Clinical actionability of comprehensive genomic profiling for management of rare or refractory cancers

Background. The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. Methods. A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Results. Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0–10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. Conclusion. Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. Implications for Practice: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents

Comparisons of the factor structure and measurement invariance of the Spence children’s anxiety scale - parent version in children with autism spectrum disorder and typically developing anxious children

The Spence Children’s Anxiety Scale - Parent version (SCAS-P) is often used to assess anxiety in children with autism spectrum disorder (ASD), however, little is known about the validity of the tool in this population. The aim of this study was to determine whether the SCAS-P has the same factorial validity in a sample of young people with ASD (n=285), compared to a sample of typically developing young people with anxiety disorders (n=224). Poor model fit with all of the six hypothesised models precluded invariance testing. Exploratory factor analysis indicated that different anxiety phenomenology characterises the two samples. The findings suggest that cross-group comparisons between ASD and anxious samples based on the SCAS-P scores may not always be appropriat

Elevated visual dependency in young adults after chemotherapy in childhood

Chemotherapy in childhood can result in long-term neurophysiological side-effects, which could extend to visual processing, specifically the degree to which a person relies on vision to determine vertical and horizontal (visual dependency). We investigated whether adults treated with chemotherapy in childhood experience elevated visual dependency compared to controls and whether any difference is associated with the age at which subjects were treated. Visual dependency was measured in 23 subjects (mean age 25.3 years) treated in childhood with chemotherapy (CTS) for malignant, solid, non-CNS tumors. We also stratified CTS into two groups: those treated before 12 years of age and those treated from 12 years of age and older. Results were compared to 25 healthy, age-matched controls. The subjective visual horizontal (SVH) and vertical (SVV) orientations was recorded by having subjects position an illuminated rod to their perceived horizontal and vertical with and without a surrounding frame tilted clockwise and counter-clockwise 20° from vertical. There was no significant difference in rod accuracy between any CTS groups and controls without a frame. However, when assessing visual dependency using a frame, CTS in general (p = 0.006) and especially CTS treated before 12 years of age (p = 0.001) tilted the rod significantly further in the direction of the frame compared to controls. Our findings suggest that chemotherapy treatment before 12 years of age is associated with elevated visual dependency compared to controls, implying a visual bias during spatial activities. Clinicians should be aware of symptoms such as visual vertigo in adults treated with chemotherapy in childhood

Roles and Responsibilities of Medicine Subinternship Directors : Medicine Subinternship Director Roles

BACKGROUND: The internal medicine (IM) subinternship (also referred to as acting internship) plays a crucial part in preparing medical students for residency. The roles, responsibilities, and support provided to subinternship directors have not been described. OBJECTIVE: We sought to describe the current role of IM subinternship directors with respect to their responsibilities, salary support, and reporting structure. DESIGN: Nationally representative, annually recurring thematic survey of IM core clerkship directors with membership in an academic professional association as of September 2017. PARTICIPANTS: A total of 129 core clinical medicine clerkship directors at Liaison Committee on Medical Education fully accredited U.S./U.S.-territory-based medical schools. MAIN MEASURES: Responsibilities, salary support, and reporting structure of subinternship directors. KEY RESULTS: The survey response rate was 83.0% (107/129 medical schools). Fifty-one percent (54/107) of respondents reported overseeing both core clerkship inpatient experiences and/or one or more subinternships. For oversight, 49.1% (28/53) of subinternship directors also reported that they were the clerkship director, 26.4% (14/53) that another faculty member directed all medicine subinternships, and 18.9% (10/53) that each subinternship had its own director. The most frequently reported responsibilities for the subinternship directors were administration, including scheduling, and logistics of student schedules (83.0%, 44/53), course evaluation (81.1%, 43/53), and setting grades 79.2% (42/53). The modal response for estimated FTE per course was 10-20% FTE, with 33.3% (16/48) reporting this level of support and 29.2% (14/54) reporting no FTE support. CONCLUSIONS: The role of the IM subinternship director has become increasingly complex. Since the IM subinternship is critical to preparing students for residency, IM subinternship directors require standard expectations and adequate support. Future studies are needed to determine the appropriate level of support for subinternship directors and to define essential roles and responsibilities

Is it feasible to develop a supervised learning algorithm incorporating spinopelvic mobility to predict impingement in patients undergoing total hip arthroplasty? a proof-of-concept study

Aims Precise implant positioning, tailored to individual spinopelvic biomechanics and phenotype, is paramount for stability in total hip arthroplasty (THA). Despite a few studies on instability prediction, there is a notable gap in research utilizing artificial intelligence (AI). The objective of our pilot study was to evaluate the feasibility of developing an AI algorithm tailored to individual spinopelvic mechanics and patient phenotype for predicting impingement. Methods This international, multicentre prospective cohort study across two centres encompassed 157 adults undergoing primary robotic arm-assisted THA. Impingement during specific flexion and extension stances was identified using the virtual range of motion (ROM) tool of the robotic software. The primary AI model, the Light Gradient-Boosting Machine (LGBM), used tabular data to predict impingement presence, direction (flexion or extension), and type. A secondary model integrating tabular data with plain anteroposterior pelvis radiographs was evaluated to assess for any potential enhancement in prediction accuracy. Results We identified nine predictors from an analysis of baseline spinopelvic characteristics and surgical planning parameters. Using fivefold cross-validation, the LGBM achieved 70.2% impingement prediction accuracy. With impingement data, the LGBM estimated direction with 85% accuracy, while the support vector machine (SVM) determined impingement type with 72.9% accuracy. After integrating imaging data with a multilayer perceptron (tabular) and a convolutional neural network (radiograph), the LGBM’s prediction was 68.1%. Both combined and LGBM-only had similar impingement direction prediction rates (around 84.5%). Conclusion This study is a pioneering effort in leveraging AI for impingement prediction in THA, utilizing a comprehensive, real-world clinical dataset. Our machine-learning algorithm demonstrated promising accuracy in predicting impingement, its type, and direction. While the addition of imaging data to our deep-learning algorithm did not boost accuracy, the potential for refined annotations, such as landmark markings, offers avenues for future enhancement. Prior to clinical integration, external validation and larger-scale testing of this algorithm are essential

A clinical and cost effectiveness trial of a parent group intervention to manage challenging restricted and repetitive behaviours in young children with autism spectrum disorder: study protocol for a randomized controlled trial

Background Restricted and repetitive behaviours vary greatly across the autism spectrum, and although not all are problematic some can cause distress and interfere with learning and social opportunities. We have, alongside parents, developed a parent group based intervention for families of young children with autism, which aims to offer support to parents and carers; helping them to recognise, understand and learn how to respond to their child’s challenging restricted repetitive behaviours. Methods The study is a clinical and cost-effectiveness, multi-site randomised controlled trial of the Managing Repetitive Behaviours (MRB) parent group intervention versus a psychoeducation parent group Learning About Autism (LAA) (n = 250; 125 intervention/125 psychoeducation; ~ 83/site) for parents of young children aged 3–9 years 11 months with a diagnosis of autism. All analyses will be done under intention-to-treat principle. The primary outcome at 24 weeks will use generalised estimating equation (GEE) to compare proportion of children with improved RRB between the MRB group and the LAA group. The GEE model will account for the clustering of children by parent groups using exchangeable working correlation. All secondary outcomes will be analysed in a similar way using appropriate distribution and link function. The economic evaluation will be conducted from the perspective of both NHS costs and family access to local community services. A ‘within trial’ cost-effectiveness analysis with results reported as the incremental cost per additional child achieving at least the target improvement in CGI-I scale at 24 weeks. Discussion This is an efficacy trial to investigate the clinical and cost-effectiveness of a parent group based intervention designed to help parents understand and manage their child’s challenging RRB. If found to be effective, this intervention has the potential to improve the well-being of children and their families, reduce parental stress, greatly enhance community participation and potential for learning, and improve longer-term outcomes. Trial registration Trial ID: ISRCTN15550611 Date registered: 07/08/2018. Sponsor and Monitor: Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust R&D Manager Lyndsey Dixon, Address: St Nicholas Hospital, Jubliee Road, Gosforth, Newcastle upon Tyne NE3 3XT, [email protected], Tel: 0191 246 722

Understanding Repetitive Behaviours: A clinical and cost-effectiveness, multi-site randomised controlled trial of a group for parents and carers of young autistic children

\ua9 The Author(s) 2025.Restricted and repetitive behaviours vary greatly between autistic people. Some are a source of pleasure or create opportunities for learning; others may be detrimental in day-to-day life or cause harm. We have developed, in close collaboration with parents/carers, the Understanding Repetitive Behaviours programme, designed for families of young autistic children, to help them recognise, understand and respond sensitively to their child’s impactful restricted and repetitive behaviours. This study is a clinical and cost-effectiveness, multi-site randomised controlled trial of the Understanding Repetitive Behaviours parent programme versus a psychoeducation programme (equivalent to current best practice), learning about autism. Participants were parents/carers, with an autistic child aged between 3–9 years and 11 months. The study was delivered across three sites in England and Scotland. Analyses were completed using intention-to-treat principles. Two hundred and twenty seven families were randomised (113 in LAA; 114 in Understanding Repetitive Behaviours arm). No differences were found between the arms on the primary outcome measure (The Clinical Global Impression – Improvement scale). Analysis of secondary outcomes indicated that children in the Understanding Repetitive Behaviours arm were more likely to be rated as responders in target impactful restricted and repetitive behaviours at 24 weeks but that this effect was not maintained at 52 weeks. Improvements in parent and family functioning were apparent, with no evidence of differences between the arms. The study reconfirms that it is important that clinicians consider both restricted and repetitive behaviours and social communication needs of autistic children with parents when planning appropriate support. Lay abstract: Autistic children, frequently repeat the same behaviours over and over, have specific interests or like things to stay the same. These behaviours and interests are often fun and helpful. However, sometimes they can impact negatively on day-to-day life or put the child at risk of harm. Working closely with parents of autistic children, we developed an 8-week programme (Understanding Repetitive Behaviours) to help them recognise and understand these behaviours. This study aimed to find out whether the understanding repetitive behaviour programme was helpful and good value for money. Two hundred and twenty seven families were allocated by chance to receive either Understanding Repetitive Behaviours or a learning about autism programme. When experts made judgements about whether children showed positive changes across various measures, and these were analysed, there were no differences between the programmes. However, parents who attended the Understanding Repetitive Behaviours programme reported improvement in one of their child’s specific repetitive behaviour (selected to be the main focus of the Understanding Repetitive Behaviours programme) at 24 weeks after the end of the programme. Parents who attended either programme reported more confidence, greater wellbeing and less stress up to 1 year after the end of the study

An integrated approach to neuroscience care: An innovative model to support the new integrated care system

Integrated care systems join up health and care services, so that people have the support they need, in the right place, at the right time. The aims include improving outcomes in healthcare, tackling inequalities in access and enhancing productivity and value for money. This is needed for neuroscience care as the traditional delivery of neuroscience care is inefficient, outdated and expensive, and can involve complex referral pathways and long waiting times. In preparation for the formation of the integrated care system (ICS), a novel innovative collaboration across multiple NHS trusts developed across North Central London in 2021. We developed a model where neuroscience specialists engage in collaborative care with clinicians outside the specialist hospital setting. Pivotal to the pathway is a multidisciplinary meeting, and collaborative working enables joint clinical reviews, diagnostics and medication initiation. This innovative collaboration has already significantly improved access, addressed inequalities due to borough variation and enhanced the delivery and quality of neuroscience care in our ICS. It is a translatable model that can be adapted to suit other regions in the UK. It fulfils many of the objectives of the integrated care system and these benefits are seen without the need for significantly more resource

Variability in school closure decisions in response to 2009 H1N1: a qualitative systems improvement analysis

<p>Abstract</p> <p>Background</p> <p>School closure was employed as a non-pharmaceutical intervention against pandemic 2009 H1N1, particularly during the first wave. More than 700 schools in the United States were closed. However, closure decisions reflected significant variation in rationales, decision triggers, and authority for closure. This variability presents the opportunity for improved efficiency and decision-making.</p> <p>Methods</p> <p>We identified media reports relating to school closure as a response to 2009 H1N1 by monitoring high-profile sources and searching Lexis-Nexis and Google news alerts, and reviewed reports for key themes. News stories were supplemented by observing conference calls and meetings with health department and school officials, and by discussions with decision-makers and community members.</p> <p>Results</p> <p>There was significant variation in the stated goal of closure decision, including limiting community spread of the virus, protecting particularly vulnerable students, and responding to staff shortages or student absenteeism. Because the goal of closure is relevant to its timing, nature, and duration, unclear rationales for closure can challenge its effectiveness. There was also significant variation in the decision-making authority to close schools in different jurisdictions, which, in some instances, was reflected in open disagreement between school and public health officials. Finally, decision-makers did not appear to expect the level of scientific uncertainty encountered early in the pandemic, and they often expressed significant frustration over changing CDC guidance.</p> <p>Conclusions</p> <p>The use of school closure as a public health response to epidemic disease can be improved by ensuring that officials clarify the goals of closure and tailor closure decisions to those goals. Additionally, authority to close schools should be clarified in advance, and decision-makers should expect to encounter uncertainty disease emergencies unfold and plan accordingly.</p

A group intervention for parents and carers to recognise and understand restricted and repetitive behaviour in autistic children: a multisite RCT

Background: Restricted and repetitive behaviours vary greatly between autistic people. Some are a source of pleasure or create opportunities for learning; however, others are functionally impactful and may cause harm. We have developed a parent/carer group intervention (Understanding Repetitive Behaviours), for families of young autistic children, to help parents/carers to recognise, understand and respond to their child\u27s functionally impactful restricted and repetitive behaviours. Objectives: To evaluate the clinical and cost-effectiveness of the Understanding Repetitive Behaviours intervention. Design: A clinical and cost-effectiveness, multisite randomised controlled trial of the Understanding Repetitive Behaviours intervention versus a psychoeducation parent/carer group Learning About Autism (n = 250; 125 intervention/125 psychoeducation; ~ 83/site). Analyses completed using intention-to-treat principles. Setting: Three NHS trusts and universities across England and Scotland. Participants: Parents/carers aged 18 and over, with an autistic child between 3 and 9 years and 11 months, sufficient spoken and written English, willing to be randomised and attend all group sessions, who agree to maintain their child\u27s current medication up to 24 weeks and not to participate in any other trials up to 24 weeks. Intervention: An 8-week parent/carer intervention that was delivered face to face and online using a secure digital platform. Randomisation was at the child level using equal allocation ratio. Information: Research associates and research leads were blind to trial arm allocation. Main outcome measures: The primary outcome is the Clinical Global Impression - Improvement scale, based on child data. Economic outcomes included incremental cost per additional child achieving at least the target improvement in Clinical Global Impression - Improvement scale, cost consequences and incremental cost per quality-adjusted life-year gained were calculated for the comparison of the Understanding Repetitive Behaviours and Learning About Autism groups. Results: Two hundred and sixty-two participants were consented and 227 randomised to either the Learning About Autism (113 participants) or the Understanding Repetitive Behaviours (114 participants) arms of the trial. Seventy-two families did not provide data at primary end point. Data were available for 81 Learning About Autism and 74 Understanding Repetitive Behaviours families at 24 weeks. No differences were found between the arms on the Clinical Global Impression - Improvement scale. Analysis of the secondary outcomes indicated that children in the Understanding Repetitive Behaviours arm were more likely to be rated responders in target restricted and repetitive behaviours at 24 weeks. Improvement in parent and family functioning was apparent across both arms over time, with no evidence of differences between the arms. Five serious adverse events were reported, none of which were related to study participation. Conclusions: The study had a less than expected follow-up at the primary end point and was therefore underpowered. Findings related to the potential clinical effectiveness of Understanding Repetitive Behaviours remain inconclusive. Understanding Repetitive Behaviours is unlikely to be considered cost-effective at 12 months. Future work should determine what the mechanisms of change in functionally impactful restricted and repetitive behaviours are and consider longer time horizons and different methods of valuing benefits for autistic children. Trial registration: This trial is registered as ISRCTN15550611. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/111/95) and is published in full in Health Technology Assessment; Vol. 29, No. 48. See the NIHR Funding and Awards website for further award information.Autistic children often do the same behaviours repeatedly, have specific interests or like things to stay the same each time something happens. Often this does not cause difficulties and these behaviours and interests can be helpful and fun. However, sometimes they may cause harm to the child, put them at risk and/or restrict opportunities for learning or impact on their family life. Working with parents/carers of autistic children, we developed a parent/carer programme (Understanding Repetitive Behaviours) to help parents/carers to recognise and understand these behaviours and learn approaches to reduce their child’s use of behaviours that have a functional impact. This study aimed to find out whether our parent programme was helpful and good value for money. The 227 families who agreed to participate in the study were allocated by chance into two separate groups, either the Understanding Repetitive Behaviours group or another parent/carer group (Learning About Autism). Parents/carers provided us with lots of information about their child and themselves at the beginning of the study, and then again after 10, 24 and 52 weeks. This study took place during the COVID-19 pandemic, and we had to make changes to both the delivery of parent programmes and how the research took place to comply with government guidelines. Unfortunately, 72 families did not complete the follow-up at 24 weeks. This meant that we were unable to find out whether or not the Understanding Repetitive Behaviours intervention was effective. We therefore cannot recommend either parent group intervention to help parents know how best to respond to their autistic child’s impactful repetitive behaviours. Despite this, we were able to show that both Understanding Repetitive Behaviours and Learning About Autism can be delivered by trained NHS professionals and that both groups are safe for families. Also, some families who attended Understanding Repetitive Behaviours reported improvement in their child’s functionally impactful repetitive behaviours at 24 weeks and parents/carers in both groups reported more confidence, greater well-being and less stress up to 1 year afterwards, indicating that both parent groups were beneficial and supportive for parents of autistic children