Search

Additive manufacturing can provide advantages over conventional manufacturing for alloys such as alloy 625, which is expensive and difficult to machine. Laser powder bed fusion is a type of additive manufacturing that provides advantages but introduces complex effects on mechanical properties in produced components. This work examines some of these effects by assessing laser powder bed fusion processing parameters, several heat treatment schedules, and differing strain rate and temperature testing behavior using mechanical testing. It was determined that the porosity of fabricated samples of alloy 625 could be reduced below the control of 0.43 %, though the hardness does not appear to be sensitive to processing parameters. Heat treatments at higher temperatures appear to maintain a similar hardness to as-printed samples, but a treatment at 670 °C increased the hardness from 28.0 to 31.3 HRC. In compression tests, samples had higher stress/strain ratios in the dynamic range, though they did not fracture in any tests conducted. In a range from 25 to 500 °C, samples displaced a consistent thermal softening effect, suggesting that significant microstructural change may not occur, compatible with the typical high temperature working conditions of the alloy.

In England, children and adolescents with depression can seek treatment from specialist mental health services. We know little about how they journey through these services, or whether healthcare providers collect sufficient data to accurately appraise this. We aimed to summarise the child and adolescent depression pathway for two healthcare providers. This cohort study used de-identified electronic health records extracted from Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) and South London and Maudsley NHS Foundation Trust (SLaM). We identified referrals between 2015 and 2019 during which the referred patient received their first depression diagnosis aged n = 296 (CPFT) and n = 2502 (SLaM) patients had a referral which met eligibility criteria. In both sites, patients were more frequently female (CPFT 79.3%; SLaM 69.3%) and White ethnicity (CPFT 88.9%; SLaM 57.9%) as compared to respective population estimates for the Trusts’ catchment areas. Patients typically received their first depression diagnosis during adolescence (median ages 16 in CPFT and 15 in SLaM). The most common comorbidity was anxiety disorder. Referrals were usually routine, to community teams specialising in the child age group. Commonly mentioned interventions included antidepressant medication, cognitive behavioural therapy, and dialectical behaviour therapy. However, pathways varied within and between sites, and the quality and consistency of some data was poor. These findings provide an overview of service pathways experienced by children and adolescents with depression, but also highlight that pathways can vary according to individual need and healthcare provider. More systematic collection of some data, and standardisation in record systems used by different providers, would be beneficial.

Phenomenology gives rise to certain ontological considerations that have far-reaching implications for standard conceptions of patient autonomy in medical ethics, and, as a result, the obligations of and to patients in clinical decision-making contexts. One such consideration is the phenomenological reduction in classical phenomenology, a core feature of which is the characterisation of our primary experiences as immediately and inherently meaningful. This paper builds on and extends the analyses of the phenomenological reduction in the works of Husserl, Heidegger, and Merleau-Ponty in order to identify and explain its implications for our current understanding of the principle of respect for patient autonomy and the norms of clinical decision making.

In this article, we describe the technical aspects of the Stanford volumetric modulated arc therapy (VMAT) total body irradiation (TBI) technique, compare it with other VMAT-TBI techniques, and share our initial experience.From September 2019 to August 2021, 35 patients were treated with VMAT-TBI at our institution. Treatment planning was performed using in-house developed automated planning scripts. Organ sparing depended on the regimen: myeloablative (lungs, kidneys, and lenses) and nonmyeloablative with benign disease (lungs, kidneys, lenses, gonads, brain, and thyroid). Quality assurance was performed using electronic portal imaging device portal dosimetry and Mobius3D. Robustness was evaluated for the first 10 patients by performing local and global isocenter shifts of 5 mm. Treatment was delivered using image-guided radiation therapy for every isocenter and every fraction. In vivo measurements were performed on the match line between the VMAT and anterior-posterior/posterior-anterior fields and on the testes for the first fraction.The lungs, lungs - 1 cm, and kidneys DThe Stanford VMAT-TBI technique, from simulation to treatment delivery, was presented and compared with other VMAT-TBI techniques. Together with publicly shared autoplanning scripts, our technique may provide the gateway for wider adaptation of this technology and the possibility of multi-institutional studies in the cooperative group setting.

Funder: MQ: Transforming Mental Health; Grant(s): MQDS17/40, Around a quarter of people who experience a first episode of psychosis (FEP) will develop treatment-resistant schizophrenia (TRS), but there are currently no established clinically useful methods to predict this from baseline. We aimed to explore the predictive potential for clozapine use as a proxy for TRS of routinely collected, objective biomedical predictors at FEP onset, and to externally validate the model in a separate clinical sample of people with FEP. We developed and externally validated a forced-entry logistic regression risk prediction Model fOr cloZApine tReaTment, or MOZART, to predict up to 8-year risk of clozapine use from FEP using routinely recorded information including age, sex, ethnicity, triglycerides, alkaline phosphatase levels, and lymphocyte counts. We also produced a least-absolute shrinkage and selection operator (LASSO) based model, additionally including neutrophil count, smoking status, body mass index, and random glucose levels. The models were developed using data from two UK psychosis early intervention services (EIS) and externally validated in another UK EIS. Model performance was assessed via discrimination and calibration. We developed the models in 785 patients, and validated externally in 1,110 patients. Both models predicted clozapine use well at internal validation (MOZART: C 0.70; 95%CI 0.63,0.76; LASSO: 0.69; 95%CI 0.63,0.77). At external validation, discrimination performance reduced (MOZART: 0.63; 0.58,0.69; LASSO: 0.64; 0.58,0.69) but recovered after re-estimation of the lymphocyte predictor (C: 0.67; 0.62,0.73). Calibration plots showed good agreement between observed and predicted risk in the forced-entry model. We also present a decision-curve analysis and an online data visualisation tool. The use of routinely collected clinical information including blood-based biomarkers taken at FEP onset can help to predict the individual risk of clozapine use, and should be considered equally alongside other potentially useful information such as symptom scores in large-scale efforts to predict psychiatric outcomes.

COG-UK is supported by funding from the MRC part of UK Research & Innovation, the National Institute of Health Research (Grant code MC_PC_19027), and Genome Research Limited, operating as the Welcome Sanger Institute. Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine. Publisher PDF

Additional information to provide an insight into the full kinase selectivity profile of AT7519 and full details of its pharmakokinetic parameters

Cyclin-dependent kinases (CDK), and their regulatory cyclin partners, play a central role in eukaryotic cell growth, division, and death. This key role in cell cycle progression, as well as their deregulation in several human cancers, makes them attractive therapeutic targets in oncology. A series of CDK inhibitors was developed using Astex's fragment-based medicinal chemistry approach, linked to high-throughput X-ray crystallography. A compound from this series, designated AT7519, is currently in early-phase clinical development. We describe here the biological characterization of AT7519, a potent inhibitor of several CDK family members. AT7519 showed potent antiproliferative activity (40-940 nmol/L) in a panel of human tumor cell lines, and the mechanism of action was shown here to be consistent with the inhibition of CDK1 and CDK2 in solid tumor cell lines. AT7519 caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models. Tumor regression was observed following twice daily dosing of AT7519 in the HCT116 and HT29 colon cancer xenograft models. We show that these biological effects are linked to inhibition of CDKs in vivo and that AT7519 induces tumor cell apoptosis in these xenograft models. AT7519 has an attractive biological profile for development as a clinical candidate, and the tolerability and efficacy in animal models compare favorably with other CDK inhibitors in clinical development. Studies described here formed the biological rationale for investigating the potential therapeutic benefit of AT7519 in cancer patients. [Mol Cancer Ther 2009;8(2):324–32]

Supplementary Data from Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines

We performed a retrospective study of cervical cancer pelvic radiotherapy plans to explore dosimetric parameters predictive of hematologic toxicity (HT), with specific interest in evaluating metabolic parameters and identifying the best predictive model.Active marrow was retroactively contoured as pelvic bone with SUV mean on 18F-FDG-PET. "Highly active" marrow was contoured as the hottest 10-14% volume of active marrow. Pelvic bone contour was segmented into lumbosacral, iliac crest, and lower pelvis. Predictors of HT were evaluated using logistic regression and repeated measures modeling.One hundred women were evaluated from 2009 to 2020. The plurality/majority had stage IIIC1 disease (38%) and underwent IMRT (88%) with pelvic field alone (72%). The majority received weekly cisplatin (78%), and 82% completed at least five cycles. The most common HT was leukopenia (grade 2+: 68%). Predictors of grade 2+ and 3+ HT were baseline WBC (p 0.001), and 10- and 20-Gy dosimetric parameters to the active marrow, highly active marrow, and pelvic bone. The best predictive model of leukocyte trajectory included baseline WBC (p 0.001), highly active marrow V20 (p 0.001), and interactions of baseline WBC with time (p 0.001) and highly active marrow V20 (p 0.001), such that those with low baseline WBC experienced the greatest impact of highly active marrow V20.Baseline WBC was highly predictive of HT; dosimetric predictors included dose to the active marrow, highly active marrow, and pelvic bone, with the greatest impact from V20 to the highly active marrow, particularly in women with low baseline WBC. Future studies should consider incorporating baseline WBC and limiting dose to the most highly active marrow.

PURPOSE: The aim of this study was to apply the Six Sigma methodology and failure mode and effect analysis (FMEA) to mitigate errors in intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) treatment planning with the first clinical installation of RefleXion X1. METHODS AND MATERIALS: The Six Sigma approach consisted of 5 phases: define, measure, analyze, improve, and control. The define, measure, and analyze phases consisted of process mapping and an FMEA of IMRT and SBRT treatment planning on the X1. The multidisciplinary team outlined the workflow process and identified and ranked the failure modes associated with the plan check items using the American Association of Physicists in Medicine Task Group 100 recommendations. Items with the highest average risk priority numbers (RPNs) and severity ≥7 were prioritized for automation using the Eclipse Scripting Application Programming Interface (ESAPI). The “improve” phase consisted of developing ESAPI scripts before the clinical launch of X1 to improve efficiency and safety. In the “control” phase, the FMEA ranking was re-evaluated 1 year after clinical launch. RESULTS: Overall, 100 plan check items were identified in which the RPN values ranged from 10.2 to 429.0. Fifty of these items (50%) were suitable for automation within ESAPI. Of the 10 highest-risk items, 8 were suitable for automation. Based on the results of the FMEA, 2 scripts were developed: Planning Assistant, used by the planner during preparation for planning, and Automated Plan Check, used by the planner and the plan checker during plan preparation for treatment. After 12 months of clinical use of the X1 and developed scripts, only 3 errors were reported. The average prescript RPN was 138.0, compared with the average postscript RPN of 47.8 (P < .05), signifying a safer process. CONCLUSIONS: Implementing new technology in the clinic can be an error-prone process in which the likelihood of errors increases with increasing pressure to implement the technology quickly. To limit errors in clinical implementation of the novel RefleXion X1 system, the Six Sigma method was used to identify failure modes, establish quality control checks, and re-evaluate these checks 1 year after clinical implementation.

“Bodily autonomy” has received significant attention in bioethics, medical ethics, and medical law in terms of the general inviolability of a patient’s bodily sovereignty and the rights of patients to make choices (e.g., reproductive choices) that concern their own body. However, the role of the body in terms of how it can or does contribute to a patient’s capacity for, or exercises of their autonomy in clinical decision-making situations has not been explicitly addressed. The approach to autonomy in this paper is aligned with traditional theories that conceive autonomy in terms of an individual’s capacities for, and exercises of rational reflection. However, at the same time, this paper extends these accounts by arguing that autonomy is, in part, embodied. Specifically, by drawing on phenomenological conceptions of the experience of autonomy, we argue that, in principle, the body is a necessary component of the capacity for autonomy. Secondly, through the presentation of two different cases, we highlight ways in which a patient’s body can contribute to the autonomy of treatment choices. Although the primary aim is to argue that autonomy is, in part, embodied, we also outline general principles for the future development of a full-on theory of embodied autonomy. Ultimately, we hope to encourage others to explore additional conditions under which a concept of embodied autonomy should be employed in medical decision making, how its underlying principles might be operationalised in clinical situations, and its consequences for approaches to patient autonomy in healthcare practice, policy, and law.

Funder: NIHR Applied Research Centre, OBJECTIVES: Personality disorders (PDs) are often conceptualised as impacting individuals throughout their life. However, there has been limited study of the disorders in those over the age of 65. We have used the psychiatric secondary care medical records of 21,971 individuals over the age of 65 from Cambridgeshire, UK, who received care between 2014 and 2021 to characterise older patients with a PD diagnosis. METHODS: The data from all patients >65 with a diagnosis of personality disorder (PD) was extracted (n = 217) along with two comparison groups (n = 2170); patients 65 with a psychiatric diagnosis other than PD or dementia. RESULTS: Compared to younger patients with PD, older patients were more likely to be male, married, suffering from a mixed PD and live in less deprived areas. Compared to patients >65 with diagnoses other than PD, older patients were more likely to be female, single or divorced and had a higher level of social deprivation. Our most striking finding was that older patients with PDs were more likely to experience polypharmacy. A mean of 18.48 different drugs had been prescribed over their lifetime, compared to 9.51 for patients >65 with other mental health diagnoses. CONCLUSION: Here we present the largest ever description of this group of patients and provide insights that could inform clinical practice and future research.

This entry summarizes an emerging subdiscipline of both empirical bioethics and experimental philosophy (“x-phi”) which has variously been referred to as experimental philosophical bioethics, experimental bioethics, or simply “bioxphi” (Earp et al. 2020a, b; Lewis 2020; Mihailov et al. 2021a). Like empirical bioethics, bioxphi uses data-driven research methods to capture what various stakeholders think (feel, judge, etc.) about moral issues of relevance to bioethics. However, like its other parent discipline of x-phi, bioxphi tends to favor experiment-based designs drawn from the cognitive sciences (Knobe 2016) – including psychology, neuroscience, and behavioral economics – to tease out why and how stakeholders think as they do.

Funder: NIHR Imperial Biomedical Research Centre, The antipsychotic clozapine is known to have immune-modulating effects. Clozapine treatment has been reported to be associated with increased risk of COVID-19 infection. However, it remains unclear whether this is because of increased testing of this patient group, who are closely monitored. We linked anonymised health records from mental health services in Cambridgeshire (UK), for patients taking antipsychotic medication, with data from the local COVID-19 testing hub. Patients receiving clozapine were more likely to be tested for COVID-19, but not to test positive. Increased testing in patients receiving clozapine suggests prudent judgement by clinicians, considering the overall health vulnerabilities of this group.

The unfolded protein response has been increasingly implicated as an important pathological pathway and target for therapeutic intervention in neurodegeneration. The licensed antidepressant trazodone is one drug which has been proposed to act on this pathway and may therefore be a potential therapy. Previous examination of existing data for patients with dementia prescribed trazodone did not find a signal suggesting a disease modifying effect. Here we add to that literature by examining the electronic patient record of patients with dementia in Cambridgeshire UK. We found that trazodone is rarely prescribed and where it is used it is at a dose less than half that predicted to be disease modifying. We also found that patients prescribed trazodone had higher levels of neuropsychiatric symptoms and were relatively late in the disease course, likely beyond the optimal point for therapeutic intervention. We suggest it is therefore premature to discard potential therapies based on observational data alone, particularly when experimental medicine approaches to examine the effects of trazodone are feasible.