Ageism and Dementia-ism in Health Care: A Proposed Framework to Guide Treatment Decisions in Frail Older Persons.

Global population ageing underscores the imperative of ageism and dementia-ism in the heath care setting as there is both anecdotal and published evidence that older persons are liable to receive less than optimum evidence-based treatments on account of their age and apparent frailty. This article explores the reasons for this phenomenon and limitations of current approaches of clinical decision making. We propose a framework to guide decision making to optimize care, with a paradigm shift in redefining a default toward clinical practice guideline-recommended treatments, guided by evidence-based medicine within an ethical means-end proportionality framework, and regularly reviewed advance care plans and goals of care conversations to secure the best interests of older persons.

Adulteration and substitution of drugs purchased in Australia from cryptomarkets: An analysis of Test4Pay.

INTRODUCTION: Prohibited drugs in unregulated markets may be adulterated, resulting in increased risks for people who use drugs. This study investigated levels of drug adulteration and substitution of drugs purchased in Australia from cryptomarkets. METHODS: Data were collected from a darknet forum called Test4Pay from 1 September 2022 to 23 August 2023. Posts were included if they reported the results of drug samples submitted by post to the Vancouver-based Get Your Drugs Tested service, which uses Fourier-transform infrared spectroscopy with immunoassay strip tests (fentanyl and benzodiazepines). RESULTS: Of 103 samples, 65% contained only the advertised substance, 14% contained the advertised substance in combination with other psychoactive and/or potentially harmful substances and for 21%, the advertised substance was absent. Substances sold as MDMA, methamphetamine or heroin were consistently found to contain only the advertised substance, while substances sold as 2C-B, alprazolam or ketamine were the most likely to be completely substituted. Only 4 samples sold as cocaine contained solely the advertised substance, with 13 containing cocaine with adulterants like lidocaine, creatine, levamisole and boric acid (n = 19). No fentanyl contamination was detected. Novel dissociatives and novel benzodiazepines were detected, as well as a nitazene compound. DISCUSSION AND CONCLUSIONS: Drug markets under prohibition continue to contain numerous unexpected substances, some of which can elevate risk of harm. Cryptomarkets are not immune to this problem, despite review systems, which should, in theory, make vendors more accountable for the quality of their stock. These findings demonstrate a need for expansion of local drug checking services in Australia.

Triad influence on the detection of crime in Hong Kong.

We use bootstrap data envelopment analysis, adjusting for endogeneity, to examine police efficiency in detecting crime in Hong Kong. We address the following: (i) is there a correlation between the detection of crime and triad influence? (ii) does the level of triad influence affect the efficiency in translating inputs (police strength) into outputs (crime detection)? and (iii) how can the allocation of policing resources be adjusted to improve crime detection? We find that nighty-eight percent of Hong Kong police districts in our sample were found to be inefficient in the detection of crime. Variation was found across districts regarding the detection of violent, property and other crimes. Most inefficiencies and potential improvements in the detection of crime were found in the categories violent and other crimes. We demonstrate how less efficient police districts can modify police resourcing decisions to better detect certain crime types while maintaining current levels of resourcing. Finally, we highlight how the method we outline improves efficiency estimation by adjusting for endogeneity and measuring the conditional efficiency of each district (i.e. the efficiency of crime detection taking the instrumental variables (e.g. influence of triads) into consideration). The use of frontier models to assist in evaluating policing performance can lead to improved efficiency, transparency, and accountability in law enforcement, ultimately resulting in better public safety outcomes and publicly funded resource allocation.

Corrigendum: A method and app for measuring the heterogeneous costs and benefits of justice processes.

[This corrects the article DOI: 10.3389/fpsyg.2023.1094303.].

Real-world patient characteristics, treatment patterns, and clinical outcomes associated with tucatinib therapy in HER2-positive metastatic breast cancer.

Background: Tucatinib is an oral human epidermal growth factor receptor 2 (HER2)-directed therapy approved in combination with trastuzumab and capecitabine for use in patients with previously treated HER2+ metastatic breast cancer (MBC) with/without brain metastases (BM). To inform clinical decision-making, it is important to understand tucatinib use in real-world clinical practice. We describe patient characteristics, treatment patterns, and clinical outcomes for tucatinib treatment in the real-world setting. Methods: This retrospective cohort study included patients diagnosed with HER2+ MBC (January 2017-December 2022) who received tucatinib treatment in a nationwide, de-identified electronic health record-derived metastatic breast cancer database. Patient demographics and clinical characteristics were described at baseline (prior to tucatinib initiation). Key outcomes included real-world time to treatment discontinuation (rwTTD), time to next treatment (rwTTNT), and overall survival (rwOS). Results: Of 3,449 patients with HER2+ MBC, 216 received tucatinib treatment (n=153 with BM; n=63 without BM) and met inclusion criteria. Median (range) age of patients was 56 (28-84) years, 57.9% were White, and 68.5% had Eastern Cooperative Oncology Group performance status ≤1. Median (IQR) follow-up from start of tucatinib treatment was 12 (6-18) months. Among all patients who received tucatinib treatment, median (95% CI) rwTTD was 6.5 (5.4-8.8) months with 39.8% and 21.4% remaining on treatment at 12 and 24 months, respectively. Median (95% CI) rwTTNT was 8.7 (6.8-10.7) months. Patients who received the approved tucatinib triplet combination after ≥1 HER2-directed regimen in the metastatic setting had a similar median (95% CI) rwTTD (any line: 8.1 [5.7-9.5] months; second-line (2L) and third-line (3L): 9.4 [6.3-14.1] months) and rwTTNT (any line: 8.8 [7.1-11.8] months; 2L and 3L: 9.8 [6.8-14.1] months) to the overall population. Overall, median (95% CI) rwOS was 26.6 (20.2-not reached [NR]) months, with similar findings for patients who received the tucatinib triplet (26.1 [18.8-NR] months) and was NR in the subgroup limited to the 2L/3L population. Conclusion: Tucatinib treatment in the real-world setting was associated with a similar median rwTTD, rwTTNT, and rwOS as in the pivotal HER2CLIMB trial, with particular effectiveness in patients in the 2L/3L setting. These results highlight the importance of earlier use of tucatinib in HER2+ MBC.

A method and app for measuring the heterogeneous costs and benefits of justice processes.

Can the impact of justice processes be enhanced with the inclusion of a heterogeneous component into an existing cost-benefit analysis (CBA) APP that demonstrates how benefactors and beneficiaries are affected? Such a component requires: (i) moving beyond the traditional cost benefit conceptual framework of utilising averages; (ii) identification of social group or population-specific variation; (iii) identification of how justice processes differ across groups/populations; (iv) distribution of costs and benefits according to the identified variations; and (v) utilisation of empirically informed statistical techniques to gain new insights from data and maximise impact to beneficiaries. In this paper, we outline a method for capturing heterogeneity. We test our method and the CBA online APP we developed using primary data collected from a developmental crime prevention intervention in Australia. We identify how subgroups in the intervention display different behavioural adjustments across the reference period revealing the heterogeneous distribution of costs and benefits. Finally, we discuss the next version of the CBA APP, which incorporates an AI-driven component that reintegrates individual CBA projects using machine learning and other modern data science techniques. We argue that the APP, enhances CBA, development outcomes, and policy making efficiency for optimal prioritization of criminal justice resources. Further, the APP advances policy accessibility of enhanced, social group-specific data illuminating policy orientation for more inclusive, just, and resilient societal outcomes.

Safety and tolerability of obeticholic acid in chronic liver disease: a pooled analysis of 1878 individuals.

BACKGROUND AND AIMS: Obeticholic acid (OCA) is a farnesoid X receptor agonist used in primary biliary cholangitis (PBC) treatment. Recent studies have expanded OCA use for NASH treatment and results from phase 3 clinical trial have shown beneficial reduction of ≥1 stage of fibrosis with no NASH worsening. However, safety concerns still preside, thus we systematically examine the safety profile of OCA in chronic liver disease. MATERIALS AND METHODS: A search was conducted in Medline and Embase databases for OCA randomized controlled trials in chronic liver disease. Binary events were pooled with Paule-Mandel random effects model and proportional events were examined in a generalized linear mixed model with Clopper-Pearson intervals. RESULTS: A total of 8 studies and 1878 patients were analyzed. There was a 75% [risk ratio (RR): 1.75, 95% CI: 1.43-2.15, p < 0.01] increased pruritis risk. OCA increased constipation incidence (RR: 1.88, 95% CI: 1.45-2.43, p < 0.01), decreased diarrhea (RR: 0.62, 95% CI: 0.50-0.77, p < 0.01), and increased development of hyperlipidemia (RR: 2.69, 95% CI: 1.85-3.92, p < 0.01) relative to placebo. Sensitivity analysis in NASH-only studies found a dose-dependent effect with pruritis which increases to RR: 3.07 (95% CI: 1.74-5.41) at 25 mg. However, up to 9.98% (95% CI: 5.01%-18.89%) of NAFLD patients with placebo similarly experience pruritis events. Overall, 16.55% (95% CI: 6.47%-36.24%) of patients with NAFLD on OCA experienced pruritis. There was no significant increase in cardiovascular events. CONCLUSIONS: OCA may represent the first pharmacological treatment approved for NASH. However, pruritis, constipation, diarrhea, and hyperlipidemia were major events with evident dose-dependent effect that affect tolerability in NASH. Future long-term studies for longitudinal safety events are required.

Music festival drug checking: evaluation of an Australian pilot program.

BACKGROUND: This paper explores the feasibility of delivering a music festival-based drug checking service in Australia, evaluating service design and stakeholder acceptability. METHODS: Questionnaire and interview data were collected from adult service users and key stakeholders. A mixed methods approach was used to analyse the data on implementation, impact and acceptability. RESULTS: The trial service tested 170 substances with more than 230 patrons (including individuals who attended in groups). Adult service users had an average age of 21 years. Voluntary participation in the evaluation resulted in 158 participants completing the pre-service questionnaire, most of whom also completed the post-service (147 participants). Eleven in-depth qualitative interviews were conducted with patrons in the weeks following the drug checking. Concordance between what the patron expected the drug to be and drug checking results occurred in 88 per cent (n = 139) of the sample. Evaluation results show that the experience of testing and the accompanying harm reduction brief interventions positively impacted on patrons' self-reported drug harm reduction knowledge, trust of health providers and stated drug use intentions. The service was received positively by service users. CONCLUSION: This is the first independent evaluation of a pilot drug checking service in Australia. Consideration of operational feasibility and self-reported behavioural change suggests that the program was successful, although communication about the interpretation of drug checking results could be improved. Future studies should develop strategies for follow-up and consider the applicability of behavioural change theory.

Financial Fraud against Older People in Hong Kong: Assessing and Predicting the Fear and Perceived Risk of Victimization.

While the majority of studies on the fear of crime focus on the impact of violent and property crimes at the population level, financial fraud against senior citizens is often under-investigated. This study uses data collected from 1061 older citizens in the community through a cross-sectional survey in Hong Kong to examine the levels of fear and perceived risk among Chinese senior citizens toward financial fraud and the factors behind them. Logistic regression analyses were conducted to assess the explanatory power of four theoretical perspectives (vulnerability, victimization, social integration, and satisfaction with police) on fear and perceived risk of fraud victimization. The results indicate significant predictive effects of victimization experience and satisfaction with police fairness and integrity on both the fear and the perceived risk of fraud among respondents. The findings not only confirm the differential impact of theoretical explanations on these constructs but can also contribute to crime prevention policy and practice in an aging society.

A randomized study of the safety and pharmacokinetics of GSK3358699, a mononuclear myeloid-targeted bromodomain and extra-terminal domain inhibitor.

AIMS: GSK3358699 is a mononuclear myeloid-targeted bromodomain and extra-terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995). METHODS: Part A (N = 23) included three dose-escalating periods of 1-40 mg of GSK3358699 or placebo in two cohorts in a single ascending-dose crossover design. Part C (N = 25) was planned as an initial dose of 10 mg of GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts. RESULTS: In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half-life ranged from 0.7 to 1.1 (GSK3358699) and 2.1 to 2.9 (GSK3206944) hours after a single dose of 1-40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1-hour post-dose following 10 mg of GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide-induced monocyte chemoattractant protein (MCP)-1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)-6 and tumour necrosis factor (TNF). The most common adverse event (AE) was headache. Four AEs of nonsustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization. CONCLUSIONS: Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac-related AEs, resulting in an inability to identify a suitable repeat-dose regimen and study termination.

Worse outcomes and higher costs of care in fibrostenotic Crohn's disease: a real-world propensity-matched analysis in the USA.

BACKGROUND: Patients with Crohn's disease (CD) may develop fibrostenotic strictures. No currently available therapies prevent or treat fibrostenotic CD (FCD), making this a critical unmet need. AIM: To compare health outcomes and resource utilisation between CD patients with and without fibrostenotic disease. METHODS: Patients aged ≥18 years with FCD and non-FCD between 30 October 2015 and 30 September 2018 were identified in the Truven MarketScan Commercial Claims and Encounters Database. We conducted 1:3 nearest neighbour propensity score matching on age, sex, malnutrition, payer type, anti-tumour necrosis factor use, and Charlson Comorbidity Index score. Primary outcomes up to 1 year from the index claim were ≥1 hospitalisation, ≥1 procedure, ≥1 surgery, and steroid dependency (>100 day supply). Associations between FCD diagnosis and outcomes were estimated with a multivariable logistic regression model. This study was exempt from institutional review board approval. RESULTS: Propensity score matching yielded 11 022 patients. Compared with non-FCD, patients with FCD had increased likelihood of hospitalisations (17.1% vs 52.4%; p<0.001), endoscopic procedures (4.4% vs 8.6%; p<0.001), IBD-related surgeries (4.7% vs 9.1%; p<0.001), steroid dependency (10.0% vs 15.7%; p<0.001), and greater mean annual costs per patient ($47 575 vs $77 609; p<0.001). FCD was a significant risk factor for ≥1 hospitalisation (adjusted OR (aOR), 6.1), ≥1 procedure (aOR, 2.1), ≥1 surgery (aOR, 2.0), and steroid dependency (aOR, 1.7). CONCLUSIONS: FCD was associated with higher risk for hospitalisation, procedures, abdominal surgery, and steroid dependency. Patients with FCD had a greater mean annual cost per patient. FCD represents an ongoing unmet medical need.

Entanglement entropy and edge modes in topological string theory. Part I. Generalized entropy for closed strings.

Progress in identifying the bulk microstate interpretation of the Ryu-Takayanagi formula requires understanding how to define entanglement entropy in the bulk closed string theory. Unfortunately, entanglement and Hilbert space factorization remains poorly understood in string theory. As a toy model for AdS/CFT, we study the entanglement entropy of closed strings in the topological A-model in the context of Gopakumar-Vafa duality. We will present our results in two separate papers. In this work, we consider the bulk closed string theory on the resolved conifold and give a self-consistent factorization of the closed string Hilbert space using extended TQFT methods. We incorporate our factorization map into a Frobenius algebra describing the fusion and splitting of Calabi-Yau manifolds, and find string edge modes transforming under a q-deformed surface symmetry group. We define a string theory analogue of the Hartle-Hawking state and give a canonical calculation of its entanglement entropy from the reduced density matrix. Our result matches with the geometrical replica trick calculation on the resolved conifold, as well as a dual Chern-Simons theory calculation which will appear in our next paper [1]. We find a realization of the Susskind-Uglum proposal identifying the entanglement entropy of closed strings with the thermal entropy of open strings ending on entanglement branes. We also comment on the BPS microstate counting of the entanglement entropy. Finally we relate the nonlocal aspects of our factorization map to analogous phenomenon recently found in JT gravity.

A systematic review of the malnutrition prevalence in hospitalized hip fracture patients and its associated outcomes.

BACKGROUND: Malnutrition is associated with poorer outcomes in hospitalized patients. However, in hip fracture patients, the associations between malnutrition and poorer outcomes are unclear because of the use of nonestablished nutrition assessment tools in previous studies that may have some degree of misclassification bias. Therefore, this review aims to determine (1) the prevalence of malnutrition diagnosed in hospitalized hip fracture patients using established nutrition assessment tools and (2) the outcomes associated with malnutrition given some of the nonestablished nutrition assessment tools used in previous studies. METHODS: Four electronic databases were used. Studies that used established nutrition assessment tools to diagnose malnutrition in hip fracture patients within 48 h of hospital admission were included. RESULTS: Nine studies were included (n = 1665). Patients' mean age ranged from 79.9 to 86.1 years. Eight studies reported the frequencies of each sex, and for females, it ranged from 70% to 81.8%. The prevalence of malnutrition was 4.0% to 39.4%. Malnutrition was independently associated with (1) increased mortality and (2) functional dependence. There was also a trend towards more supported living arrangements and impaired mobility in the longer term. Malnutrition was not associated with (1) hospital length of stay, (2) hospital readmissions, and (3) incidence of complications. CONCLUSION: The prevalence of malnutrition in hip fracture patients is highly variable and is associated with poorer outcomes. Therefore, identifying malnourished hip fracture patients using established nutrition assessment tools is important, and adequate resources can be allocated to prevent malnutrition through early screening and intervention.

CARD14-associated papulosquamous eruption (CAPE) in a toddler responding to treatment with acitretin.

CARD14-associated papulosquamous eruption (CAPE) is a rare autosomal dominant dermatosis that presents classically in early childhood with clinical features of both psoriasis and pityriasis rubra pilaris (PRP). The disease is known to be refractory to topical and systemic therapies classically used for psoriasis, with the majority of reported cases requiring treatment with biologics, such as ustekinumab and secukinumab. We present a toddler with a clinical presentation consistent with CAPE and found to have a novel heterozygous variant of the CARD14 gene. She was refractory to treatment with topical emollients and topical corticosteroids, but responsive to oral acitretin.

Molecular landscape of IDH-mutant primary astrocytoma Grade IV/glioblastomas.

WHO 2016 classified glioblastomas into IDH-mutant and IDH-wildtype with the former having a better prognosis but there was no study on IDH-mutant primary glioblastomas only, as previous series included secondary glioblastomas. We recruited a series of 67 IDH-mutant primary glioblastomas/astrocytoma IV without a prior low-grade astrocytoma and examined them using DNA-methylation profiling, targeted sequencing, RNA sequencing and TERT promoter sequencing, and correlated the molecular findings with clinical parameters. The median OS of 39.4 months of 64 cases and PFS of 25.9 months of 57 cases were better than the survival data of IDH-wildtype glioblastomas and IDH-mutant secondary glioblastomas retrieved from datasets. The molecular features often seen in glioblastomas, such as EGFR amplification, combined +7/-10, and TERT promoter mutations were only observed in 6/53 (11.3%), 4/53 (7.5%), and 2/67 (3.0%) cases, respectively, and gene fusions were found only in two cases. The main mechanism for telomere maintenance appeared to be alternative lengthening of telomeres as ATRX mutation was found in 34/53 (64.2%) cases. In t-SNE analyses of DNA-methylation profiles, with an exceptional of one case, a majority of our cases clustered to IDH-mutant high-grade astrocytoma subclass (40/53; 75.5%) and the rest to IDH-mutant astrocytoma subclass (12/53; 22.6%). The latter was also enriched with G-CIMP high cases (12/12; 100%). G-CIMP-high status and MGMT promoter methylation were independent good prognosticators for OS (p = 0.022 and p = 0.002, respectively) and TP53 mutation was an independent poor prognosticator (p = 0.013) when correlated with other clinical parameters. Homozygous deletion of CDKN2A/B was not correlated with OS (p = 0.197) and PFS (p = 0.278). PDGFRA amplification or mutation was found in 16/59 (27.1%) of cases and was correlated with G-CIMP-low status (p = 0.010). Aside from the three well-known pathways of pathogenesis in glioblastomas, chromatin modifying and mismatch repair pathways were common aberrations (88.7% and 20.8%, respectively), the former due to high frequency of ATRX involvement. We conclude that IDH-mutant primary glioblastomas have better prognosis than secondary glioblastomas and have major molecular differences from other commoner glioblastomas. G-CIMP subgroups, MGMT promoter methylation, and TP53 mutation are useful prognostic adjuncts.

Refeeding Hypophosphatemia in Patients Receiving Parenteral Nutrition: Prevalence, Risk Factors, and Predicting Its Occurrence.

BACKGROUND: Patients receiving parenteral nutrition (PN) support may develop refeeding hypophosphatemia (RH), and its prevalence is highly variable in the literature. Identifying at-risk patients is crucial to minimize clinical complications. The National Institute for Health and Clinical Excellence (NICE) guidelines are used widely to assess the risk of RH, but they lack validation. We aim to (1) identify the prevalence of RH by multiple diagnostic criteria; (2) assess the predictive ability of the NICE guidelines for RH; and (3) identify important risk factors for RH and evaluate their predictive abilities for RH in a new model. METHODS: This is a single-center retrospective study on adult patients with PN ≥48 hours. Prevalence of RH was determined by 4 established diagnostic criteria. Prognostic accuracy of the NICE guidelines were assessed by the area under the receiver operating characteristic (ROC) curve. Multivariable logistic regressions were performed to develop a new risk-assessment model. RESULTS: Of 149 enrolled patients, 23%-48% (35 to 72 of 149 patients) developed RH (depending on the diagnostic criteria used). The NICE guidelines demonstrated poor discrimination across all diagnostic criteria (ROC, 0.43-0.53). Critical illness, the use of diuretics, and hypomagnesemia prior to PN were independently associated with RH. These risk factors formed the new model for predicting RH and had good discrimination (ROC 0.74; 95% confidence interval, 0.66-0.82). CONCLUSION: Prevalence of RH varied according to established diagnostic criteria. The current NICE guidelines poorly predict the occurrence of RH, and modification is likely beneficial. A new risk-assessment model was developed; nevertheless, further validation is required.

Hepatocellular carcinoma and other complications of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in Japan: A structured review of published works.

AIMS: Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality in Japan. As the treatment of viral hepatitis improves, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are rapidly becoming leading causes of HCC in Japan. This structured review aims to characterize the morbidity and mortality of HCC and other malignant and non-malignant complications among Japanese NAFLD and NASH patients. METHODS: An English and Japanese structured search of published works was undertaken in PubMed, Embase, and Ichushi Web databases, identifying 6553 studies, 34 of which met predefined inclusion criteria. RESULTS: Hepatocellular carcinoma was the most common incident malignancy among NAFLD/NASH patients, with higher incidence in patients with advanced/severe fibrosis (F3/F4) of 10.5%-20.0%. Although NASH results in a lower HCC cumulative incidence than hepatitis C virus (HCV) (11.3% vs. 30.5%), they have similar impacts on health outcomes, including overall mortality. Among Japanese NASH patients, HCC was found to be the main driver of mortality (40.0% in 2.7 years in NASH-HCC). With longer follow-up, higher mortality rates are observed in F3/4 patients: 25.0% in NASH F3/F4 versus 0.0% in NASH F0/2 over 7.7 years. The NASH-HCC patients also have a higher post-operative mortality than HCV-HCC patients. Additionally, NAFLD/NASH patients had higher rates of cardiovascular disease than non-NAFLD/NASH controls, and slightly higher rates of gastric cancer than HCV patients. CONCLUSION: Hepatocellular carcinoma is the most common malignancy and cause of death among NAFLD/NASH patients in Japan, with higher mortality observed among those with advanced disease and complications. Early identification and effective treatments are needed.

Clinical and mutational profiles of adult medulloblastoma groups.

Adult medulloblastomas are clinically and molecularly understudied due to their rarity. We performed molecular grouping, targeted sequencing, and TERT promoter Sanger sequencing on a cohort of 99 adult medulloblastomas. SHH made up 50% of the cohort, whereas Group 3 (13%) was present in comparable proportion to WNT (19%) and Group 4 (18%). In contrast to paediatric medulloblastomas, molecular groups had no prognostic impact in our adult cohort (p = 0.877). Most frequently mutated genes were TERT (including promoter mutations, mutated in 36% cases), chromatin modifiers KMT2D (31%) and KMT2C (30%), TCF4 (31%), PTCH1 (27%) and DDX3X (24%). Adult WNT patients showed enrichment of TP53 mutations (6/15 WNT cases), and 3/6 TP53-mutant WNT tumours were of large cell/anaplastic histology. Adult SHH medulloblastomas had frequent upstream pathway alterations (PTCH1 and SMO mutations) and few downstream alterations (SUFU mutations, MYCN amplifications). TERT promoter mutations were found in 72% of adult SHH patients, and were restricted to this group. Adult Group 3 tumours lacked hallmark MYC amplifications, but had recurrent mutations in KBTBD4 and NOTCH1. Adult Group 4 tumours harboured recurrent mutations in TCF4 and chromatin modifier genes. Overall, amplifications of MYC and MYCN were rare (3%). Since molecular groups were not prognostic, alternative prognostic markers are needed for adult medulloblastoma. KMT2C mutations were frequently found across molecular groups and were associated with poor survival (p = 0.002). Multivariate analysis identified histological type (p = 0.026), metastasis (p = 0.031) and KMT2C mutational status (p = 0.046) as independent prognosticators in our cohort. In summary, we identified distinct clinical and mutational characteristics of adult medulloblastomas that will inform their risk stratification and treatment.