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Metastatic prostate cancer remains a major clinical challenge and metastatic lesions are highly heterogeneous and difficult to biopsy. Liquid biopsy provides opportunities to gain insights into the underlying biology. Here, using the highly sensitive enrichment-based sequencing technology, we provide analysis of 60 and 175 plasma DNA methylomes from patients with localized and metastatic prostate cancer, respectively. We show that the cell-free DNA methylome can capture variations beyond the tumor. A global hypermethylation in metastatic samples is observed, coupled with hypomethylation in the pericentromeric regions. Hypermethylation at the promoter of a glucocorticoid receptor gene NR3C1 is associated with a decreased immune signature. The cell-free DNA methylome is reflective of clinical outcomes and can distinguish different disease types with 0.989 prediction accuracy. Finally, we show the ability of predicting copy number alterations from the data, providing opportunities for joint genetic and epigenetic analysis on limited biological samples. Metastatic prostate cancer can be difficult to biopsy and characterise. Here, the authors use cell-free DNA methylation analysis to illustrate changes in hypermethylation in metastatic disease.

The provision of continuous passive, and intent-based assisted movements for neuromuscular training can be incorporated into a robotic elbow sleeve. The objective of this study is to propose the design and test the functionality of a soft robotic elbow sleeve in assisting flexion and extension of the elbow, both passively and using intent-based motion reinforcement. First, the elbow sleeve was developed, using elastomeric and fabric-based pneumatic actuators, which are soft and lightweight, in order to address issues of non-portability and poor alignment with joints that conventional robotic rehabilitation devices are faced with. Second, the control system was developed to allow for: (i) continuous passive actuation, in which the actuators will be activated in cycles, alternating between flexion and extension; and (ii) an intent-based actuation, in which user intent is detected by surface electromyography (sEMG) sensors attached to the biceps and triceps, and passed through a logic sequence to allow for flexion or extension of the elbow. Using this setup, the elbow sleeve was tested on six healthy subjects to assess the functionality of the device, in terms of the range of motion afforded by the device while in the continuous passive actuation. The results showed that the elbow sleeve is capable of achieving approximately 50% of the full range of motion of the elbow joint among all subjects. Next, further experiments were conducted to test the efficacy of the intent-based actuation on these healthy subjects. The results showed that all subjects were capable of achieving electromyography (EMG) control of the elbow sleeve. These preliminary results show that the elbow sleeve is capable of carrying out continuous passive and intent-based assisted movements. Further investigation of the clinical implementation of the elbow sleeve for the neuromuscular training of neurologically-impaired persons, such as stroke survivors, is needed.

Purpose This study examined whether combining antioxidants could enhance protection and permit lower dosing for treating noise-induced hearing loss (NIHL). The therapeutic effects of D-methionine (DMET) and N-acetylcysteine (NAC) were evaluated in a guinea pig model. Methods Ninety-six guinea pigs were randomly assigned to eight groups: control, saline, three NAC-only groups (100, 150, 200 mg/kg), and three NAC + DMET groups (100, 200, 400 mg/kg). One hour after six hours of broadband noise exposure, treatments were administered intraperitoneally every 12 h for seven days. Auditory brainstem responses (ABR) were measured before exposure and on day 14. Cochlear tissues were analyzed for Na⁺/K⁺-ATPase and Ca²⁺-ATPase activities and lipid peroxidation (LPO) levels. Results No significant body weight differences were observed between saline and treated groups. NAC alone and in combination with DMET improved ABR thresholds in a dose-dependent manner. The combined NAC (200 mg/kg) + DMET (400 mg/kg) group achieved complete ABR recovery. Noise-induced reductions in ATPase activities were dose-dependently reversed by both treatments. The highest-dose combination restored 87.3% of Na⁺/K⁺-ATPase and 94.7% of Ca²⁺-ATPase activity compared to controls. LPO levels declined with increasing NAC doses, with NAC 200 mg/kg alone showing the greatest reduction. Conclusions Combined NAC (200 mg/kg) and DMET (400 mg/kg) yielded the most substantial functional protection against NIHL. This combination was accompanied by lower LPO levels and higher Na⁺/K⁺-ATPase and Ca²⁺-ATPase activities in the cochlear lateral wall, indicating a potential role in maintaining cochlear homeostasis following acoustic injury.

Background Cognitive deficits are associated with poor functional outcomes in individuals recovering from a first episode of psychosis (FEP). Existing treatments that target cognitive deficits in FEP may enhance cognitive function, but improvements to real-world functioning are less consistent. Furthermore, these treatments may not adequately address the personal recovery goals of young people attending FEP services. A novel cognitive strengths-based approach may overcome these shortcomings. Methods This qualitative study used semi-structured interviews to explore clinicians’ ( N =  12) perspectives toward the potential development of a cognitive strengths-based assessment or treatment in FEP. The interviews were analysed using thematic analysis. Results Five higher-order themes emerged: (1) pro-strengths attitude despite unfamiliarity and minimal use, (2) default to a cognitive deficit lens, (3) potential benefits of a cognitive strengths approach, (4) potential risks and barriers, and (5) considerations for successful implementation. While clinicians acknowledged their current deficit approach, they supported implementing a cognitive strengths assessment or treatment and highlighted their potential benefits for the personal recovery needs of young people with FEP. Conclusions These findings suggest that a deficit-focused approach to cognitive function amongst clinicians may be common practice in FEP services. Nevertheless, a cognitive strengths approach was viewed favourably by clinicians and may represent a novel method of supporting personal recovery. Thus, the design and implementation of a cognitive strengths approach may be worthwhile. Future exploration of other stakeholder perspectives, such as young people with FEP, is essential.

BackgroundThe Paediatric Research in Emergency Departments International Collaborative (PREDICT) performs multicentre research in Australia and New Zealand. Research priorities are difficult to determine, often relying on individual interests or prior work.ObjectiveTo identify the research priorities of paediatric emergency medicine (PEM) specialists working in Australia and New Zealand.MethodsOnline surveys were administered in a two-stage, modified Delphi study. Eligible participants were PEM specialists (consultants and senior advanced trainees in PEM from 14 PREDICT sites). Participants submitted up to 3 of their most important research questions (survey 1). Responses were collated and refined, then a shortlist of refined questions was returned to participants for prioritisation (survey 2). A further prioritisation exercise was carried out at a PREDICT meeting using the Hanlon Process of Prioritisation. This determined the priorities of active researchers in PEM including an emphasis on the feasibility of a research question.ResultsOne hundred and six of 254 (42%) eligible participants responded to survey 1 and 142/245 (58%) to survey 2. One hundred and sixty-eight (66%) took part in either or both surveys. Two hundred forty-six individual research questions were submitted in survey 1. Survey 2 established a prioritised list of 35 research questions. Priority topics from both the Delphi and Hanlon process included high flow oxygenation in intubation, fluid volume resuscitation in sepsis, imaging in cervical spine injury, intravenous therapy for asthma and vasopressor use in sepsis.ConclusionThis prioritisation process has established a list of research questions, which will inform multicentre PEM research in Australia and New Zealand. It has also emphasised the importance of the translation of new knowledge.

PurposeCoronary CT angiography (CCTA) is well established for the diagnostic evaluation and prognostication of coronary artery disease (CAD). The growing burden of CAD in Asia and the emergence of novel CT-based risk markers highlight the need for an automated platform that integrates patient data with CCTA findings to provide tailored, accurate cardiovascular risk assessments. This study aims to develop an artificial intelligence (AI)-driven platform for CAD assessment using CCTA in Singapore’s multiethnic population. We will conduct a hybrid retrospective-prospective recruitment of patients who have undergone CCTA as part of the diagnostic workup for CAD, along with prospective follow-up for clinical endpoints. CCTA images will be analysed locally and by a core lab for coronary stenosis grading, Agatston scoring, epicardial adipose tissue evaluation and plaque analysis. The images and analyses will also be uploaded to an AI platform for deidentification, integration and automated reporting, generating precision AI toolkits for each parameter.ParticipantsCCTA images and baseline characteristics have been collected and verified for 4196 recruited patients, comprising 75% Chinese, 6% Malay, 10% Indian and 9% from other ethnic groups. Among the participants, 41% are female, with a mean age of 55±11 years. Additionally, 41% have hypertension, 51% have dyslipidaemia, 15% have diabetes and 22% have a history of smoking.Findings to dateThe cohort data have been used to develop four AI modules for training, testing and validation. During the development process, data preprocessing standardised the format, resolution and other relevant attributes of the images.Future plansWe will conduct prospective follow-up on the cohort to track clinical endpoints, including cardiovascular events, hospitalisations and mortality. Additionally, we will monitor the long-term impact of the AI-driven platform on patient outcomes and healthcare delivery.Trial registration numberNCT05509010.

Recently, a number of ion channel mutations have been identified in the smooth muscle cells of the human jejunum. Although these are potentially significant in understanding diseases that are currently of unknown etiology, no suitable computational cell model exists to evaluate the effects of such mutations. Here, therefore, a biophysically based single cell model of human jejunal smooth muscle electrophysiology is presented. The resulting cellular description is able to reproduce experimentally recorded slow wave activity and produces realistic responses to a number of perturbations, providing a solid platform on which the causes of intestinal myopathies can be investigated.

IntroductionSystematic documentation of chemotoxicities in outpatient clinics is challenging. Incorporating patient-reported outcome (PRO) measures in clinical workflows can be an efficient strategy to strengthen the assessment of symptomatic treatment toxicities in oncology clinical practice. We compared the adequateness, feasibility, and acceptability of toxicity documentation using systematic, prospective, application of the PRO Common Toxicity Criteria for Adverse Events (PRO-CTCAE) tool.MethodsAt a comprehensive cancer center, data abstraction of electronic health record reviews elucidated current methods and degree of chemotoxicity documentation. Web-based 32-item PRO-CTCAE questionnaires, administered in ambulatory clinics of patients receiving chemotherapy, captured chemotoxicities and respective severities. Patient telephone surveys assessed whether healthcare providers had addressed chemotoxicities to the patients’ satisfaction.ResultsOver a broad demographic of 497 patients receiving chemotherapy, 90% (95% CI 84–96%) with significant chemotoxicities (n = 107) reported that their providers had discussed toxicities with them; of these, 70% received a therapy management change, while among the rest, 17% desired a change in management. Of patients surveyed, 91% (95% CI 82–99%) were satisfied with their current chemotoxicity management. Clinician chart documentation varied greatly; descriptors rather than numerical grading scales were typically used. Although 93% of patients were willing to complete the PRO survey, only 50% thought that it would be acceptable to complete this survey at routine clinic visits.ConclusionUse of PRO-CTCAE in routine clinical practice promotes systematic evaluation of symptomatic toxicities and improves the clarity, consistency, and efficiency of clinician documentation; however, methods to improve patient willingness to complete this tool routinely are needed.

Background Convulsive status epilepticus (CSE) is the most common life-threatening childhood neurological emergency. Despite this, there is a lack of high quality evidence supporting medication use after first line benzodiazepines, with current treatment protocols based solely on non-experimental evidence and expert opinion. The current standard of care, phenytoin, is only 60% effective, and associated with considerable adverse effects. A newer anti-convulsant, levetiracetam, can be given faster, is potentially more efficacious, with a more tolerable side effect profile. The primary aim of the study presented in this protocol is to determine whether intravenous (IV) levetiracetam or IV phenytoin is the better second line treatment for the emergency management of CSE in children. Methods/Design 200 children aged between 3 months and 16 years presenting to 13 emergency departments in Australia and New Zealand with CSE, that has failed to stop with first line benzodiazepines, will be enrolled into this multicentre open randomised controlled trial. Participants will be randomised to 40 mg/kg IV levetiracetam infusion over 5 min or 20 mg/kg IV phenytoin infusion over 20 min. The primary outcome for the study is clinical cessation of seizure activity five minutes following the completion of the infusion of the study medication. Blinded confirmation of the primary outcome will occur with the primary outcome assessment being video recorded and assessed by a primary outcome assessment team blinded to treatment allocation. Secondary outcomes include: Clinical cessation of seizure activity at two hours; Time to clinical seizure cessation; Need for rapid sequence induction; Intensive care unit (ICU) admission; Serious adverse events; Length of Hospital/ICU stay; Health care costs; Seizure status/death at one-month post discharge. Discussion This paper presents the background, rationale, and design for a randomised controlled trial comparing levetiracetam to phenytoin in children presenting with CSE in whom benzodiazepines have failed. This study will provide the first high quality evidence for management of paediatric CSE post first-line benzodiazepines. Trial registration Prospectively registered with the Australian and New Zealand Clinical Trial Registry (ANZCTR): ACTRN12615000129583 (11/2/2015). UTN U1111–1144-5272. ConSEPT protocol version 4 (12/12/2014).

Purpose of Review To examine evidence from randomized controlled trials (RCTs) on how modifiable factors such as exercise and nutrition, with a focus on dairy products, play a role in improving bone health across the lifespan. Recent Findings Meta-analyses of RCTs demonstrate the advantages of consuming dairy products to improve bone mineral density/content (BMD/BMC) and markers of bone metabolism and turnover (BTMs). Eighteen RCTs were conducted investigating the combined effects of dairy and exercise, with most indicating a benefit in youth and adult populations. Results were less conclusive in older adults, perhaps due to altered requirements for dairy/nutrients and exercise with increased age.   Summary RCTs demonstrate that dairy product consumption alone benefits bone health and can enhance the effects of exercise on bone. This may help improve skeletal growth and development in adolescence and prevent osteoporosis with increased age. Future RCTs should account for habitual nutrient intakes, and dairy dosage, timing, and matrix effects.