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.

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.

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.

[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.

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.

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.

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.

Direct observation of long chain enrichment in flow-induced nuclei from molecular dynamics simulations of bimodal blends.

Modelling of flow-induced nucleation in polymers suggest that long chains are enriched in nuclei, relative to their melt concentration. This enrichment has important consequences for the nucleation rate and mechanism, but cannot be directly observed with current experimental techniques. Instead, we ran united atom molecular dynamics simulations of bimodal polyethylene blends, comprising linear chains at a 50 : 50 mix of long (1000 carbon) and short (500-125 carbon) chains, under shear flow. We developed a method to extract the nucleus composition during a transient start-up flow. Our simulations show significant and systematic enrichment of long-chains for all nucleus sizes up to and beyond the critical nucleus. This enrichment is quantitatively predicted by the recent polySTRAND model [Read et al. Phys. Rev. Lett. 2020, 124, 147802]. The same model parameters also correctly capture the nucleus induction time in our simulations. All parameters of the model were fitted to a small subset of our data in which long chain enhancement was absent. We conclude that long-chain enrichment is central to the mechanism of flow-induced nucleation and that this enrichment must be captured to correctly predict the nucleation rate.

Venous thromboembolism in children with central nervous system tumors: Comparison of an institutional cohort to a national administrative database.

BACKGROUND: Central nervous system (CNS) tumors are the second most common malignancy of childhood, and published data on venous thromboembolism (VTE) rate and risk factors for these patients are outdated or incomplete. Here, we determine the cumulative incidence and risk factors for VTE in this population. PROCEDURE: VTE diagnosis and associated clinical risk factors were abstracted and analyzed for two cohorts of children (0-21 years) diagnosed with CNS tumors between January 1, 2010 to September 30, 2018. The first study was a retrospective single institution cohort study. The initial observations were confirmed across multiple pediatric hospitals using the Pediatric Health Information System (PHIS) administrative database. RESULTS: The single-institution cohort included 338 patients aged 3 days to 20.9 years (median age, 8.6 years); VTE developed in eight (2.4%) patients. The PHIS cohort included 17 634 patients aged from 0 to 21.9 years (median: 9.5 years); VTE developed in 354 (2.0%) patients. Univariate analysis for the single-institution cohort identified central venous catheter (CVC) placement as a risk factor for VTE (odds ratio [OR] 8.40, 95% confidence interval [CI] 1.43-49.41, P = .0186). Multivariable analysis of the PHIS dataset identified CVC placement (OR 1.97, 95% CI 1.57-2.46; P < .0001), obesity (OR 2.96, 95% CI 1.21-7.26; P = .0177), and more than one hospital admission (OR 3.54, 95% CI 2.69-4.64; P < .0001) as significant predictors of VTE. VTE diagnosis was not associated with increased mortality in either cohort. CONCLUSIONS: The VTE rate in children with CNS tumors is low (2%). CVC placement was identified as a modifiable risk factor in both cohorts.

Multi-institutional analysis of treatment modalities in basal ganglia and thalamic germinoma.

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of nonmetastatic BGTGs, the 5- and 10-year event-free survivals (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survivals (OS) were 100% and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980-2400); WBI: 2340 cGy/cGy(RBE) (1800-3000); WVI: 2340 cGy/cGy(RBE) (1800-2550); focal: 3600 cGy (3060-5400). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p = .84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p = .0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

Pediatric Gliosarcoma With and Without Neurofibromatosis Type 1: A Whole-exome Comparison of 2 Patients.

Gliosarcoma is rare among pediatric patients and among individuals with Neurofibromatosis Type 1 (NF1). Here we compare 2 pediatric gliosarcoma patients, one of whom has NF1. We performed whole-exome sequencing, methylation, and copy number analysis on tumor and blood for both patients. Whole-exome sequencing showed higher mutational burden in the tumor of the patient without NF1. Copy number analysis showed differences in chromosomal losses/gains between the tumors. Neither tumor showed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The NF1 patient survived without progression while the other expired. This is the first reported case of gliosarcoma in a child with NF1.

Gaussian process models of potential energy surfaces with boundary optimization.

A strategy is outlined to reduce the number of training points required to model intermolecular potentials using Gaussian processes, without reducing accuracy. An asymptotic function is used at a long range, and the crossover distance between this model and the Gaussian process is learnt from the training data. The results are presented for different implementations of this procedure, known as boundary optimization, across the following dimer systems: CO-Ne, HF-Ne, HF-Na+, CO2-Ne, and (CO2)2. The technique reduces the number of training points, at fixed accuracy, by up to ∼49%, compared to our previous work based on a sequential learning technique. The approach is readily transferable to other statistical methods of prediction or modeling problems.

PolySTRAND Model of Flow-Induced Nucleation in Polymers.

We develop a thermodynamic continuum-level model, polySTRAND, for flow-induced nucleation in polymers suitable for use in computational process modeling. The model's molecular origins ensure that it accounts properly for flow and nucleation dynamics of polydisperse systems and can be extended to include effects of exhaustion of highly deformed chains and nucleus roughness. It captures variations with the key processing parameters, flow rate, temperature, and molecular weight distribution. Under strong flow, long chains are over-represented within the nucleus, leading to superexponential nucleation rate growth with shear rate as seen in experiments.

Development of a structured process for fair allocation of critical care resources in the setting of insufficient capacity: a discussion paper.

Early in the COVID-19 pandemic there was widespread concern that healthcare systems would be overwhelmed, and specifically, that there would be insufficient critical care capacity in terms of beds, ventilators or staff to care for patients. In the UK, this was avoided by a threefold approach involving widespread, rapid expansion of critical care capacity, reduction of healthcare demand from non-COVID-19 sources by temporarily pausing much of normal healthcare delivery, and by governmental and societal responses that reduced demand through national lockdown. Despite high-level documents designed to help manage limited critical care capacity, none provided sufficient operational direction to enable use at the bedside in situations requiring triage. We present and describe the development of a structured process for fair allocation of critical care resources in the setting of insufficient capacity. The document combines a wide variety of factors known to impact on outcome from critical illness, integrated with broad-based clinical judgement to enable structured, explicit, transparent decision-making founded on robust ethical principles. It aims to improve communication and allocate resources fairly, while avoiding triage decisions based on a single disease, comorbidity, patient age or degree of frailty. It is designed to support and document decision-making. The document has not been needed to date, nor adopted as hospital policy. However, as the pandemic evolves, the resumption of necessary non-COVID-19 healthcare and economic activity mean capacity issues and the potential need for triage may yet return. The document is presented as a starting point for stakeholder feedback and discussion.

Predictors of effective management of acute pain in children within a UK ambulance service: A cross-sectional study.

OBJECTIVE: We aimed to identify predictors of effective management of acute pain in children in the pre-hospital setting. METHODS: A retrospective cross-sectional study using electronic clinical records from one large UK ambulance service during 01-Oct-2017 to 30-Sep-2018 was performed using multivariable logistic regression. We included all children <18 years suffering acute pain. Children with a Glasgow Coma Scale score of <15, no documented pain or without a second pain score were excluded. The outcome measure was effective pain management (abolition or reduction of pain by ≥2 out of 10 using the numeric pain rating scale, Wong-Baker FACES® scale or FLACC [face, legs, activity, crying and consolability] scale). RESULTS: 2312 patients were included for analysis. Median (IQR) age was 13 (9-16), 54% were male and the cause of pain was trauma in 66% of cases. Predictors of effective pain management include children who were younger (0-5 years) compared to older (12-17 years) (adjusted odds ratio [AOR] 1.53; 95% confidence interval [CI] 1.18-1.97), administered analgesia (AOR 2.26; CI 1.87-2.73), attended by a paramedic (AOR 1.46; CI 1.19-1.79) or living in an area of low deprivation (index of multiple deprivation [IMD] 8-10) compared to children in an area of high deprivation (IMD 1-3) (AOR 1.37; CI 1.04-1.80). Child sex, type of pain, transport time, non-pharmacological treatments and clinician experience were not significant. CONCLUSION: These predictors highlight disparity in effective pre-hospital management of acute pain in children. Qualitative research is needed to help explain these findings.

Molecular dynamics simulations of crystal nucleation in entangled polymer melts under start-up shear conditions.

Understanding the flow induced crystallisation process is necessary due to its technological relevance to polymer processing. Polymer crystallisation controls the morphology of semi-crystalline polymers and hence the properties of the end product. We perform molecular dynamics simulations of polymer melts consisting of sufficiently entangled linear chains under shear flow. We determine the Rouse relaxation time (τR) for linear polymer chains using an established rheological model at different temperatures and fit the simulation data with the Arrhenius and Williams-Landel-Ferry equations. We simulate the crystallisation induction times for different values of the Rouse-Weissenberg number (WiR=γ̇τR) at different temperatures. We observe that the level of strain and stretch required to induce crystallisation increases with temperature. We find that the induction times follow a power law in shear rate and observe a more pronounced effect of flow rate for higher temperatures than at lower temperatures. Moreover, we determine that nucleation events occur relatively early in the shear transient and at a stretch value that is smaller than its steady state value. We also report the values of strain at which the occurrence of a nucleation event is most likely to happen.

Active learning in Gaussian process interpolation of potential energy surfaces.

Three active learning schemes are used to generate training data for Gaussian process interpolation of intermolecular potential energy surfaces. These schemes aim to achieve the lowest predictive error using the fewest points and therefore act as an alternative to the status quo methods involving grid-based sampling or space-filling designs like Latin hypercubes (LHC). Results are presented for three molecular systems: CO2-Ne, CO2-H2, and Ar3. For each system, two of the active learning schemes proposed notably outperform LHC designs of comparable size, and in two of the systems, produce an error value an order of magnitude lower than the one produced by the LHC method. The procedures can be used to select a subset of points from a large pre-existing data set, to select points to generate data de novo, or to supplement an existing data set to improve accuracy.

Learning Through Chain Event Graphs: The Role of Maternal Factors in Childhood Type 1 Diabetes.

Chain event graphs (CEGs) are a graphical representation of a statistical model derived from event trees. They have previously been applied to cohort studies but not to case-control studies. In this paper, we apply the CEG framework to a Yorkshire, United Kingdom, case-control study of childhood type 1 diabetes (1993-1994) in order to examine 4 exposure variables associated with the mother, 3 of which are fully observed (her school-leaving-age, amniocenteses during pregnancy, and delivery type) and 1 with missing values (her rhesus factor), while incorporating previous type 1 diabetes knowledge. We conclude that the unknown rhesus factor values were likely to be missing not at random and were mainly rhesus-positive. The mother's school-leaving-age and rhesus factor were not associated with the diabetes status of the child, whereas having at least 1 amniocentesis procedure and, to a lesser extent, birth by cesarean delivery were associated; the combination of both procedures further increased the probability of diabetes. This application of CEGs to case-control data allows for the inclusion of missing data and prior knowledge, while investigating associations in the data. Communication of the analysis with the clinical expert is more straightforward than with traditional modeling, and this approach can be applied retrospectively or when assumptions for traditional analyses are not held.

A survey of renal impairment pharmacokinetic studies for new oncology drug approvals in the USA from 2010 to early 2015: a focus on development strategies and future directions.

The US Food and Drug Administration (FDA) issued a guidance document in 2010 on pharmacokinetic (PK) studies in renal impairment (RI) on the basis of observations that substances such as uremic toxins might result in altered drug metabolism and excretion. No specific recommendations for oncology drugs were included. We surveyed the publicly available FDA review documents of 29 small molecule oncology drugs approved between 2010 and the first quarter of 2015. The objectives were as follows: (i) summarize the impact of RI on PK at the time of the initial new drug application; (ii) identify limitations of the guidance; and (iii) outline an integrated approach to study the impact of RI on these drugs. Our survey indicates that the current FDA guidance does not appear to provide clear strategic or decision pathways for RI studies in terms of small molecule oncology drugs. The FDA review documents indicate an individualized approach to the review because of the complex pharmacologic nature of these drugs and patient populations. Overall, the strategy for carrying out a RI study during clinical development or as a postmarketing study requires integration with the totality of data, including mass balance, absolute bioavailability, drug-drug interaction, hepatic dysfunction, population PK, exposure-response analysis, the therapeutic window for best guidance, and determination of the optimal doses for special oncology populations.