Significant healthcare resource utilisation in the management of skin and soft tissue infections in the Torres Strait, Australia.

INTRODUCTION: Aboriginal and Torres Strait Islander Peoples (First Nations Australians) living in remote communities are hospitalised with skin and soft tissue infections (SSTIs) at three times the rate of non-First Nations Australians. The Torres Strait in tropical northern Australia has a highly dispersed population mainly comprising First Nations Australians. This study aimed to define the health service utilisation and health system costs associated with SSTIs in the Torres Strait and to improve the quality of regional healthcare delivery. METHODS: The research team conducted a retrospective, de-identified audit of health records for a 2-year period, 2018-2019. The aim was to define health service utilisation, episodes of outpatient care, emergency department care, inpatient care and aeromedical retrieval services for SSTIs. RESULTS: Across 2018 - 2019, there were 3509 outpatient episodes of care for SSTIs as well as 507 emergency department visits and 100 hospitalisations. For individuals with an SSTI, the mean outpatient clinic episode cost $240; the mean emergency department episode cost $400.85, the mean inpatient episode cost $8403.05 while an aeromedical retrieval service cost $18,670. The total costs to the health system for all services accessed for SSTI management was $6,169,881 per year, 3% of the total annual health service budget. CONCLUSION: Healthcare costs associated with SSTIs in the Torres Strait are substantial. The implementation of effective preventative and primary care interventions may enable resources to be reallocated to address other health priorities in the Torres Strait.

Overlapping Streptococcus pyogenes and Streptococcus dysgalactiae subspecies equisimilis household transmission and mobile genetic element exchange.

Streptococcus dysgalactiae subspecies equisimilis (SDSE) and Streptococcus pyogenes share skin and throat niches with extensive genomic homology and horizontal gene transfer (HGT) possibly underlying shared disease phenotypes. It is unknown if cross-species transmission interaction occurs. Here, we conduct a genomic analysis of a longitudinal household survey in remote Australian First Nations communities for patterns of cross-species transmission interaction and HGT. Collected from 4547 person-consultations, we analyse 294 SDSE and 315 S. pyogenes genomes. We find SDSE and S. pyogenes transmission intersects extensively among households and show that patterns of co-occurrence and transmission links are consistent with independent transmission without inter-species interference. We identify at least one of three near-identical cross-species mobile genetic elements (MGEs) carrying antimicrobial resistance or streptodornase virulence genes in 55 (19%) SDSE and 23 (7%) S. pyogenes isolates. These findings demonstrate co-circulation of both pathogens and HGT in communities with a high burden of streptococcal disease, supporting a need to integrate SDSE and S. pyogenes surveillance and control efforts.

Integrated electrophysiological and genomic profiles of single cells reveal spiking tumor cells in human glioma.

Prior studies have described the complex interplay that exists between glioma cells and neurons, however, the electrophysiological properties endogenous to tumor cells remain obscure. To address this, we employed Patch-sequencing on human glioma specimens and found that one third of patched cells in IDH mutant (IDH mut ) tumors demonstrate properties of both neurons and glia by firing single, short action potentials. To define these hybrid cells (HCs) and discern if they are tumor in origin, we developed a computational tool, Single Cell Rule Association Mining (SCRAM), to annotate each cell individually. SCRAM revealed that HCs represent tumor and non-tumor cells that feature GABAergic neuron and oligodendrocyte precursor cell signatures. These studies are the first to characterize the combined electrophysiological and molecular properties of human glioma cells and describe a new cell type in human glioma with unique electrophysiological and transcriptomic properties that are likely also present in the non-tumor mammalian brain.

Use of computed tomography coronary calcium score for prediction of cardiovascular events in cancer patients: a retrospective cohort analysis.

BACKGROUND: CT- coronary calcium score, is one of the most studied and widely available modalities in cardiovascular medicine. Coronary artery calcium score (CACS) is an established predictor of coronary artery disease. The 'standard of care' diagnostic modality to measure CACS is ECG-gated Cardiac Multi-Detector Computed Tomography. There is convincing evidence of a strong association between CACS and major cardiovascular (CV) events in asymptomatic individuals. Cancer patients (C) may have a higher risk for CV disease than non-cancer patients (NC) related not only to cancer treatments but also to shared biological factors and pathways. Thus, identifying tools for early detection of CV disease in this population is of utmost importance. METHODS: A retrospective cohort analysis was performed with patients from Cleveland Clinic Florida and Ohio who had CACS from 2017 to 2021. Patients who had cancer diagnosis prior to CACS were matched to NC for age and sex. CV events after their index CACS events were compared between C and NC, and matched control and propensity analysis were conducted. RESULTS: Ten thousand seven hundred forty-two patients had CACS; 703 cancer patients had CACS and were eligible. Extensive CACS (> 400) were significantly higher in cancer, 94 (13.37%) vs non-cancer patients, 76 (10.83%), P = 0.011. Furthermore, after propensity matched analysis, CACS > 400 was 14.8% in C vs 9.6% in NC, P = < 0.05. CV events were similar in both cohorts (p = NS), despite less CV risk factors in cancer patients (P = < 0.05). For the combined moderate (101-400) & extensive (> 400) CACS, the prevalence of stroke and peripheral arterial disease, a marker of systemic atherosclerosis, was significantly higher in patients with cancer (P < 0.01). CONCLUSIONS: Despite having fewer CV risk factors in our study, similar CACS in cancer patients are suggestive of a higher prevalence of CV disease independent of traditional risk factors. High CACS and the overall prevalence of vascular events were more frequent in patients with cancer. Higher prevalence of peripheral arterial disease and cerebrovascular accident further suggests the increased atherosclerotic burden in C.

Tumor-specific polycistronic miRNA delivered by engineered exosomes for the treatment of glioblastoma.

BACKGROUND: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs. METHODS: We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to hone in on miRs that were most likely to be clinically effective. To enhance delivery and expression of the miRs, we generated a polycistronic plasmid encoding 3 miRs (pPolymiR) and used HEK293T cells as biofactories to package pPolymiR into engineered exosomes (eExos) that incorporate viral proteins (Gag/VSVg) in their structure (eExos+pPolymiR) to enhance function. RESULTS: Our stepwise screen identified miR-124-2, miR-135a-2, and let-7i as the most effective miRs across all GBM subtypes with clinical relevance. Delivery of eExos+pPolymiR resulted in high expression of all 3 miRs in GSCs, and significantly decreased GSC proliferation in vitro. eExos+pPolymiR prolonged survival of GSC-bearing mice in vivo when compared with eExos carrying each of the miRs individually or as a cocktail. CONCLUSION: eExos+pPolymiR, which includes a pan-subtype anti-glioma-specific miR combination encoded in a polycistronic plasmid and a novel exosome delivery platform, represents a new and potentially powerful anti-GBM therapeutic.

Erratum: Potentially preventable dementia in a First Nations population in the Torres Strait and Northern Peninsula Area of North Queensland, Australia: a cross sectional analysis using population attributable fractions.

[This corrects the article DOI: 10.1016/j.lanwpc.2023.100855.][This corrects the article DOI: 10.1016/j.lanwpc.2022.100532.].

Prevalence of pathogenic germline variants in adult-type diffuse glioma.

Background: No consensus germline testing guidelines currently exist for glioma patients, so the prevalence of germline pathogenic variants remains unknown. This study aims to determine the prevalence and type of pathogenic germline variants in adult glioma. Methods: A retrospective review at a single institution with paired tumor/normal sequencing from August 2018-April 2022 was performed and corresponding clinical data were collected. Results: We identified 152 glioma patients of which 15 (9.8%) had pathogenic germline variants. Pathogenic germline variants were seen in 11/84 (13.1%) of Glioblastoma, IDH wild type; 3/42 (7.1%) of Astrocytoma, IDH mutant; and 1/26 (3.8%) of Oligodendroglioma, IDH mutant, and 1p/19q co-deleted patients. Pathogenic variants in BRCA2, MUTYH, and CHEK2 were most common (3/15, 20% each). BRCA1 variants occurred in 2/15 (13%) patients, with variants in NF1, ATM, MSH2, and MSH3 occurring in one patient (7%) each. Prior cancer diagnosis was found in 5/15 patients (33%). Second-hit somatic variants were seen in 3/15 patients (20%) in NF1, MUTYH, and MSH2. Referral to genetics was performed in 6/15 (40%) patients with pathogenic germline variants. 14/15 (93%) of patients discovered their pathogenic variant as a result of their paired glioma sequencing. Conclusions: These findings suggest a possible overlooked opportunity for determination of hereditary cancer syndromes with impact on surveillance as well as potential broader treatment options. Further studies that can determine the role of variants in gliomagenesis and confirm the occurrence and types of pathogenic germline variants in patients with IDH wild type compared to IDH mutant tumors are necessary.

Effect of experimental hookworm infection on insulin resistance in people at risk of type 2 diabetes.

The reduced prevalence of insulin resistance and type 2 diabetes in countries with endemic parasitic worm infections suggests a protective role for worms against metabolic disorders, however clinical evidence has been non-existent. This 2-year randomised, double-blinded clinical trial in Australia of hookworm infection in 40 male and female adults at risk of type 2 diabetes assessed the safety and potential metabolic benefits of treatment with either 20 (n = 14) or 40 (n = 13) Necator americanus larvae (L3) or Placebo (n = 13) (Registration ACTRN12617000818336). Primary outcome was safety defined by adverse events and completion rate. Homoeostatic model assessment of insulin resistance, fasting blood glucose and body mass were key secondary outcomes. Adverse events were more frequent in hookworm-treated participants, where 44% experienced expected gastrointestinal symptoms, but completion rates were comparable to Placebo. Fasting glucose and insulin resistance were lowered in both hookworm-treated groups at 1 year, and body mass was reduced after L3-20 treatment at 2 years. This study suggests hookworm infection is safe in people at risk of type 2 diabetes and associated with improved insulin resistance, warranting further exploration of the benefits of hookworms on metabolic health.

Integrated clinical genomic analysis reveals xenobiotic metabolic genes are downregulated in meningiomas of current smokers.

INTRODUCTION: Meningiomas are the most common primary intracranial tumor. Recently, various genetic classification systems for meningioma have been described. We sought to identify clinical drivers of different molecular changes in meningioma. As such, clinical and genomic consequences of smoking in patients with meningiomas remain unexplored. METHODS: 88 tumor samples were analyzed in this study. Whole exome sequencing (WES) was used to assess somatic mutation burden. RNA sequencing data was used to identify differentially expressed genes (DEG) and genes sets (GSEA). RESULTS: Fifty-seven patients had no history of smoking, twenty-two were past smokers, and nine were current smokers. The clinical data showed no major differences in natural history across smoking status. WES revealed absence of AKT1 mutation rate in current or past smokers compared to non-smokers (p = 0.046). Current smokers had increased mutation rate in NOTCH2 compared to past and never smokers (p < 0.05). Mutational signature from current and past smokers showed disrupted DNA mismatch repair (cosine-similarity = 0.759 and 0.783). DEG analysis revealed the xenobiotic metabolic genes UGT2A1 and UGT2A2 were both significantly downregulated in current smokers compared to past (Log2FC = - 3.97, padj = 0.0347 and Log2FC = - 4.18, padj = 0.0304) and never smokers (Log2FC = - 3.86, padj = 0.0235 and Log2FC = - 4.20, padj = 0.0149). GSEA analysis of current smokers showed downregulation of xenobiotic metabolism and enrichment for G2M checkpoint, E2F targets, and mitotic spindle compared to past and never smokers (FDR < 25% each). CONCLUSION: In this study, we conducted a comparative analysis of meningioma patients based on their smoking history, examining both their clinical trajectories and molecular changes. Meningiomas from current smokers were more likely to harbor NOTCH2 mutations, and AKT1 mutations were absent in current or past smokers. Moreover, both current and past smokers exhibited a mutational signature associated with DNA mismatch repair. Meningiomas from current smokers demonstrate downregulation of xenobiotic metabolic enzymes UGT2A1 and UGT2A2, which are downregulated in other smoking related cancers. Furthermore, current smokers exhibited downregulation xenobiotic metabolic gene sets, as well as enrichment in gene sets related to mitotic spindle, E2F targets, and G2M checkpoint, which are hallmark pathways involved in cell division and DNA replication control. In aggregate, our results demonstrate novel alterations in meningioma molecular biology in response to systemic carcinogens.

Remote neuronal activity drives glioma progression through SEMA4F.

The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity-dependent infiltrating population present at the leading edge of mouse and human tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity.

A good life for people living with disability: the story from Far North Queensland.

PURPOSE: People with disability in regional, rural and remote Australia have poorer service access compared to people from metropolitan areas. There is urgent need for reform. This study's aim was to explore the needs and aspirations of people with lived experience of disability in Far North Queensland (FNQ) to inform a new service framework. MATERIALS AND METHODS: Twenty-five individuals with diverse experience of disability were engaged in semi-structured interviews. Participants were recruited from four sites that differed geographically, culturally, and socioeconomically. Using an inductive then deductive thematic approach to data analysis, statements of needs and aspirations were compiled and aligned with three pre-determined vision statements. RESULTS: Needs and aspirations aligned well with the vision statements which were to: feel "included, connected, safe and supported"; have "opportunities to choose one's own life and follow one's hopes and dreams"; and have "access to culturally safe services close to home." To realise this vision in FNQ, support to navigate and coordinate services across sectors is essential. CONCLUSION: People of FNQ of all abilities, need and aspire to experience "a good life" like their fellow Australians. Any new service model must focus on providing service navigation and co-ordination amid the complexities of service delivery in FNQ.Implications for RehabilitationThe perspective of people with lived experience of disability needs to be heard and respected when designing services to support them.Service navigation and co-ordination are required to manage the complexity of service delivery for people living in regional, rural and remote Australia.Engaging with the whole the community is prudent when designing community disability, rehabilitation, and lifestyle services in regional, rural, and remote Australia.

Democratising data to address health system inequities in Australia.

Understanding the health status of a population or community is crucial to equitable service planning. Among other uses, data on health status can help local and national planners and policy makers understand patterns and trends in current or emerging health and well-being, especially how disparities relating to geography, ethnicity, language and living with disability influence access to services. In this practice paper we draw attention to the nature of Australia's health data challenges and call for greater 'democratisation' of health data to address health system inequities. Democratisation implies the need for greater quality and representativeness of health data as well as improved access and usability that enable health planners and researchers to respond to health and health service disparities efficiently and cost-effectively. We draw on learnings from two practice examples, marred by inaccessibility, reduced interoperability and limited representativeness. We call for renewed and urgent attention to, and investment in, improved data quality and usability for all levels of health, disability and related service delivery in Australia.

Evaluating the role of asymptomatic throat carriage of Streptococcus pyogenes in impetigo transmission in remote Aboriginal communities in Northern Territory, Australia: a retrospective genomic analysis.

BACKGROUND: Streptococcus pyogenes, or group A Streptococcus (GAS), infections contribute to a high burden of disease in Aboriginal Australians, causing skin infections and immune sequelae such as rheumatic heart disease. Controlling skin infections in these populations has proven difficult, with transmission dynamics being poorly understood. We aimed to identify the relative contributions of impetigo and asymptomatic throat carriage to GAS transmission. METHODS: In this genomic analysis, we retrospectively applied whole genome sequencing to GAS isolates that were collected as part of an impetigo surveillance longitudinal household survey conducted in three remote Aboriginal communities in the Northern Territory of Australia between Aug 6, 2003, and June 22, 2005. We included GAS isolates from all throats and impetigo lesions of people living in two of the previously studied communities. We classified isolates into genomic lineages based on pairwise shared core genomes of more than 99% with five or fewer single nucleotide polymorphisms. We used a household network analysis of epidemiologically and genomically linked lineages to quantify the transmission of GAS within and between households. FINDINGS: We included 320 GAS isolates in our analysis: 203 (63%) from asymptomatic throat swabs and 117 (37%) from impetigo lesions. Among 64 genomic lineages (encompassing 39 emm types) we identified 264 transmission links (involving 93% of isolates), for which the probable source was asymptomatic throat carriage in 166 (63%) and impetigo lesions in 98 (37%). Links originating from impetigo cases were more frequent between households than within households. Households were infected with GAS for a mean of 57 days (SD 39 days), and once cleared, reinfected 62 days (SD 40 days) later. Increased household size and community presence of GAS and scabies were associated with slower clearance of GAS. INTERPRETATION: In communities with high prevalence of endemic GAS-associated skin infection, asymptomatic throat carriage is a GAS reservoir. Public health interventions such as vaccination or community infection control programmes aimed at interrupting transmission of GAS might need to include consideration of asymptomatic throat carriage. FUNDING: Australian National Health and Medical Research Council.

Remote neuronal activity drives glioma infiltration via Sema4f.

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent infiltration. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of tumor infiltration that are regulated by neuronal activity.

Surgery for rheumatic heart disease in the Northern Territory, Australia, 1997-2016: what have we gained?

BACKGROUND: Between 1964 and 1996, the 10-year survival of patients having valve replacement surgery for rheumatic heart disease (RHD) in the Northern Territory, Australia, was 68%. As medical care has evolved since then, this study aimed to determine whether there has been a corresponding improvement in survival. METHODS: A retrospective study of Aboriginal patients with RHD in the Northern Territory, Australia, having their first valve surgery between 1997 and 2016. Survival was examined using Kaplan-Meier and Cox regression analysis. FINDINGS: The cohort included 281 adults and 61 children. The median (IQR) age at first surgery was 31 (18-42) years; 173/342 (51%) had a valve replacement, 113/342 (33%) had a valve repair and 56/342 (16%) had a commissurotomy. There were 93/342 (27%) deaths during a median (IQR) follow-up of 8 (4-12) years. The overall 10-year survival was 70% (95% CI: 64% to 76%). It was 62% (95% CI: 53% to 70%) in those having valve replacement. There were 204/281 (73%) adults with at least 1 preoperative comorbidity. Preoperative comorbidity was associated with earlier death, the risk of death increasing with each comorbidity (HR: 1.3 (95% CI: 1.2 to 1.5), p<0.001). Preoperative chronic kidney disease (HR 6.5 (95% CI: 3.0 to 14.0) p≤0.001)), coronary artery disease (HR 3.3 (95% CI: 1.3 to 8.4) p=0.012) and pulmonary artery systolic pressure>50 mm Hg before surgery (HR 1.9 (95% CI: 1.2 to 3.1) p=0.007) were independently associated with death. INTERPRETATION: Survival after valve replacement for RHD in this region of Australia has not improved. Although the patients were young, many had multiple comorbidities, which influenced long-term outcomes. The increasing prevalence of complex comorbidity in the region is a barrier to achieving optimal health outcomes.

Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation.

Seizures are a frequent pathophysiological feature of malignant glioma. Recent studies implicate peritumoral synaptic dysregulation as a driver of brain hyperactivity and tumor progression; however, the molecular mechanisms that govern these phenomena remain elusive. Using scRNA-seq and intraoperative patient ECoG recordings, we show that tumors from seizure patients are enriched for gene signatures regulating synapse formation. Employing a human-to-mouse in vivo functionalization pipeline to screen these genes, we identify IGSF3 as a mediator of glioma progression and dysregulated neural circuitry that manifests as spreading depolarization (SD). Mechanistically, we discover that IGSF3 interacts with Kir4.1 to suppress potassium buffering and found that seizure patients exhibit reduced expression of potassium handlers in proliferating tumor cells. In vivo imaging reveals that dysregulated synaptic activity emanates from the tumor-neuron interface, which we confirm in patients. Our studies reveal that tumor progression and seizures are enabled by ion dyshomeostasis and identify SD as a driver of disease.

A computer vision approach to identifying the manufacturer of posterior thoracolumbar instrumentation systems.

OBJECTIVE: Knowledge of the manufacturer of the previously implanted pedicle screw systems prior to revision spinal surgery may facilitate faster and safer surgery. Often, this information is unavailable because patients are referred by other centers or because of missing information in the patients' records. Recently, machine learning and computer vision have gained wider use in clinical applications. The authors propose a computer vision approach to classify posterior thoracolumbar instrumentation systems. METHODS: Lateral and anteroposterior (AP) radiographs obtained in patients undergoing posterior thoracolumbar pedicle screw implantation for any indication at the authors' institution (2015-2021) were obtained. DICOM images were cropped to include both the pedicle screws and rods. Images were labeled with the manufacturer according to the operative record. Multiple feature detection methods were tested (SURF, MESR, and Minimum Eigenvalues); however, the bag-of-visual-words technique with KAZE feature detection was ultimately used to construct a computer vision support vector machine (SVM) classifier for lateral, AP, and fused lateral and AP images. Accuracy was tested using an 80%/20% training/testing pseudorandom split over 100 iterations. Using a reader study, the authors compared the model performance with the current practice of surgeons and manufacturer representatives identifying spinal hardware by visual inspection. RESULTS: Among the three image types, 355 lateral, 379 AP, and 338 fused radiographs were obtained. The five pedicle screw implants included in this study were the Globus Medical Creo, Medtronic Solera, NuVasive Reline, Stryker Xia, and DePuy Expedium. When the two most common manufacturers used at the authors' institution were binarily classified (Globus Medical and Medtronic), the accuracy rates for lateral, AP, and fused images were 93.15% ± 4.06%, 88.98% ± 4.08%, and 91.08% ± 5.30%, respectively. Classification accuracy decreased by approximately 10% with each additional manufacturer added. The multilevel five-way classification accuracy rates for lateral, AP, and fused images were 64.27% ± 5.13%, 60.95% ± 5.52%, and 65.90% ± 5.14%, respectively. In the reader study, the model performed five-way classification on 100 test images with 79% accuracy in 14 seconds, compared with an average of 44% accuracy in 20 minutes for two surgeons and three manufacturer representatives. CONCLUSIONS: The authors developed a KAZE feature detector with an SVM classifier that successfully identified posterior thoracolumbar hardware at five-level classification. The model performed more accurately and efficiently than the method currently used in clinical practice. The relative computational simplicity of this model, from input to output, may facilitate future prospective studies in the clinical setting.

Is Liver Transplant Justified at Any MELD Score?

BACKGROUND: Assessing the survival benefit of transplantation in patients with end-stage liver disease is critical in guiding the decision-making process for liver allocation. Previous studies established increased mortality risk for those transplanted below Model for End-Stage Liver Disease (MELD) 18 compared with candidates who remained on the waitlist; however, improved outcomes of liver transplantation and a changing landscape in the donor supply warrant re-evaluation of this idea. METHODS: Using the United Network for Organ Sharing database, we analyzed 160 290 candidates who were waitlisted for liver transplantation within MELD cohorts. We compared patients who were transplanted in a MELD cohort with those listed but not transplanted in that listed MELD cohort with an intent-to-treat analysis. RESULTS: Those transplanted at a MELD between 6 and 11 showed a 31% reduction in adjusted mortality (HR = 0.69 [95% confidence interval [CI], 0.66-0.75]; P < 0.001) compared with the intent-to-treat cohort in a Cox multivariate regression. This mortality benefit increased to a 37% adjusted reduction for those transplanted at MELD between 12 and 14 (HR = 0.63 [95% CI, 0.60-0.66]; P < 0.001) and a 46% adjusted reduction for those transplanted at a MELD between 15 and 17 (HR = 0.54 [95% CI, 0.52-0.57]; P < 0.001), effects that remained in sensitivity analyses excluding patients with hepatocellular carcinoma, encephalopathy, ascites, and variceal bleeds. A multivariate analysis of patients transplanted at MELD < 18 found younger age and cold ischemia time were protective, whereas older age, lower functional status, and socioeconomic factors increased mortality risk. CONCLUSIONS: These findings challenge the current practice of deferring liver transplants below a particular MELD score by demonstrating survival benefits for most transplant patients at the lowest MELD scores and providing insight into who benefits within these subgroups.

Community antibiotic management of skin infections in the Torres Strait.

BACKGROUND: There is a high burden of skin and soft tissue infections (SSTI) - including cellulitis - among Aboriginal and Torres Strait Islander peoples living in remote communities. In tropical environments, such as the Torres Strait, cellulitis accounts for 37% of potentially preventable hospitalisations. This study aimed to evaluate the safety, effectiveness and community acceptance of outpatient antibiotic treatment for the management of skin infections in the Torres Strait. CONCLUSIONS: Outpatient management of skin infection in the Torres Strait is effective, safe and appreciated by patients. METHODS: This was a 12-month prospective, observational study commencing in January 2019 involving 295 adults with a skin infection across the Torres Strait. RESULTS: Most (276/295 (94%)) participants were treated successfully in the community. Of 295 enrolled patients, 151 of 295 (51%) had cellulitis, 59 of 295 (20%) had a skin abscess and 85 of 295 (28%) had a wound infection. Of the 77 of 278 (27%) infections accompanied by systemic features, 63 of 77 (82%) were managed in the community. Staphylococcus aureus was the most frequent isolate, at 165 of 261 (63%); 56 of 165 (33%) were methicillin resistant. In the 276 community-managed cases, oral trimethoprim/sulfamethoxazole was initially used in 159 (57%), oral flucloxacillin in 75 (27%) and intravenous cefazolin plus oral probenecid in 32 (13%). The clinical course was complicated in eight of 232 (3%) patients who had complete follow-up data: seven patients required hospitalisation after initial treatment in the communityand one had an antibiotic side-effect. All 232 patients with complete follow-up data were content with the care they received.

Varied histomorphology and clinical outcomes of FGFR3-TACC3 fusion gliomas.

Targeted therapies for driver gene fusions in cancers have yielded substantial improvements in care. Here, the authors outline a case series of 6 patients with FGFR3-TACC3 fusion in primary brain tumors ranging from polymorphous low-grade neuroepithelial tumor of the young to papillary glioneuronal tumors and glioblastoma (GBM). Previous studies indicated the FGFR3-TACC3 fusion provides survival benefit to GBM patients. Consistent with this, 2 patients with GBM had unexpectedly good outcomes and survived for 5 and 7 years, respectively. In contrast, 2 patients with initially lower graded tumors survived only 3 years and 1 year, respectively. One patient received erdafitinib, a targeted FGFR inhibitor, for 3 months at late disease recurrence and no response was seen. There were varied histomorphological features, including many cases that lacked the characteristic FGFR3-TACC3 pathology. The findings of this cohort suggest that molecular testing is justified, even for glioma cases lacking classic histopathological signatures. Currently, FGFR3-TACC3 fusion gliomas are often classified on the basis of histopathological features. However, further research is needed to examine whether IDH1/2-wild-type tumors with FGFR3-TACC3 fusion should be classified as a subtype on the basis of this molecular fusion. Because patients with IDH1/2-wild-type GBM with FGFR3-TACC3 fusion have improved survival, routine molecular testing for this mutation in patients enrolled in clinical trials and subsequent stratification may be warranted.