53, p=0.005) and that this relationship appeared strongest between the ventral SN-VTA and associative striatum in schizophrenia. CONCLUSIONS: Our results suggest that neuromelanin levels are higher in patients with schizophrenia relative to controls, particularly in midbrain regions that project to parts of the striatum which receive innervation from the limbic and association cortices. The direct relationship between measures of neuromelanin and dopamine synthesis suggests that these aspects of schizophrenia pathophysiology are linked. Our findings highlight specific mesostriatal circuits as the loci of dopamine dysfunction in schizophrenia and, thus, potential therapeutic targets.

Provider-to-provider telemedicine for sepsis is used less frequently in communities with high social vulnerability.

PURPOSE: Sepsis disproportionately affects patients in rural and socially vulnerable communities. A promising strategy to address this disparity is provider-to-provider emergency department (ED)-based telehealth consultation (tele-ED). The objective of this study was to determine if county-level social vulnerability index (SVI) was associated with tele-ED use for sepsis and, if so, which SVI elements were most strongly associated. METHODS: We used data from the TELEmedicine as a Virtual Intervention for Sepsis in Rural Emergency Department study. The primary exposures were SVI aggregate and component scores. We used multivariable generalized estimating equations to model the association between SVI and tele-ED use. FINDINGS: Our study cohort included 1191 patients treated in 23 Midwestern rural EDs between August 2016 and June 2019, of whom 326 (27.4%) were treated with tele-ED. Providers in counties with a high SVI were less likely to use tele-ED (adjusted odds ratio [aOR] = 0.51, 95% confidence interval [CI] 0.31‒0.87), an effect principally attributable to the housing type and transportation component of SVI (aOR = 0.44, 95% CI 0.22-0.89). Providers who treated fewer sepsis patients (1‒10 vs. 31+ over study period) and therefore may have been less experienced in sepsis care, were more likely to activate tele-ED (aOR = 3.91, 95% CI 2.08‒7.38). CONCLUSIONS: Tele-ED use for sepsis was lower in socially vulnerable counties and higher among providers who treated fewer sepsis patients. These findings suggest that while tele-ED increases access to specialized care, it may not completely ameliorate sepsis disparities due to its less frequent use in socially vulnerable communities.

Risk of Cardiac Reoperation: An Analysis of The STS Congenital Heart Surgery Database.

BACKGROUND: The increasing number of congenital heart disease patients undergoing reoperative cardiac surgery presents critical and growing challenges. Our objective was to evaluate the association between number of prior cardiopulmonary bypass operations and operative mortality and morbidity in a national cohort. METHODS: The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) was reviewed for index cardiac operations on cardiopulmonary bypass during 2016-2021. Infants and patients with functionally univentricular physiology were excluded. Multivariable logistic regression adjusted for covariates in the STS-CHSD Mortality Risk Model, STAT Mortality Category, and institutional volume. RESULTS: Of 50,625 eligible operations, 22,100 (44%) were performed on patients with ≥1 prior cardiopulmonary bypass operation. Most common diagnoses were Tetralogy of Fallot (4,340/22,100 [19.6%]), pulmonary atresia/ventricular septal defect (1,334/22,100 [6.0%]), and aortic stenosis (966/22,100 [4.4%]). Operative mortality correlated with number of prior cardiopulmonary bypass operations, 157/28,525 (0.6%) for zero, 127/13,488 (0.9%) for one, 81/5,664 (1.4%) for two, 61/2,039 (3.0%) for three, 35/623 (5.6%) for four, 10/207 (4.8%) for five, and 5/79 (6.3%) for ≥6 (p<0.001). On multivariable analysis, patients with ≥3 prior cardiopulmonary bypass operations had higher risk of operative mortality (OR 2.31, p<0.001) and major morbidity (OR 1.60, p<0.001). Annual institutional volume and age were not associated with either outcome. CONCLUSIONS: Three or more prior cardiopulmonary bypass operations was an independent risk factor for operative mortality/morbidity, even after controlling for risk factors and institutional volume. Future research is needed to identify modifiable factors to optimize outcomes, particularly for those with ≥3 prior cardiopulmonary bypass operations.

Development of an inhibitor of the mutagenic SOS response that suppresses the evolution of quinolone antibiotic resistance.

Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There is therefore an urgent need for new molecules that function through novel mechanisms of action to combat AMR. The bacterial DNA-repair and SOS-response pathways promote survival of pathogens in infection settings and also activate hypermutation and resistance mechanisms, making these pathways attractive targets for new therapeutics. Small molecules, such as IMP-1700, potentiate DNA damage and inhibit the SOS response in methicillin-resistant S. aureus; however, understanding of the structure-activity relationship (SAR) of this series is lacking. We report here the first comprehensive SAR study of the IMP-1700 scaffold, identifying key pharmacophoric groups and delivering the most potent analogue reported to date, OXF-077. Furthermore, we demonstrate that as a potent inhibitor of the mutagenic SOS response, OXF-077 suppresses the rate of ciprofloxacin resistance emergence in S. aureus. This work supports SOS-response inhibitors as a novel means to combat AMR, and delivers OXF-077 as a tool molecule for future development.

Skimming genomes for systematics and DNA barcodes of corals.

Numerous genomic methods developed over the past two decades have enabled the discovery and extraction of orthologous loci to help resolve phylogenetic relationships across various taxa and scales. Genome skimming (or low-coverage genome sequencing) is a promising method to not only extract high-copy loci but also 100s to 1000s of phylogenetically informative nuclear loci (e.g., ultraconserved elements [UCEs] and exons) from contemporary and museum samples. The subphylum Anthozoa, including important ecosystem engineers (e.g., stony corals, black corals, anemones, and octocorals) in the marine environment, is in critical need of phylogenetic resolution and thus might benefit from a genome-skimming approach. We conducted genome skimming on 242 anthozoan corals collected from 1886 to 2022. Using existing target-capture baitsets, we bioinformatically obtained UCEs and exons from the genome-skimming data and incorporated them with data from previously published target-capture studies. The mean number of UCE and exon loci extracted from the genome skimming data was 1837 ± 662 SD for octocorals and 1379 ± 476 SD loci for hexacorals. Phylogenetic relationships were well resolved within each class. A mean of 1422 ± 720 loci was obtained from the historical specimens, with 1253 loci recovered from the oldest specimen collected in 1886. We also obtained partial to whole mitogenomes and nuclear rRNA genes from >95% of samples. Bioinformatically pulling UCEs, exons, mitochondrial genomes, and nuclear rRNA genes from genome skimming data is a viable and low-cost option for phylogenetic studies. This approach can be used to review and support taxonomic revisions and reconstruct evolutionary histories, including historical museum and type specimens.

Salmonella Saintpaul outbreak associated with cantaloupe consumption, the United Kingdom and Portugal, September to November 2023.

In September 2023, the UK Health Security Agency identified cases of Salmonella Saintpaul distributed across England, Scotland, and Wales, all with very low genetic diversity. Additional cases were identified in Portugal following an alert raised by the United Kingdom. Ninety-eight cases with a similar genetic sequence were identified, 93 in the United Kingdom and 5 in Portugal, of which 46% were aged under 10 years. Cases formed a phylogenetic cluster with a maximum distance of six single nucleotide polymorphisms (SNPs) and average of less than one SNP between isolates. An outbreak investigation was undertaken, including a case-control study. Among the 25 UK cases included in this study, 13 reported blood in stool and 5 were hospitalized. One hundred controls were recruited via a market research panel using frequency matching for age. Multivariable logistic regression analysis of food exposures in cases and controls identified a strong association with cantaloupe consumption (adjusted odds ratio: 14.22; 95% confidence interval: 2.83-71.43; p-value: 0.001). This outbreak, together with other recent national and international incidents, points to an increase in identifications of large outbreaks of Salmonella linked to melon consumption. We recommend detailed questioning and triangulation of information sources to delineate consumption of specific fruit varieties during Salmonella outbreaks.

Improving MR axon radius estimation in human white matter using spiral acquisition and field monitoring.

PURPOSE: To compare MR axon radius estimation in human white matter using a multiband spiral sequence combined with field monitoring to the current state-of-the-art echo-planar imaging (EPI)-based approach. METHODS: A custom multiband spiral sequence was used for diffusion-weighted imaging at ultra-high b $$ b $$ -values. Field monitoring and higher order image reconstruction were employed to greatly reduce artifacts in spiral images. Diffusion weighting parameters were chosen to match a state-of-the art EPI-based axon radius mapping protocol. The spiral approach was compared to the EPI approach by comparing the image signal-to-noise ratio (SNR) and performing a test-retest study to assess the respective variability and repeatability of axon radius mapping. Effective axon radius estimates were compared over white matter voxels and along the left corticospinal tract. RESULTS: Increased SNR and reduced artifacts in spiral images led to reduced variability in resulting axon radius maps, especially in low-SNR regions. Test-retest variability was reduced by a factor of approximately 1.5 using the spiral approach. Reduced repeatability due to significant bias was found for some subjects in both spiral and EPI approaches, and attributed to scanner instability, pointing to a previously unknown limitation of the state-of-the-art approach. CONCLUSION: Combining spiral readouts with field monitoring improved mapping of the effective axon radius compared to the conventional EPI approach.

Discovering melting temperature prediction models of inorganic solids by combining supervised and unsupervised learning.

The melting temperature is important for materials design because of its relationship with thermal stability, synthesis, and processing conditions. Current empirical and computational melting point estimation techniques are limited in scope, computational feasibility, or interpretability. We report the development of a machine learning methodology for predicting melting temperatures of binary ionic solid materials. We evaluated different machine-learning models trained on a dataset of the melting points of 476 non-metallic crystalline binary compounds using materials embeddings constructed from elemental properties and density-functional theory calculations as model inputs. A direct supervised-learning approach yields a mean absolute error of around 180 K but suffers from low interpretability. We find that the fidelity of predictions can further be improved by introducing an additional unsupervised-learning step that first classifies the materials before the melting-point regression. Not only does this two-step model exhibit improved accuracy, but the approach also provides a level of interpretability with insights into feature importance and different types of melting that depend on the specific atomic bonding inside a material. Motivated by this finding, we used a symbolic learning approach to find interpretable physical models for the melting temperature, which recovered the best-performing features from both prior models and provided additional interpretability.

Diffuse intrinsic pontine glioma (DIPG): A review of current and emerging treatment strategies.

Diffuse intrinsic pontine glioma (DIPG) is a childhood malignancy of the brainstem with a dismal prognosis. Despite recent advances in its understanding at the molecular level, the prognosis of DIPG has remained unchanged. This article aims to review the current understanding of the genetic pathophysiology of DIPG and to highlight promising therapeutic targets. Various DIPG treatment strategies have been investigated in pre-clinical studies, several of which have shown promise and have been subsequently translated into ongoing clinical trials. Ultimately, a multifaceted therapeutic approach that targets cell-intrinsic alterations, the micro-environment, and augments the immune system will likely be necessary to eradicate DIPG.

Characteristics and Outcomes of a Single-Centre Cohort of Adult Congenital Heart Disease Patients Referred for Heart Transplant.

BACKGROUND: Adult congenital heart disease (ACHD) services increasingly encounter heart failure (HF) in the ageing ACHD population. Optimal timing of referral for heart transplant (HTx) evaluation in this heterogeneous population is complex and ill-defined. We aim to outline the characteristics and outcomes of ACHD patients referred for HTx from a large Australian ACHD centre. METHOD: Retrospective review of ACHD patients referred for HTx from a primary ACHD centre (1992-2021). Database analysis of patient demographics, characteristics, wait-listing, and transplantation outcomes was performed. RESULTS: A total of 45 patients (mean age 37±9.9 years old; 69% male) were referred for HTx with a mean follow-up of 5.9±6.3 years. Of these, 22 of 45 (49%) were listed and transplanted, including one heart-lung transplant. The commonest diagnosis was dextro-transposition of the great arteries (13/45, 29%). Most patients, 33 of 45 (73.3%) had undergone at least one cardiac surgery in childhood. Indications for HTx referral included HF in 34 of 45 (75%), followed by pulmonary hypertension in 7 of 45 (11%). Median transplant wait-list time was 145 days (interquartile range, 112-256). Of the 23 patients not wait-listed, the reasons included clinical stability in 13 of 45 (29%), psychosocial factors in 2 of 45 (4.4%) and prohibitive surgical risk, including multiorgan dysfunction, in 8 of 45 (17.7%). Transplant was of a single organ in most, 21 of 22 (95.5%). Overall mortality was 5 of 22 (22.7%) in those after HTx, and 14 of 23 (60.9%) in those not listed (p=0.0156). CONCLUSIONS: Increasingly, ACHD patients demonstrate the need for advanced HF treatments. HTx decision-making is complex, and increased mortality is seen in those not wait-listed. Ultimately, the referral of ACHD patients for HTx is underpinned by local decision-making and experience, wait-list times and outcomes.