Chaetocin-mediated SUV39H1 inhibition targets stemness and oncogenic networks of diffuse midline gliomas and synergizes with ONC201.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG/DMG) are devastating pediatric brain tumors with extraordinarily limited treatment options and uniformly fatal prognosis. Histone H3K27M mutation is a common recurrent alteration in DIPG and disrupts epigenetic regulation. We hypothesize that genome-wide H3K27M-induced epigenetic dysregulation makes tumors vulnerable to epigenetic targeting. METHODS: We performed a screen of compounds targeting epigenetic enzymes to identify potential inhibitors for the growth of patient-derived DIPG cells. We further carried out transcriptomic and genomic landscape profiling including RNA-seq and CUT&RUN-seq as well as shRNA-mediated knockdown to assess the effects of chaetocin and SUV39H1, a target of chaetocin, on DIPG growth. RESULTS: High-throughput small-molecule screening identified an epigenetic compound chaetocin as a potent blocker of DIPG cell growth. Chaetocin treatment selectively decreased proliferation and increased apoptosis of DIPG cells and significantly extended survival in DIPG xenograft models, while restoring H3K27me3 levels. Moreover, the loss of H3K9 methyltransferase SUV39H1 inhibited DIPG cell growth. Transcriptomic and epigenomic profiling indicated that SUV39H1 loss or inhibition led to the downregulation of stemness and oncogenic networks including growth factor receptor signaling and stemness-related programs; however, D2 dopamine receptor (DRD2) signaling adaptively underwent compensatory upregulation conferring resistance. Consistently, a combination of chaetocin treatment with a DRD2 antagonist ONC201 synergistically increased the antitumor efficacy. CONCLUSIONS: Our studies reveal a therapeutic vulnerability of DIPG cells through targeting the SUV39H1-H3K9me3 pathway and compensatory signaling loops for treating this devastating disease. Combining SUV39H1-targeting chaetocin with other agents such as ONC201 may offer a new strategy for effective DIPG treatment.

Technical concepts on blood pool phase SPECT (acquisition, reconstruction).

Guidelines for bone scintigraphy are well established and recommend the use of planar early phase images to investigate a number of clinical indications. With recent advances in gamma camera technology the use of SPECT/CT imaging in the early phases is now possible, offering the potential of improved diagnostic confidence and prognostic value. To date little work has been carried out to optimize the acquisition of early phase bone images using SPECT/CT with most of the available studies acquiring SPECT images after the traditional planar images to allow comparison of the two techniques. Imaging durations of 7 to 10 minutes have been commonly used. However, the use of iterative reconstruction algorithms has been investigated with rapid SPECT imaging to allow imaging durations as low as 4 minutes. The use of CZT based systems with increased sensitivity and improved energy and spatial resolution also offers the potential to reduce imaging times. The optimization of projection measurement order has been investigated as a method of reducing image artefacts as a result of changing tracer distribution during the SPECT acquisition. In this article we consider the current state of early phase SPECT imaging and possible areas for future investigation as well as recommendations for departments looking to adopt blood pool SPECT imaging as part of their routine clinical practice.

Minithoracotomy vs Conventional Sternotomy for Mitral Valve Repair: A Randomized Clinical Trial.

Importance: The safety and effectiveness of mitral valve repair via thoracoscopically-guided minithoracotomy (minithoracotomy) compared with median sternotomy (sternotomy) in patients with degenerative mitral valve regurgitation is uncertain. Objective: To compare the safety and effectiveness of minithoracotomy vs sternotomy mitral valve repair in a randomized trial. Design, Setting, and Participants: A pragmatic, multicenter, superiority, randomized clinical trial in 10 tertiary care institutions in the UK. Participants were adults with degenerative mitral regurgitation undergoing mitral valve repair surgery. Interventions: Participants were randomized 1:1 with concealed allocation to receive either minithoracotomy or sternotomy mitral valve repair performed by an expert surgeon. Main Outcomes and Measures: The primary outcome was physical functioning and associated return to usual activities measured by change from baseline in the 36-Item Short Form Health Survey (SF-36) version 2 physical functioning scale 12 weeks after the index surgery, assessed by an independent researcher masked to the intervention. Secondary outcomes included recurrent mitral regurgitation grade, physical activity, and quality of life. The prespecified safety outcomes included death, repeat mitral valve surgery, or heart failure hospitalization up to 1 year. Results: Between November 2016 and January 2021, 330 participants were randomized (mean age, 67 years, 100 female [30%]); 166 were allocated to minithoracotomy and 164 allocated to sternotomy, of whom 309 underwent surgery and 294 reported the primary outcome. At 12 weeks, the mean between-group difference in the change in the SF-36 physical function T score was 0.68 (95% CI, -1.89 to 3.26). Valve repair rates (≈ 96%) were similar in both groups. Echocardiography demonstrated mitral regurgitation severity as none or mild for 92% of participants at 1 year with no difference between groups. The composite safety outcome occurred in 5.4% (9 of 166) of patients undergoing minithoracotomy and 6.1% (10 of 163) undergoing sternotomy at 1 year. Conclusions and relevance: Minithoracotomy is not superior to sternotomy in recovery of physical function at 12 weeks. Minithoracotomy achieves high rates and quality of valve repair and has similar safety outcomes at 1 year to sternotomy. The results provide evidence to inform shared decision-making and treatment guidelines. Trial Registration: isrctn.org Identifier: ISRCTN13930454.

Parallel Implementation of Nonadditive Gaussian Process Potentials for Monte Carlo Simulations.

A strategy is presented to implement Gaussian process potentials in molecular simulations through parallel programming. Attention is focused on the three-body nonadditive energy, though all algorithms extend straightforwardly to the additive energy. The method to distribute pairs and triplets between processes is general to all potentials. Results are presented for a simulation box of argon, including full box and atom displacement calculations, which are relevant to Monte Carlo simulation. Data on speed-up are presented for up to 120 processes across four nodes. A 4-fold speed-up is observed over five processes, extending to 20-fold over 40 processes and 30-fold over 120 processes.

The clinical implications of digital technology.

The proliferation of digital technology within the lives of children and young people (CYP) provides arguably one of the most significant clinical and ethical paradigm shifts in Child and Adolescent Psychiatry. One can argue that mental health research has taken a myopic approach to understanding the interaction between young people's technology use and their mental health. Mental health clinicians also need a better understanding of the digital lives of CYP and how technology may be supporting or harming their mental health. Within this paper, we argue that greater longitudinal research is required, particularly in vulnerable groups, and that there is an essential need for a standardised digital use assessment (DUA) tool, which assimilates CYP use of technology and their vulnerabilities/resilience to online risks. We subsequently offer a series of questions clinicians can use to explore technology use by CYP. Such an aide memoire may empower clinicians to have wider discussions around digital technology use with CYP, while also helping to develop appropriate safety and management plans.

Whole-body single photon emission computed tomography/computed tomography for assessment of oncological bone disease - is an extended field of view (from vertex to toes) of clinical value?

OBJECTIVES: Whole-body single photon emission computed tomography/computed tomography (WB-SPECT/CT) is useful for diagnosing bone metastases. When performed on a dual-headed gamma camera, this may cover from clavicles to proximal femurs due to time constraints. In contrast, the novel 360 o cadmium-zinc-telluride scanner can perform WB-SPECT/CT (from vertex to toes) in approximately 20 min. The aim was to assess the prevalence of additional findings above the clavicles and below the lesser trochanters and the prevalence of incidental findings in the CT component. METHODS: Retrospective study of 117 WB-SPECT/CT scans for oncological bone assessment over a 4-month-period. Scan analysis was performed by two independent experienced radionuclide radiologists. RESULTS: The male:female ratio was 71:46 and the mean patient age was 68 years. The primary malignancies were predominantly prostate 65/117 (55.6%) and breast 40/117 (34.2%). There were additional findings of malignancy above the clavicles in 16/116 scans (13.8%) and below the lesser trochanters in 16/117 scans (13.7%). Two cases in the 'above the clavicles' group were suspected solitary metastases, whereas four cases in the 'below lesser trochanters' group were bone metastases at risk of pathological fracture. Incidental findings of clinical significance included suspected new malignancy in 11/117 (9.4%). CONCLUSION: A WB-SPECT/CT (from vertex to toes) oncological bone protocol is useful for the detection of additional findings of clinical significance above the clavicles and below the lesser trochanters. Reviewing and reporting the CT findings in SPECT/CT is important.

Optimising ambulance conveyance rates and staff costs by adjusting proportions of rapid-response vehicles and dual-crewed ambulances: an economic decision analytical modelling study.

AIM: To model optimum proportions of dual-crewed ambulances (DCAs) and rapid-response vehicles (RRVs) in Ambulance Trusts with a view to generating a policy brief for one Ambulance Trust and a modelling tool for other Trusts on the strategic procurement and allocation of emergency vehicle (EV) resources. METHODS: Historical EV assignments for 12 months of emergency calls in 2019 were provided by an NHS Ambulance Trust and analysed for backup, see and treat, and patient to hospital conveyance. Unit costs were derived for paramedics and technicians using Agenda for Change pay rates. Time cycles were assigned for RRV and DCA attendances and unit costs assigned to these. Information was put into a decision analytical model to estimate the costs and numbers of vehicles attending incidents based on relative proportions of available RRVs and DCAs. RESULTS: Of 711 992 calls attended by 837 107 EVs, 514 766 (72.3%) required at least one emergency department conveyance. The rate of conveyance was significantly lower when RRVs arrived first on the scene. 27 883 out of 529 693 (5.3%) DCAs first arriving at an incident required some backup, and this was also factored into the model. Modelling demonstrated high conveyance rates were counterproductive when increasing the relative proportions of RRVs to DCAs. For example, with conveyance rates of 65%, increasing the RRVs increased the cost and numbers of vehicles attending per incident. At lower conveyance rates, however, there was a levelling around 30% where it could become cost-effective to increase the relative proportions of RRVs to DCAs. CONCLUSION: At current overall conveyance rates, there is no benefit in increasing the relative proportions of RRVs to DCAs unless additional benefits can be realised that bring the conveyance rates down.

Update on Imaging of Inflammatory Arthritis and Related Disorders.

Arthritis and other rheumatic disorders are very frequent in the general population and responsible for a huge physical and disability burden to affected patients as well as a major cost to the society. Precise evaluation often relies on clinical data only but additional imaging may be required i) for a more objective assessment of the disease status, such as in rheumatoid arthritis (RA) or ankylosing spondyloarthritis (AS), ii) for providing prognostic information and evaluating response to treatment or iii) for establishing diagnosis, in patients with unclear clinical picture, such as polymyalgia rheumatica (PMR) and large-vessel vasculitis (LVV). Besides radiological techniques (x-rays, ultrasound, and MRI), functional and molecular imaging has emerged as a valid tool for this purpose in several disorders. Bone scanning has long been a method of choice but is now more used as a triage tool in patients with unclear complaints, including degenerative disorders (eg osteoarthritis). 18F-FDG-PET/CT (FDG) proved efficient in assessing the extent of the disease and response to treatment in RA and related disorders, and to provide accurate diagnosis in some systemic disorders, including PMR and LVV. Based on glucose metabolism, FDG-PET/CT is able to show increased metabolism in peripheral cells involved in inflammation (eg neutrophils, lymphocytes or monocytes/macrophages) but also in fibroblasts that proliferate in the pannus. The lack of specificity of FDG is a limitation and many alternative tracers were developed at the preclinical stage or applied in the clinics, especially within clinical trials. They include imaging of macrophages using translocator protein (TSPO), folate-receptors or other targets on activated cells. These new tools will undoubtedly become more and more available in the everyday clinical workup of patients with rheumatisms. Finally, it should be kept in mind that a very simple tracer, 18F-fluoride is widely more performant in AS than FDG.

Preventing cardiotoxicity in patients with breast cancer and lymphoma: protocol for a multicentre randomised controlled trial (PROACT).

INTRODUCTION: Anthracyclines are included in chemotherapy regimens to treat several different types of cancer and are extremely effective. However, it is recognised that a significant side effect is cardiotoxicity; anthracyclines can cause irreversible damage to cardiac cells and ultimately impaired cardiac function and heart failure, which may only be evident years after exposure. The PROACT trial will establish the effectiveness of the ACE inhibitor enalapril maleate (enalapril) in preventing cardiotoxicity in patients with breast cancer and non-Hodgkin's lymphoma (NHL) receiving anthracycline-based chemotherapy. METHODS AND ANALYSIS: PROACT is a prospective, randomised, open-label, blinded end-point, superiority trial which will recruit adult patients being treated for breast cancer and NHL at NHS hospitals throughout England. The trial aims to recruit 106 participants, who will be randomised to standard care (high-dose anthracycline-based chemotherapy) plus enalapril (intervention) or standard care alone (control). Patients randomised to the intervention arm will receive enalapril (starting at 2.5 mg two times per day and titrating up to a maximum dose of 10 mg two times per day), commencing treatment at least 2 days prior to starting chemotherapy and finishing 3 weeks after their last anthracycline dose. The primary outcome is the presence or absence of cardiac troponin T release at any time during anthracycline treatment, and 1 month after the last dose of anthracycline. Secondary outcomes will focus on cardiac function measured using echocardiogram assessment, adherence to enalapril and side effects. ETHICS AND DISSEMINATION: A favourable opinion was given following research ethics committee review by West Midlands-Edgbaston REC, Ref: 17/WM/0248. Trial findings will be disseminated through engagement with patients, the oncology and cardiology communities, NHS management and commissioning groups and through peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT03265574.

[18F]FDG PET/CT in rheumatoid arthritis.

[18F]fluorodeoxyglucose (FDG) PET/CT can be used to image the inflammation in rheumatoid arthritis. Specifically, the synovial metabolic activity can be evaluated visually and measured using standard uptake values. Fluorine-18-labeled Sodium fluoride (NaF) PET/CT can be used to determine synovial osteoblastic activity. Response assessment using FDG PET/CT is routine in many cancers and this is now an emerging technique for rheumatoid arthritis. Vasculitis in rheumatoid arthritis (RA) can be also studied with FDG PET/CT and aortic calcification with NaF PET/CT. These techniques could be useful in determining RA disease severity. FDG PET/CT is a useful technique to exclude underlying malignancy when RA does not follow the expected course. A number of novel tracers are being studied with regard to their applicability in rheumatoid arthritis and some of these could even be used in a theranostic manner in the future.

British Nuclear Medicine Society Clinical Guideline for bone scintigraphy.

This guideline must be read in conjunction with the British Nuclear Medicine Society (BNMS) Generic guidelines. The purpose of this guideline is to assist specialists in Nuclear Medicine and Radionuclide Radiology in recommending, performing, interpreting and reporting the results of bone scintigraphy studies. This guideline could also be used to help individual departments formulate their own local protocols. This does not aim to be prescriptive regarding technical aspects of individual camera acquisitions, which should be developed in conjunction with the local medical physics expert.

Machine learning for non-additive intermolecular potentials: quantum chemistry to first-principles predictions.

Prediction of thermophysical properties from molecular principles requires accurate potential energy surfaces (PES). We present a widely-applicable method to produce first-principles PES from quantum chemistry calculations. Our approach accurately interpolates three-body non-additive interaction data, using the machine learning technique, Gaussian Processes (GP). The GP approach needs no bespoke modification when the number or type of molecules is changed. Our method produces highly accurate interpolation from significantly fewer training points than typical approaches, meaning ab initio calculations can be performed at higher accuracy. As an exemplar we compute the PES for all three-body cross interactions for CO2-Ar mixtures. From these we calculate the CO2-Ar virial coefficients up to 5th order. The resulting virial equation of state (EoS) is convergent for densities up to the critical density. Where convergent, the EoS makes accurate first-principles predictions for a range of thermophysical properties for CO2-Ar mixtures, including the compressibility factor, speed of sound and Joule-Thomson coefficient. Our method has great potential to make wide-ranging first-principles predictions for mixtures of comparably sized molecules. Such predictions can replace the need for expensive, laborious and repetitive experiments and inform the continuum models required for applications.

Improving ambulance care for children suffering acute pain: a qualitative interview study.

BACKGROUND: Pain is a highly complex sensory and emotional experience. When a child suffers acute pain through illness or injury, they are often transported to hospital by ambulance. Pre-hospital pain management in children is poor, with 61% of children receiving suboptimal pain management. Consequences of poor pain management include the risk of developing post-traumatic stress disorder and altered pain perception. We aimed to identify clinicians' perceptions of barriers, facilitators and potential improvements for the management of pre-hospital acute pain in children. METHODS: Qualitative face to face semi-structured recorded interviews were performed in one large UK ambulance service. Audio files were transcribed verbatim with thematic analysis used to generate themes. NVivo 12 was used to support data analysis. Findings were combined with existing evidence to generate a driver diagram. RESULTS: Twelve ambulance clinicians participated, including 9 registered paramedics and 3 emergency medical technicians. Median (IQR) age was 43.50 (41.50, 45.75) years, 58% were male, median (IQR) experience was 12 (4.25, 15.50) years and 58% were parents. Several themes relating to barriers and facilitators were identified, including physical, emotional, social, organisational, environmental, management, knowledge and experience. Improvement themes were identified relating to management, organisation and education. These data were combined to create a driver diagram; the three primary drivers were 1) explore methods to increase rates of analgesic administration, including utilising intranasal or inhaled routes; 2) reduce fear and anxiety in children, by using child friendly uniform, additional non-pharmacological techniques and more public interaction and 3) reduce fear and anxiety in clinicians, by enhancing training and optimising crew mix. CONCLUSIONS: The quality of care that children receive for acute pain in the ambulance service may be improved by increasing rates of analgesic administration and reducing the fear and anxiety experienced by children and clinicians. Future research involving children and parents would be useful to determine the most important outcome measures and facilitate intervention development.

Multi-institutional analysis of central nervous system germ cell tumors in patients with Down syndrome.

PURPOSE: Primary germ cell tumors (GCTs) are the most common central nervous system (CNS) neoplasm in patients with Down syndrome (DS). However, a standard of care has not been established due to paucity of data. METHODS: A retrospective multi-institutional analysis was conducted, in addition to a comprehensive review of the literature. RESULTS: Ten patients from six institutions (five USA, one Brazil) were identified, in addition to 31 patients in the literature from 1975 to 2021. Of the 41 total patients (mean age 9.9 years; 61% male), 16 (39%) had non-germinomatous germ cell tumors (NGGCTs), 16 (39%) had pure germinomas, and eight (19.5%) had teratomas. Basal ganglia was the most common tumor location (n = 13; 31.7%), followed by posterior fossa (n = 7; 17%). Nine patients (22%) experienced disease relapse or progression, of which four died from tumor progression (one germinoma, three teratomas). Sixteen patients (39%) experienced treatment-related complications, of which eight (50%) died (five germinomas, three NGGCTs). Of the germinoma patients, two died from chemotherapy-related sepsis, one from postsurgery cardiopulmonary failure, one from pneumonia, and one from moyamoya following radiation therapy (RT). Of the NGGCT patients, one died from chemotherapy-related sepsis, one from postsurgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival was 66% for all histological types: 62% germinomas, 79% for NGGCTs, and 53% for teratomas. CONCLUSION: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered to mitigate treatment-related complications and long-term neurocognitive sequelae.

Air guns and their wider relevance to the dental profession.

Crimes involving air guns have declined over the last 16 years in England and Wales; however, still represent a significant occurrence, with 3,028 crimes involving air guns reported in 2019 (just under one-third of all firearm crime). We aim to present points regarding air gun injuries and their wider relevance to the dental profession which have not been covered in previous publications.This article covers air gun licensing in the UK and the relevant safeguarding issues, as well as optimal imaging of suspected retained pellets in the head and neck.Whilst there are numerous case reports of retained air gun pellets found in various regions of the head and neck, only a handful of papers discuss the issues in leaving retained pellets or a surgical approach to removal of these pellets. This article summarises the current approaches and provides a suggested protocol for the management of pellets in the head and neck, as well as highlighting the need for further development in this field.Air gun pellets as retained foreign bodies may be identified on routine examination of the head and neck, both in general dental practice and in oral and maxillofacial surgery departments. This article acts as an overview and guide for dental professionals to gain a wider understanding of these injuries and their management.

Cellular analysis using label-free parallel array microscopy with Fourier ptychography.

Quantitative phase imaging (QPI) is an ideal method to non-invasively monitor cell populations and provide label-free imaging and analysis. QPI offers enhanced sample characterization and cell counting compared to conventional label-free techniques. We demonstrate this in the current study through a comparison of cell counting data from digital phase contrast (DPC) imaging and from QPI using a system based on Fourier ptychographic microscopy (FPM). Our FPM system offers multi-well, parallel imaging and a QPI-specific cell segmentation method to establish automated and reliable cell counting. Three cell types were studied and FPM showed improvement in the ability to resolve fine details and thin cells, despite limitations of the FPM system incurred by imaging artifacts. Relative to manually counted fluorescence ground-truth, cell counting results after automated segmentation showed improved accuracy with QPI over DPC.

Prognostic factors for patients with relapsed central nervous system nongerminomatous germ cell tumors.

We aimed toidentify prognostic factors that may help better understand the behavior of relapsed central nervous system nongerminomatous germ cell tumors. We identified nine studies, including 101 patients; 33 patients (33%) were alive 12 months post-initial relapse. Sixty percent of patients with serum/cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) level ≤25 ng/mL at initial diagnosis were survivors compared with 28% among patients with serum/CSF AFP level >25 ng/mL (P = 0.01). Seventy-one percent of patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy at relapse were survivors compared with 7% among patients who had less than CR/CCR (P < 0.0001). Forty-eight percent of patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) following relapse were survivors compared with 12% among patients who did not receive HDCx/AuHCR (P = 0.0001). Local relapse site, gross total surgical resection, and radiotherapy at relapse were not associated with improved outcomes.