The Influence of the Extracorporeal Membrane Oxygenation Circuit and Components on Anticoagulation Management: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding the influence of extracorporeal membrane oxygenation (ECMO) circuit components on anticoagulation practices for pediatric ECMO for the Pediatric ECMO Anticoagulation CollaborativE. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Management of ECMO anticoagulation in the setting of different ECMO circuit components. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Twenty-nine references were used for data extraction and informed recommendations, evidence-based consensus statements, and good practice statements. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements or good practice statements for the influence of ECMO circuit and components on anticoagulation management. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. One good practice statement, 2 weak recommendations, and 2 consensus statements are presented. CONCLUSIONS: The incorporation of new component technologies into clinical practice has outpaced clinical investigations of anticoagulation strategies for pediatric ECMO. Future investigations should leverage academic and industrial collaborations, translational platforms, and modern biostatistical methods to improve patient outcomes.

Scale matters: Large language models with billions (rather than millions) of parameters better match neural representations of natural language.

Recent research has used large language models (LLMs) to study the neural basis of naturalistic language processing in the human brain. LLMs have rapidly grown in complexity, leading to improved language processing capabilities. However, neuroscience researchers haven't kept up with the quick progress in LLM development. Here, we utilized several families of transformer-based LLMs to investigate the relationship between model size and their ability to capture linguistic information in the human brain. Crucially, a subset of LLMs were trained on a fixed training set, enabling us to dissociate model size from architecture and training set size. We used electrocorticography (ECoG) to measure neural activity in epilepsy patients while they listened to a 30-minute naturalistic audio story. We fit electrode-wise encoding models using contextual embeddings extracted from each hidden layer of the LLMs to predict word-level neural signals. In line with prior work, we found that larger LLMs better capture the structure of natural language and better predict neural activity. We also found a log-linear relationship where the encoding performance peaks in relatively earlier layers as model size increases. We also observed variations in the best-performing layer across different brain regions, corresponding to an organized language processing hierarchy.

Biosocial determinants inform on enduring cancer disparities.

Social, environmental, and biological risk factors influence exposures to newly termed 'biosocial determinants of health'. As molecular factors that lie at the intersection between lived experiences and individual biology, biosocial determinants may inform on the enduring complexity of cancer disparity across transdisciplinary studies.

Cost-effectiveness of craniotomy versus decompressive craniectomy for UK patients with traumatic acute subdural haematoma.

OBJECTIVE: To estimate the cost-effectiveness of craniotomy, compared with decompressive craniectomy (DC) in UK patients undergoing evacuation of acute subdural haematoma (ASDH). DESIGN: Economic evaluation undertaken using health resource use and outcome data from the 12-month multicentre, pragmatic, parallel-group, randomised, Randomised Evaluation of Surgery with Craniectomy for Patients Undergoing Evacuation-ASDH trial. SETTING: UK secondary care. PARTICIPANTS: 248 UK patients undergoing surgery for traumatic ASDH were randomised to craniotomy (N=126) or DC (N=122). INTERVENTIONS: Surgical evacuation via craniotomy (bone flap replaced) or DC (bone flap left out with a view to replace later: cranioplasty surgery). MAIN OUTCOME MEASURES: In the base-case analysis, costs were estimated from a National Health Service and Personal Social Services perspective. Outcomes were assessed via the quality-adjusted life-years (QALY) derived from the EuroQoL 5-Dimension 5-Level questionnaire (cost-utility analysis) and the Extended Glasgow Outcome Scale (GOSE) (cost-effectiveness analysis). Multiple imputation and regression analyses were conducted to estimate the mean incremental cost and effect of craniotomy compared with DC. The most cost-effective option was selected, irrespective of the level of statistical significance as is argued by economists. RESULTS: In the cost-utility analysis, the mean incremental cost of craniotomy compared with DC was estimated to be -£5520 (95% CI -£18 060 to £7020) with a mean QALY gain of 0.093 (95% CI 0.029 to 0.156). In the cost-effectiveness analysis, the mean incremental cost was estimated to be -£4536 (95% CI -£17 374 to £8301) with an OR of 1.682 (95% CI 0.995 to 2.842) for a favourable outcome on the GOSE. CONCLUSIONS: In a UK population with traumatic ASDH, craniotomy was estimated to be cost-effective compared with DC: craniotomy was estimated to have a lower mean cost, higher mean QALY gain and higher probability of a more favourable outcome on the GOSE (though not all estimated differences between the two approaches were statistically significant). ETHICS: Ethical approval for the trial was obtained from the North West-Haydock Research Ethics Committee in the UK on 17 July 2014 (14/NW/1076). TRIAL REGISTRATION NUMBER: ISRCTN87370545.

Supporting self-management of low back pain with an internet intervention with and without telephone support in primary care (SupportBack 2): a randomised controlled trial of clinical and cost-effectiveness.

BACKGROUND: Low back pain is prevalent and a leading cause of disability. We aimed to determine the clinical and cost-effectiveness of an accessible, scalable internet intervention for supporting behavioural self-management (SupportBack). METHODS: Participants in UK primary care with low back pain without serious spinal pathology were randomly assigned 1:1:1 using computer algorithms stratified by disability level and telephone-support centre to usual care, usual care and SupportBack, or usual care and SupportBack with physiotherapist telephone-support (three brief calls). The primary outcome was low back pain-related disability (Roland Morris Disability Questionnaire [RMDQ] score) at 6 weeks, 3 months, 6 months, and 12 months using a repeated measures model, analysed by intention to treat using 97·5% CIs. A parallel economic evaluation from a health services perspective was used to estimate cost-effectiveness. People with lived experience of low back pain were involved in this trial from the outset. This completed trial was registered with ISRCTN, ISRCTN14736486. FINDINGS: Between Nov 29, 2018, and Jan 12, 2021, 825 participants were randomly assigned (274 to usual care, 275 to SupportBack only, 276 to SupportBack with telephone-support). Participants had a mean age of 54 (SD 15), 479 (58%) of 821 were women and 342 (42%) were men, and 591 (92%) of 641 were White. Follow-up rates were 687 (83%) at 6 weeks, 598 (73%) at 3 months, 589 (72%) at 6 months, and 652 (79%) at 12 months. For the primary analysis, 736 participants were analysed (249 usual care, 245 SupportBack, and 242 SupportBack with telephone support). At a significance level of 0·025, there was no difference in RMDQ over 12 months with SupportBack versus usual care (adjusted mean difference -0·5 [97·5% CI -1·2 to 0·2]; p=0·085) or SupportBack with telephone-support versus usual care (-0·6 [-1·2 to 0·1]; p=0·048). There were no treatment-related serious adverse events. The economic evaluation showed that the SupportBack group dominated usual care, being both more effective and less costly. Both interventions were likely to be cost-effective at a threshold of £20 000 per quality adjusted life year compared with usual care. INTERPRETATION: The SupportBack internet interventions did not significantly reduce low back pain-related disability over 12 months compared with usual care. They were likely to be cost-effective and safe. Clinical effectiveness, cost-effectiveness, and safety should be considered together when determining whether to apply these interventions in clinical practice. FUNDING: National Institute for Health and Care Research Health Technology Assessment (16/111/78).

Implementing Entrustable Professional Activities in Pediatric Fellowships: Facilitating the Process.

BACKGROUND AND OBJECTIVES: Entrustable professional activities (EPAs) will be used for initial certification by the American Board of Pediatrics by 2028. Less than half of pediatric fellowships currently use EPAs for assessment, yet all will need to adopt them. Our objectives were to identify facilitators and barriers to the implementation of EPAs to assess pediatric fellows and to determine fellowship program directors' (FPD) perceptions of EPAs and Milestones. METHODS: We conducted a survey of FPDs from 15 pediatric subspecialties. EPA users were asked about their implementation of EPAs, barriers encountered, and perceptions of EPAs. Nonusers were queried about deterrents to using EPAs. Both groups were asked about potential facilitators of implementation and their perceptions of Milestones. RESULTS: The response rate was 65% (575/883). Of these, 344 (59.8%) were EPA users and 231 (40.2%) were nonusers. Both groups indicated work burden as a barrier to implementation. Nonusers reported more barriers than users (mean [SD]: 7 [3.8] vs 5.8 [3.4], P < .001). Both groups identified training materials and premade assessment forms as facilitators to implementation. Users felt that EPAs were easier to understand than Milestones (89%) and better reflected what it meant to be a practicing subspecialty physician (90%). In contrast, nonusers felt that Milestones were easy to understand (57%) and reflected what it meant to be a practicing subspecialist (58%). CONCLUSIONS: Implementing EPA-based assessment will require a substantial investment by FPDs, facilitated by guidance and easily accessible resources provided by multiple organizations. Perceived barriers to be addressed include FPD time constraints, a need for additional assessment tools, and outcomes data.

Population pharmacokinetics and CD20 binding dynamics for mosunetuzumab in relapsed/refractory B-cell non-Hodgkin lymphoma.

Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step-up dose regimen of 1/2/60/30 mg IV is designed to mitigate cytokine release syndrome (CRS) and maximize efficacy in early cycles. A population pharmacokinetic (popPK) model was developed from 439 patients with relapsed/refractory B-Cell Non-Hodgkin lymphoma receiving Mosun IV monotherapy, including fixed dosing (0.05-2.8 mg IV every 3 weeks (q3w)) and Cycle 1 step-up dosing groups (0.4/1/2.8-1/2/60/30 mg IV q3w). Prior to Mosun treatment, ~50% of patients had residual levels of anti-CD20 drugs (e.g., rituximab or obinutuzumab) from prior treatment. CD20 receptor binding dynamics and rituximab/obinutuzumab PK were incorporated into the model to calculate the Mosun CD20 receptor occupancy percentage (RO%) over time. A two-compartment model with time-dependent clearance (CL) best described the data. The typical patient had an initial CL of 1.08 L/day, transitioning to a steady-state CL of 0.584 L/day. Statistically relevant covariates on PK parameters included body weight, albumin, sex, tumor burden, and baseline anti-CD20 drug concentration; no covariate was found to have a clinically relevant impact on exposure at the approved dose. Mosun CD20 RO% was highly variable, attributed to the large variability in residual baseline anti-CD20 drug concentration (median = 10 µg/mL). The 60 mg loading doses increased Mosun CD20 RO% in Cycle 1, providing efficacious exposures in the presence of the competing anti-CD20 drugs. PopPK model simulations, investigating Mosun dose delays, informed treatment resumption protocols to ensure CRS mitigation.

Regulation by the RNA-binding protein Unkempt at its effector interface.

How RNA-binding proteins (RBPs) convey regulatory instructions to the core effectors of RNA processing is unclear. Here, we document the existence and functions of a multivalent RBP-effector interface. We show that the effector interface of a conserved RBP with an essential role in metazoan development, Unkempt, is mediated by a novel type of 'dual-purpose' peptide motifs that can contact two different surfaces of interacting proteins. Unexpectedly, we find that the multivalent contacts do not merely serve effector recruitment but are required for the accuracy of RNA recognition by Unkempt. Systems analyses reveal that multivalent RBP-effector contacts can repurpose the principal activity of an effector for a different function, as we demonstrate for the reuse of the central eukaryotic mRNA decay factor CCR4-NOT in translational control. Our study establishes the molecular assembly and functional principles of an RBP-effector interface.

Level of Supervision for the Entrustable Professional Activities Common to General Pediatrics and the Subspecialties Decreases from Residency to Fellowship.

OBJECTIVES: To compare level of supervision (LOS) ratings of graduating pediatric residents with their assessments as fellows for the five Entrustable Professional Activities (EPAs) common to general pediatrics and the subspecialties and to determine if the difference between ratings from residency to fellowship is less for the QI and Practice Management EPAs, since the skills needed to perform these may be less context-dependent. METHODS: We compared ratings of graduating residents with their assessments as fellows using LOS data from two sequential EPA studies. RESULTS: There were 65 ratings from 41 residents at the first fellow assessment. At graduation, most residents needed little to no supervision for all EPAs with 94% (61/65) of ratings level four or five. In contrast, only 5/65 (8%) of the first fellow assessments were level four or five. The ratings difference for the QI and Practice Management EPAs was similar to the others. CONCLUSIONS: LOS ratings for the EPAs common to generalists and subspecialists reset as residents become fellows. There was no evidence that the QI and Practice Management EPAs are less context-dependent. This study provides additional validity evidence for using these LOS scales to assess trainees in pediatric residency and fellowship.

1.55 µm wavelength band photonic crystal surface emitting laser with n-side photonic crystal and operation at up to 85 °C.

We describe the structure, fabrication, and measured performance of a 1543 nm wavelength photonic crystal surface emitting laser. An asymmetric double lattice design was used to achieve single mode lasing with side mode suppression ratios >40 dB. The photonic crystal was formed using encapsulated air holes in an n-doped InGaAsP layer with an InGaAlAs active layer then grown above it. In this way a laser with a low series resistance of 0.32 Ω capable of pulsed output powers of 171 mW at 25 °C and 40 mW at 85 °C was demonstrated.

Developing a core outcome set for evaluating medication adherence interventions for adults prescribed long-term medication in primary care.

BACKGROUND: Approximately half of people prescribed medications do not take them as prescribed. There is a significant unmet need regarding the barriers to medication adherence not being addressed in primary care. There is no agreement on which outcomes should be measured and reported in trials of medication adherence interventions. OBJECTIVE: To develop a core outcome set (COS) for trials of medication adherence interventions in primary care for adults prescribed medications for long-term health conditions. METHODS: A list of potentially relevant outcomes from the literature was developed. Using a two-round Delphi survey of stakeholder groups representing patients and their carers; primary care staff; and academic researchers with an interest in medication adherence; each outcome was scored in terms of importance for determining the effectiveness of medication adherence interventions in primary care. This was followed by two consensus workshops, where importance, as well as feasibility and acceptability of measurement, were considered in order to finalise the COS. RESULTS: One hundred and fifty people took part in Delphi Round 1 and 101 took part in Round 2. Eight people attended the workshops (four attendees per workshop). Seven outcomes were identified as most important, feasible and acceptable to collect in medication adherence trials: Health-related quality of life, number of doses taken, persistence with medicines, starting (initiating) a medicine, relevance of the medication adherence intervention for an individual, mortality, and adverse medicine events. CONCLUSIONS: This COS represents the minimum outcomes that should be collected and reported in all medication adherence trials undertaken in primary care. When developing and finalizing the COS, feasibility and acceptability of collection of outcomes has been considered. In addition to the COS, medication adherence trials can choose to include outcomes to suit their specific context such as the health condition associated with their medication adherence intervention.

A Study on Auto-Catalysis and Product Inhibition: A Nucleophilic Aromatic Substitution Reaction Catalysed within the Cavity of an Octanuclear Coordination Cage.

The ability of an octanuclear cubic coordination cage to catalyse a nucleophilic aromatic substitution reaction on a cavity-bound guest was studied with 2,4-dinitrofluorobenzene (DNFB) as the guest/substrate. It was found that DNFB undergoes a catalysed reaction with hydroxide ions within the cavity of the cubic cage (in aqueous buffer solution, pH 8.6). The rate enhancement of kcat/kuncat was determined to be 22, with cavity binding of the guest being required for catalysis to occur. The product, 2,4-dinitrophenolate (DNP), remained bound within the cavity due to electrostatic stabilisation and exerts two apparently contradictory effects: it initially auto-catalyses the reaction when present at low concentrations, but at higher concentrations inhibits catalysis when a pair of DNP guests block the cavity. When encapsulated, the UV/Vis absorption spectrum of DNP is red-shifted when compared to the spectrum of free DNP in aqueous solution. Further investigations using other aromatic guests determined that a similar red-shift on cavity binding also occurred for 4-nitrophenolate (4NP) at pH 8.6. The red-shift was used to determine the stoichiometry of guest binding of DNP and 4NP within the cage cavity, which was confirmed by structural analysis with X-ray crystallography; and was also used to perform catalytic kinetic studies in the solution-state.

A Top-Down Proteomic Assay to Evaluate KRAS4B-Compound Engagement.

Development of new targeted inhibitors for oncogenic KRAS mutants may benefit from insight into how a given mutation influences the accessibility of protein residues and how compounds interact with mutant or wild-type KRAS proteins. Targeted proteomic analysis, a key validation step in the KRAS inhibitor development process, typically involves both intact mass- and peptide-based methods to confirm compound localization or quantify binding. However, these methods may not always provide a clear picture of the compound binding affinity for KRAS, how specific the compound is to the target KRAS residue, and how experimental conditions may impact these factors. To address this, we have developed a novel top-down proteomic assay to evaluate in vitro KRAS4B-compound engagement while assessing relative quantitation in parallel. We present two applications to demonstrate the capabilities of our assay: maleimide-biotin labeling of a KRAS4BG12D cysteine mutant panel and treatment of three KRAS4B proteins (WT, G12C, and G13C) with small molecule compounds. Our results show the time- or concentration-dependence of KRAS4B-compound engagement in context of the intact protein molecule while directly mapping the compound binding site.

Analysis of fellowship program director opinions of entrustable professional activities in adolescent medicine fellowship.

OBJECTIVES: This study aimed to explore the minimum entrustable professional activity (EPA) supervision levels at which pediatric fellowship program directors (FPDs) would be willing to graduate fellows and the levels deemed necessary for safe and effective practice for each of the common pediatric subspecialty and the four adolescent medicine-specific EPAs. METHODS: This cross-sectional study utilized survey data from pediatric FPDs in 2017. FPDs indicated the minimum level of supervision (LOS) for fellows at graduation and for safe and effective practice. RESULTS: 82 percent (23/28) of adolescent medicine FPDs completed the survey. For each EPA, there were differences (p<0.05) between LOS expected for graduation and for safe and effective practice. There was also variability in the level at which FPDs would graduate fellows. CONCLUSIONS: This study summarizes pediatric FPD opinions regarding the minimum levels of supervision required for fellows at the time of graduation as well as the levels deemed necessary for safe and effective practice. The difference between the minimum LOS at which FPDs would graduate a fellow and that deemed appropriate for safe and effective practice, along with variability in minimum LOS for graduation, highlight the need for clearer standards for fellowship graduation as well as more structured early career support for ongoing learning. These data highlight variability in FPD opinion regarding such expectations and both the need to better define desired training outcomes and potential need for post-graduation supervision in clinical practice.

Optically Transparent Lead Halide Perovskite Polycrystalline Ceramics.

We utilize room-temperature uniaxial pressing at applied loads achievable with low-cost, laboratory-scale presses to fabricate freestanding CH3NH3PbX3 (X- = Br-, Cl-) polycrystalline ceramics with millimeter thicknesses and optical transparency up to ∼70% in the infrared. As-fabricated perovskite ceramics can be produced with desirable form factors (i.e., size, shape, and thickness) and high-quality surfaces without any postprocessing (e.g., cutting or polishing). This method should be broadly applicable to a large swath of metal halide perovskites, not just the compositions shown here. In addition to fabrication, we analyze microstructure-optical property relationships through detailed experiments (e.g., transmission measurements, electron microscopy, X-ray tomography, optical profilometry, etc.) as well as modeling based on Mie theory. The optical, electrical, and mechanical properties of perovskite polycrystalline ceramics are benchmarked against those of single-crystalline analogues through spectroscopic ellipsometry, Hall measurements, and nanoindentation. Finally, γ-ray scintillation from a transparent MAPbBr3 ceramic is demonstrated under irradiation from a 137Cs source. From a broader perspective, scalable methods to produce freestanding polycrystalline lead halide perovskites with comparable properties to their single-crystal counterparts could enable key advancements in the commercial production of perovskite-based technologies (e.g., direct X-ray/γ-ray detectors, scintillators, and nonlinear optics).

Stabilization of Lantern-Type Metal-Organic Cages (MOCs) by Protective Control of Ligand Exchange Rates.

Self-assembling systems in nature display remarkable complexity with assemblies of different sub-units to generate functional species. Synthetic analogues of such systems are a challenge, often requiring the ability to bias distributions that are under thermodynamic assembly control. Using lantern-type MOCs (metal-organic cages) as a prototypical self-assembling system, herein we explore the role that steric bulk plays in controlling the exchange rate of ligands in paddlewheel-based assemblies, and thus the stability of cages, in competitive self-assembling scenarios. The effective lifetime of the lantern-type MOCs varies over an order of magnitude depending on the steric bulk proximal to the metal nodes with lifetimes of the cages ranging from tens of minutes to several hours. The bulk of the coordinating solvents likewise reduces the rate of ligand exchange, and thus yields longer-lived species. Understanding this subtle effect has implications for controlling the stability of complex assemblies in competitive environments with implications for guest release and application.

Amine-Based MOF for Precious Metal Remediation.

Due to the continuous growth rate of the electronic industry, hi-tech companies depend on mining and extracting precious metals to meet the public demand. The high turnover of modern devices generates an alarming amount of electronic waste (e-waste), which contains more precious metals than mined ores and therefore needs efficient recovery procedures. A highly stable homopiperazine-derived Cd-MOF, poly-[Cd(H2L)]·9H2O, with a protonated amine ligand core, exists as a twofold interpenetrated 3D framework with 1D channels into which the N+-H bond is directed. The geometry of these channels appears to be suitable to host square planar metalate complexes. Under acidic conditions, [MCl4]x- anions containing Au, Cu, Ni, and Pt, representing common components of e-waste under extraction conditions, were tested for capture and recovery. Cd-MOF exhibits remarkable selectivity and uptake performance toward Au with an adsorbent capacity of 25 mg g-1ads and shows a marked selectivity for Au over Cu in competitive experiments. The adsorption mechanism of Au appears to be predominantly physical adsorption at the surface of the material.

Exploring Factors for Implementation of EPAs in Pediatric Subspecialty Fellowships: A Qualitative Study of Program Directors.

OBJECTIVE: To understand fellowship program directors' (FPDs) perspectives on facilitators and barriers to using entrustable professional activities (EPAs) in pediatric subspecialty training. METHODS: We performed a qualitative study of FPDs, balancing subspecialty, program size, geographic region and current uses of EPAs. A study coordinator conducted 1-on-1 interviews using a semistructured approach to explore EPA use or nonuse and factors supporting or preventing their use. Investigators independently coded transcribed interviews using an inductive approach and the constant comparative method. Group discussion informed code structure development and refinement. Iterative data collection and analysis continued until theoretical sufficiency was achieved, yielding a thematic analysis. RESULTS: Twenty-eight FPDs representing 11 pediatric subspecialties were interviewed, of whom 16 (57%) reported current EPA use. Five major themes emerged: (1) facilitators including the intuitive nature and simple wording of EPAs; (2) barriers such as workload burden and lack of a regulatory requirement; (2) variable knowledge and training surrounding EPAs, leading to differing levels of understanding; (3) limited current use of EPAs, even among self-reported users; and (4) complementary nature of EPAs and milestones. FPDs acknowledged the differing strengths of both EPAs and milestones but sought additional knowledge about the value added by EPAs for assessing trainees, including the impact on outcomes. CONCLUSIONS: Identified themes can inform effective and meaningful EPA implementation strategies: Supporting and educating FPDs, ongoing assessment of the value of EPAs in training, and practical integration with current workflow. Generating additional data and engaging stakeholders is critical for successful implementation for the pediatric subspecialties.