Selection, engineering, and in vivo testing of a human leukocyte antigen-independent T-cell receptor recognizing human mesothelin.

BACKGROUND: Canonical α/ß T-cell receptors (TCRs) bind to human leukocyte antigen (HLA) displaying antigenic peptides to elicit T cell-mediated cytotoxicity. TCR-engineered T-cell immunotherapies targeting cancer-specific peptide-HLA complexes (pHLA) are generating exciting clinical responses, but owing to HLA restriction they are only able to target a subset of antigen-positive patients. More recently, evidence has been published indicating that naturally occurring α/ß TCRs can target cell surface proteins other than pHLA, which would address the challenges of HLA restriction. In this proof-of-concept study, we sought to identify and engineer so-called HLA-independent TCRs (HiTs) against the tumor-associated antigen mesothelin. METHODS: Using phage display, we identified a HiT that bound well to mesothelin, which when expressed in primary T cells, caused activation and cytotoxicity. We subsequently engineered this HiT to modulate the T-cell response to varying levels of mesothelin on the cell surface. RESULTS: The isolated HiT shows cytotoxic activity and demonstrates killing of both mesothelin-expressing cell lines and patient-derived xenograft models. Additionally, we demonstrated that HiT-transduced T cells do not require CD4 or CD8 co-receptors and, unlike a TCR fusion construct, are not inhibited by soluble mesothelin. Finally, we showed that HiT-transduced T cells are highly efficacious in vivo, completely eradicating xenografted human solid tumors. CONCLUSION: HiTs can be isolated from fully human TCR-displaying phage libraries against cell surface-expressed antigens. HiTs are able to fully activate primary T cells both in vivo and in vitro. HiTs may enable the efficacy seen with pHLA-targeting TCRs in solid tumors to be translated to cell surface antigens.

Solvent-Free and Cost-Efficient Fabrication of a High-Performance Nanocomposite Sensor for Recording of Electrophysiological Signals.

Carbon nanotube (CNT)-based nanocomposites have found applications in making sensors for various types of physiological sensing. However, the sensors' fabrication process is usually complex, multistep, and requires longtime mixing and hazardous solvents that can be harmful to the environment. Here, we report a flexible dry silver (Ag)/CNT/polydimethylsiloxane (PDMS) nanocomposite-based sensor made by a solvent-free, low-temperature, time-effective, and simple approach for electrophysiological recording. By mechanical compression and thermal treatment of Ag/CNT, a connected conductive network of the fillers was formed, after which the PDMS was added as a polymer matrix. The CNTs make a continuous network for electrons transport, endowing the nanocomposite with high electrical conductivity, mechanical strength, and durability. This process is solvent-free and does not require a high temperature or complex mixing procedure. The sensor shows high flexibility and good conductivity. High-quality electroencephalography (EEG) and electrooculography (EOG) were performed using fabricated dry sensors. Our results show that the Ag/CNT/PDMS sensor has comparable skin-sensor interface impedance with commercial Ag/AgCl-coated dry electrodes, better performance for noninvasive electrophysiological signal recording, and a higher signal-to-noise ratio (SNR) even after 8 months of storage. The SNR of electrophysiological signal recording was measured to be 26.83 dB for our developed sensors versus 25.23 dB for commercial Ag/AgCl-coated dry electrodes. Our process of compress-heating the functional fillers provides a universal approach to fabricate various types of nanocomposites with different nanofillers and desired electrical and mechanical properties.

A model for estimating peak skin dose in CT.

In interventional radiology patient care can be improved by accurately assessing peak skin dose (PSD) from procedures, as it is the main predictor for tissue-reactions such as erythema. Historically, high skin dose procedures performed in radiology departments were almost exclusively planar fluoroscopy. However, with the increase in use of technologies involving repeated or adjacent computed tomography (CT) such as CT fluoroscopy and multi-modality rooms, the peak skin dose delivered by CT needs to be considered. In this paper, a model to estimate the PSD delivered to a patient undergoing CT has been developed to assist in determining the overall PSD. This model relates the PSD to the device-reported CT Dose Index (CTDIvol) by accounting for a variety of CT technique and patient factors. It includes a novel method for estimating dose contributions as a function of patient or phantom size, scanner geometry, and physical measurement of lateral and depth-based beam profiles. Physical measurements of PSD using radiochromic film on several phantoms have been used to determine needed model parameters. The resulting fitted model was found to agree with measured data to a standard deviation of 5.1% for the data used to fit the model, and 6.8% for measurements that were not used for fitting the model. Two methods for adapting the model for specific scanners are provided, one based on local PSD measurements with radiochromic film and another using CTDIvol measurements. The model, when suitably adapted, can accurately assess individual patients' CT PSD. This information can be integrated with radiation exposure data from other modalities, such as planar fluoroscopy, to predict the overall risk of tissue reactions, allowing for more tailored patient care.

Outcomes of the EMDataResource Cryo-EM Ligand Modeling Challenge.

The EMDataResource Ligand Model Challenge aimed to assess the reliability and reproducibility of modeling ligands bound to protein and protein/nucleic-acid complexes in cryogenic electron microscopy (cryo-EM) maps determined at near-atomic (1.9-2.5 Å) resolution. Three published maps were selected as targets: E. coli beta-galactosidase with inhibitor, SARS-CoV-2 RNA-dependent RNA polymerase with covalently bound nucleotide analog, and SARS-CoV-2 ion channel ORF3a with bound lipid. Sixty-one models were submitted from 17 independent research groups, each with supporting workflow details. We found that (1) the quality of submitted ligand models and surrounding atoms varied, as judged by visual inspection and quantification of local map quality, model-to-map fit, geometry, energetics, and contact scores, and (2) a composite rather than a single score was needed to assess macromolecule+ligand model quality. These observations lead us to recommend best practices for assessing cryo-EM structures of liganded macromolecules reported at near-atomic resolution.

Oral medroxyprogesterone acetate for the use of ovulation suppression in in vitro fertilization: a cohort trial.

OBJECTIVE: To broadly assess the efficacy of medroxyprogesterone acetate (MPA) for ovulatory suppression during in vitro stimulation compared with gonadotropin-releasing hormone (GnRH) antagonist cycles. DESIGN: Cohort trial. SETTING: A single academic-affiliated private fertility practice. PATIENTS: Patients of all diagnoses aged 18-44 years undergoing autologous in vitro fertilization (IVF) for fertility treatment between 2020 and 2023. INTERVENTIONS: Comparison of MPA vs. antagonist IVF stimulation cycles. MAIN OUTCOME MEASURES: Rates of premature ovulation, oocyte and embryo yield, embryo quality, pregnancy rates, and logistical benefits. RESULTS: Prospective data was collected on 418 patients who underwent MPA protocol ovarian stimulation (MPA group), which was compared with 419 historical control gonadotropin hormone-releasing hormone antagonist cycles (control group). Age was similar between groups (35.6 ± 4.6 vs. 35.7 ± 4.8 years; P = .75). There were no cases of premature ovulation in the MPA group compared with a total of five cases in the control group (0% vs. 1.2%; risk ratio [RR] = 0.09; 95% confidence interval [CI], 0.01, 1.66). No differences were seen between number of oocytes retrieved (14.3 ± 10.2 vs. 14.3 ± 9.7; P = .83), blastocysts (4.9 ± 4.6 vs. 5.0 ± 4.6; P = .89), or euploid blastocysts (2.4 ± 2.6 vs. 2.2 ± 2.4; P = .18) in the MPA vs. control group respectively. Clinical pregnancy rate was similar between groups (70.4% vs. 64.2%; RR = 0.92; 95% CI, 0.72, 1.18). There was no difference in length of IVF stimulation or dose of stimulation medications. Patients in the MPA group saved an average of $491 ± $119 on medications, had an average of one less monitoring visit (4.4 ± 0.9 vs. 5.6 ± 1.1; P<.01), and 5.0 ± 1.2 less injections per cycle. When adjusting for age and ovarian reserve, protocol group (MPA vs. control) did not influence having an embryo available for transfer (76.6% vs. 73.4%; adjusted RR = 1.05; 95% CI, 0.94, 1.14). CONCLUSION: For ovulatory suppression during IVF cycles, MPA was effective at preventing ovulation while demonstrating similar cycle and reproductive outcomes, with the additional benefits of patient cost savings, increased convenience with decreased number of visits, and fewer injections.

Improving the mental health of farmers: what types of remote support are acceptable, feasible, and improve outcomes? A feasibility RCT.

BACKGROUND: The farming community have high rates of poor mental health, and are relatively 'hard to reach' with mental health services. The aim of this study was therefore to undertake a feasibility RCT, based on two mental health interventions. These were (1) CBT based 'Living Life to the Full for Farming Communities' (LLTTF-F; www.llttf.com ), and (2) a holistic social and emotional support service delivered by the Royal Scottish Agricultural Benevolent Institution (RSABI). The feasibility was supplemented by process evaluation. METHODS: This feasibility study aimed to recruit 40 individuals from the farming community who were experiencing a common health problem defined as a score of > = 8 on PHQ-9. A snowball approach was used to recruit interested individuals who had an association with farming. An initial telephone call screened for eligibility and obtained consent to randomisation to the two specified interventions, or to a thirdly group receiving a combination of both LLTTF-F and 'Social and emotional support'. Participants were permitted to override the randomised option if they expressed a strong preference before the interventions began. RESULTS: Thirty-two participants provided baseline and three-month data. All three interventions showed positive improvements on PHQ-9 scores as follows: the 'combined intervention' mean baseline score was 18.1 compared to 12.0 at 3-month follow-up (mean change 6.1). 'Social and emotional support' mean baseline score was 11.3 compared to 6.7 at 3-month follow-up (mean change 4.6). 'LLTTF-F CBT-based intervention only' mean baseline score was 11.8 compared to 4.5 at 3-month follow-up (mean change 7.3). The retention rate was 81% at three months. In a sub-group of the LLTTF-F CBT-based intervention online materials were supplemented by telephone guided support. This approach received very positive feedback. CONCLUSIONS: Recruitment from the farming community required intense effort, and good engagement can then be retained for at least three months. There is evidence that the interventions used were feasible, and tentative evidence that they had a demonstrable effect on mental wellbeing, with the LLTTFF providing the largest effect on PHQ-9 scores. Trial Registration Number ISRCTN27173711, submitted 25/08/2023, confirmed 22/092023.

Fast HPLC-based affinity method to determine capsid titer and full/empty ratio of adeno-associated viral vectors.

Recombinant adeno-associated viruses (rAAVs) are promising gene delivery vectors in the emerging field of in vivo gene therapies. To ensure their consistent quality during manufacturing and process development, multiple analytical techniques have been proposed for the characterization and quantification of rAAV capsids. Despite their indisputable capabilities for performing this task, current analytical methods are rather time-consuming, material intensive, complicated, and costly, restricting their suitability for process development in which time and sample throughput are severe constraints. To eliminate this bottleneck, we introduce here an affinity-based high-performance liquid chromatography method that allows the determination of the capsid titer and the full/empty ratio of rAAVs within less than 5 min. By packing the commercially available AAVX affinity resin into small analytical columns, the rAAV fraction of diverse serotypes can be isolated from process-related impurities and analyzed by UV and fluorescence detection. As demonstrated by both method qualification data and side-by-side comparison with AAV enzyme-linked immunosorbent assay results for rAAV8 samples as well as by experiments using additional rAAV2, rAAV8, and rAAV9 constructs, our approach showed good performance, indicating its potential as a fast, simple and efficient tool for supporting the development of rAAV gene therapies.

An outbreak of Salmonella Typhimurium associated with the consumption of raw liver at an Eid al-Adha celebration in Wales (UK), July 2021.

In July 2021, Public Health Wales received two notifications of salmonella gastroenteritis. Both cases has attended the same barbecue to celebrate Eid al-Adha, two days earlier. Additional cases attending the same barbecue were found and an outbreak investigation was initiated. The barbecue was attended by a North African community's social network. On same day, smaller lunches were held in three homes in the social network. Many people attended both a lunch and the barbecue. Cases were defined as someone with an epidemiological link to the barbecue and/or lunches with diarrhoea and/or vomiting with date of onset following these events. We undertook a cohort study of 36 people attending the barbecue and/or lunch, and a nested case-control study using Firth logistic regression. A communication campaign, sensitive towards different cultural practices, was developed in collaboration with the affected community. Consumption of a traditional raw liver dish, 'marrara', at the barbecue was the likely vehicle for infection (Firth logistic regression, aOR: 49.99, 95%CI 1.71-1461.54, p = 0.02). Meat and offal came from two local butchers (same supplier) and samples yielded identical whole genome sequences as cases. Future outbreak investigations should be relevant to the community affected by considering dishes beyond those found in routine questionnaires.

Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification.

Background: The introduction of magnetic resonance (MR)-guided radiation treatment planning has opened a new space for theranostic nanoparticles to reduce acute toxicity while improving local control. In this work, second-generation AGuIX® nanoparticles (AGuIX-Bi) are synthesized and validated. AGuIX-Bi are shown to maintain MR positive contrast while further amplifying the radiation dose by the replacement of some Gd3+ cations with higher Z Bi3+. These next-generation nanoparticles are based on the AGuIX® platform, which is currently being evaluated in multiple Phase II clinical trials in combination with radiotherapy. Methods: In this clinically scalable methodology, AGuIX® is used as an initial chelation platform to exchange Gd3+ for Bi3+. AGuIX-Bi nanoparticles are synthesized with three ratios of Gd/Bi, each maintaining MR contrast while further amplifying radiation dose relative to Bi3+. Safety, efficacy, and theranostic potential of the nanoparticles were evaluated in vitro and in vivo in a human non-small cell lung cancer model. Results: We demonstrated that increasing Bi3+ in the nanoparticles is associated with more DNA damage and improves in vivo efficacy with a statistically significant delay in tumor growth and 33% complete regression for the largest Bi/Gd ratio tested. The addition of Bi3+ by our synthetic method leads to nanoparticles that present slightly altered pharmacokinetics and lengthening of the period of high tumor accumulation with no observed evidence of toxicity. Conclusions: We confirmed the safety and enhanced efficacy of AGuIX-Bi with radiation therapy at the selected ratio of 30Gd/70Bi. These results provide crucial evidence towards patient translation.

Integrated therapist and online CBT for depression in primary care (INTERACT): study protocol for a multi-centre randomised controlled trial.

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for depression. Self-directed online CBT interventions have made CBT more accessible at a lower cost. However, adherence is often poor and, in the absence of therapist support, effects are modest and short-term. Delivering CBT online using instant messaging is clinically and cost-effective; however, most existing platforms are limited to instant messaging sessions, without the support of between-session "homework" activities. The INTERACT intervention integrates online CBT materials and 'high-intensity' therapist-led CBT, delivered remotely in real-time. The INTERACT trial will evaluate this novel integration in terms of clinical and cost-effectiveness, and acceptability to therapists and clients. METHODS: Pragmatic, two parallel-group multi-centre individually randomised controlled trial, with 434 patients recruited from primary care practices in Bristol, London and York. Participants with depression will be identified via General Practitioner record searches and direct referrals. INCLUSION CRITERIA: aged ≥ 18 years; score ≥ 14 on Beck Depression Inventory (BDI-II); meeting International Classification of Diseases (ICD-10) criteria for depression. EXCLUSION CRITERIA: alcohol or substance dependency in the past year; bipolar disorder; schizophrenia; psychosis; dementia; currently under psychiatric care for depression (including those referred but not yet seen); cannot complete questionnaires unaided or requires an interpreter; currently receiving CBT/other psychotherapy; received high-intensity CBT in the past four years; participating in another intervention trial; unwilling/unable to receive CBT via computer/laptop/smartphone. Eligible participants will be randomised to integrated CBT or usual care. Integrated CBT utilises the standard Beckian intervention for depression and comprises nine live therapist-led sessions, with (up to) a further three if clinically appropriate. The first session is 60-90 min via videocall, with subsequent 50-min sessions delivered online, using instant messaging. Participants allocated integrated CBT can access integrated online CBT resources (worksheets/information sheets/videos) within and between sessions. Outcome assessments at 3-, 6-, 9- and 12-month post-randomisation. The primary outcome is the Beck Depression Inventory (BDI-II) score at 6 months (as a continuous variable). A nested qualitative study and health economic evaluation will be conducted. DISCUSSION: If clinically and cost-effective, this model of integrated CBT could be introduced into existing psychological services, increasing access to, and equity of, CBT provision. TRIAL REGISTRATION: ISRCTN, ISRCTN13112900. Registered on 11/11/2020. Currently recruiting participants. Trial registration data are presented in Table 1.

Engaging the agricultural community in the development of mental health interventions: a qualitative research study.

BACKGROUND: Farmers and those involved in the wider agricultural industry have a high suicide rate. They are also a 'hard to reach' group who make less than average use of mental health services. There is therefore a need to understand how best to develop interventions that meet their needs. The aims of this study were to develop a deeper understanding of the farming context and target population and to engage farmers in the shaping of two potential mental health interventions that could be incorporated in a pilot RCT. METHODS: The study was informed throughout by a reference group, who assisted in co-production of the research materials. A snowball approach was used to recruit interested individuals who had an association with farming. Twenty one telephone interviews were undertaken and analysed using the six phases of thematic analysis proposed by Braun and Clarke. RESULTS: Key themes (and sub-themes shown in brackets) related to the study aims were: everyday life (work-life balance; isolation and loneliness); farm management (technology and social media; production, people management, learning and teaching; external pressures; livestock and farm production; financial aspects); demographics (effects of aging); engagement (appropriate wording when talking about mental health; recognising need for help; religion; normalising mental health issues; approaching the conversation); training (mental health training for supporters of the farming community; health & safety and the inclusion of mental health training); and personal stories and experiences, which was an emerging theme. CONCLUSIONS: Recruiting farmers into research studies is best done by meeting farmers where they are found, for example, farmers marts. Accessibility of content, tailoring to the farming community, and guided support are key to effective recruitment and retention.

The General Hopelessness Scale: Development of a measure of hopelessness for non-clinical samples.

Noting concerns about the non-clinical efficacy of the Beck Hopelessness Scale (BHS), specifically the instrument's ability to discriminate between lower levels of hopelessness, this paper describes the development of the General Hopelessness Scale (GHS) for use with general samples. Following a literature review an item pool assessing the breadth of the hopelessness construct domain was created. This was then placed in survey form and assessed within two independent studies. Study 1 (N = 305, 172 women, 133 men, Mage = 28.68) explored factorial structure, item performance, and convergent validity of the GHS in relation to standardised measures of self-esteem and trait hopelessness. In Study 2 (N = 326, 224 women, 102 men, Mage = 26.52), scrutiny of the GHS occurred using confirmatory factor analysis and invariance tests, alongside item performance and convergent validity analyses relative to measures of affect, optimism, and hope. Factor analysis (using minimum average partial correlations and exploratory factor analysis) within Study 1 revealed the existence of four dimensions (Negative Expectations, Hope, Social Comparison, and Futility), which met Rasch model assumptions (i.e., good item/person fit and item/person reliability). Further psychometric assessment within Study 2 found satisfactory model fit and gender invariance. Convergent validity testing revealed moderate to large associations between the GHS and theoretically relevant variables (self-esteem, trait hopelessness, affect, optimism, and hope) across Study 1 and 2. Further examination of performance (reliability and ceiling and floor effects) within Study 1 and 2 demonstrated that the GHS was a satisfactory measure in non-clinical settings. Additionally, unlike the BHS, the GHS does not assume that administrators are trained professionals capable of advising on appropriate interventions.

A parasitic nematode induces dysbiosis in susceptible but not resistant gastropod hosts.

Animals' gut microbiomes affect a wide array of biological processes including immunity and protection from pathogens. However, how the microbiome changes due to infection by parasites is still largely unknown, as is how the microbiome changes in hosts that differ in their susceptibility to parasites. To investigate this, we exposed two slug species of differing susceptibility to the parasitic nematode Phasmarhabditis hermaphrodita (Deroceras reticulatum is highly susceptible and Ambigolimax valentianus resistant to the nematode) and profiled the gut microbiota after 7 and 14 days. Before infection, both slug species' microbiota was dominated by similar bacterial genera: Pseudomonas (by far the most abundant), Sphingobacterium, Pedobacter, Chryseobacterium, and Flavobacterium. In the resistant host A. valentianus, there was no significant change in the bacterial genera after infection, but in D. reticulatum, the bacterial profile changed, with a decrease in the abundance of Pseudomonadaceae and an increase in the abundance of Flavobacteriaceae and Sphingobacteriaceae after 7 days postinfection. This suggests nematode infection causes dysbiosis in hosts that are susceptible to infection, but the microbiome of resistant species remains unaltered. In summary, the regulation of the immune system is tightly linked with host survival, and nematode infection can alter the microbiome structure.

Pseudoseptic reaction to an intra-articular platelet-rich plasma injection into the knee: a case report.

A variety of intra-articular injections are used for the management of osteoarthritis. A rare complication of intra-articular injections is acute pseudoseptic arthritis, which mimics true septic arthritis. To the authors knowledge, pseudosepsis has not been reported as a complication after platelet-rich plasma (PRP) injections. We present a case report of pseudoseptic arthritis resulting in acute postinjection pain and a joint effusion after an intra-articular PRP injection into the knee. Clinically, pseudosepsis can occur after PRP treatment with significantly elevated white blood cell counts in the synovial fluid, and should be a consideration in cases of post-PRP injection flares.

Isotherm model discrimination for multimodal chromatography using mechanistic models derived from high-throughput batch isotherm data.

In this work, we have examined an array of isotherm formalisms and characterized them based on their relative complexities and predictive abilities with multimodal chromatography. The set of isotherm models studied were all based on the stoichiometric displacement framework, with considerations for electrostatic interactions, hydrophobic interactions, and thermodynamic activities. Isotherm parameters for each model were first determined through twenty repeated fits to a set of mAb - Capto MMC batch isotherm data spanning a range of loading, ionic strength, and pH as well as a set of mAb - Capto Adhere batch data at constant pH. The batch isotherm data were used in two ways-spanning the full range of loading or consisting of only the high concentration data points. Predictive ability was defined through the model's capacity to capture prominent changes in salt gradient elution behavior with respect to pH for Capto MMC or unique elution patterns and yield losses with respect to gradient slope for Capto Adhere. In both cases, model performance was quantified using a scoring metric based on agreement in peak characteristics for column predictions and accuracy of fit for the batch data. These scores were evaluated for all twenty isotherm fits and their corresponding column predictions, thereby producing a statistical distribution of model performances. Model complexity (number of isotherm parameters) was then considered through use of the Akaike information criterion (AIC) calculated from the score distributions. While model performance for Capto MMC benefitted substantially from removal of low protein concentration data, this was not the case for Capto Adhere; this difference was likely due to the qualitatively different shapes of the isotherms between the two resins. Surprisingly, the top-performing (high accuracy with minimal number of parameters) isotherm model was the same for both resins. The extended steric mass action (SMA) isotherm (containing both protein-salt and protein-protein activity terms) accurately captured both the pH-dependent elution behavior for Capto MMC as well as loss in protein recovery with increasing gradient slope for Capto Adhere. In addition, this isotherm model achieved the highest median score in both resin systems, despite it lacking any explicit hydrophobic stoichiometric terms. The more complex isotherm models, which explicitly accounted for both electrostatic and hydrophobic interaction stoichiometries, were ill-suited for Capto MMC and had lower AIC model likelihoods for Capto Adhere due to their increased complexity. Interestingly, the ability of the extended SMA isotherm to predict the Capto Adhere results was largely due to the protein-salt activity coefficient, as determined via isotherm parameter sensitivity analyses. Further, parametric studies on this parameter demonstrated that it had a major impact on both binding affinity and elution behavior, therein fully capturing the impact of hydrophobic interactions. In summary, we were able to determine the isotherm formalisms most capable of consistently predicting a wide range of column behavior for both a multimodal cation-exchange and multimodal anion-exchange resin with high accuracy, while containing a minimized set of model parameters.

Thought Leader Perspectives on the Benefits, Barriers, and Enablers for Routinely Collected Electronic Health Data to Support Professional Development: Qualitative Study.

BACKGROUND: Hospitals routinely collect large amounts of administrative data such as length of stay, 28-day readmissions, and hospital-acquired complications; yet, these data are underused for continuing professional development (CPD). First, these clinical indicators are rarely reviewed outside of existing quality and safety reporting. Second, many medical specialists view their CPD requirements as time-consuming, having minimal impact on practice change and improving patient outcomes. There is an opportunity to build new user interfaces based on these data, designed to support individual and group reflection. Data-informed reflective practice has the potential to generate new insights about performance, bridging the gap between CPD and clinical practice. OBJECTIVE: This study aims to understand why routinely collected administrative data have not yet become widely used to support reflective practice and lifelong learning. METHODS: We conducted semistructured interviews (N=19) with thought leaders from a range of backgrounds, including clinicians, surgeons, chief medical officers, information and communications technology professionals, informaticians, researchers, and leaders from related industries. Interviews were thematically analyzed by 2 independent coders. RESULTS: Respondents identified visibility of outcomes, peer comparison, group reflective discussions, and practice change as potential benefits. The key barriers included legacy technology, distrust with data quality, privacy, data misinterpretation, and team culture. Respondents suggested recruiting local champions for co-design, presenting data for understanding rather than information, coaching by specialty group leaders, and timely reflection linked to CPD as enablers to successful implementation. CONCLUSIONS: Overall, there was consensus among thought leaders, bringing together insights from diverse backgrounds and medical jurisdictions. We found that clinicians are interested in repurposing administrative data for professional development despite concerns with underlying data quality, privacy, legacy technology, and visual presentation. They prefer group reflection led by supportive specialty group leaders, rather than individual reflection. Our findings provide novel insights into the specific benefits, barriers, and benefits of potential reflective practice interfaces based on these data sets. They can inform the design of new models of in-hospital reflection linked to the annual CPD planning-recording-reflection cycle.

Randomized evaluation of redo ablation procedures of atrial fibrillation with focal impulse and rotor modulation-guided procedures: the REDO-FIRM study.

AIMS: REDO-FIRM evaluated safety and effectiveness of conventional vs. focal impulse and rotor modulation (FIRM)-guided ablation of recurrent persistent or paroxysmal atrial fibrillation (AF) after an initial AF ablation procedure. METHODS AND RESULTS: This prospective, multicentre, randomized study included patients with a single prior AF ablation, but with recurrent AF and reconnected pulmonary veins (PVs). Conventional ablation generally included PV re-isolation; however, additional ablation was permitted per physician discretion. In the FIRM arm, beyond PV re-isolation, basket catheter-based FIRM mapping created dynamic animations of putative rotors, which were targeted for ablation. Between May 2016 and July 2019, 269 subjects were randomized, with 243 subjects completing 12-month follow-up. Ablation beyond re-pulmonary vein isolation, the FIRM vs. Conventional arms did not differ significantly: cavo-tricuspid isthmus -9.0% vs. 15.3%, caval vein isolation -1.5% vs. 0.8%, non-PV trigger -2.2% vs. 3.8%, other -11.9% vs. 13.0%. Single procedure 12-month freedom from AF/atrial tachycardia/atrial flutter-recurrence was 63.3% (76/120) vs. 59.0% (72/122) in the FIRM and Conventional arms (P = 0.3503). Efficacy was similar in the paroxysmal and persistent AF subgroups (P = 0.22 and P = 0.48). The 10-day and 12-month safety endpoints were achieved in 93.3% vs. 93.8% (P = 0.89) and 88.4% vs. 93.4% (P = 0.22) in the FIRM and Conventional arms, respectively. CONCLUSIONS: In REDO-FIRM, as compared to standard ablation, FIRM-guided ablation did not provide additional efficacy in redo ablation procedures, but FIRM-guided ablation was equally safe. Additional studies are necessary to identify any potential population able to benefit from FIRM-guided ablation.

Aerial additive manufacturing with multiple autonomous robots.

Additive manufacturing methods1-4 using static and mobile robots are being developed for both on-site construction5-8 and off-site prefabrication9,10. Here we introduce a method of additive manufacturing, referred to as aerial additive manufacturing (Aerial-AM), that utilizes a team of aerial robots inspired by natural builders11 such as wasps who use collective building methods12,13. We present a scalable multi-robot three-dimensional (3D) printing and path-planning framework that enables robot tasks and population size to be adapted to variations in print geometry throughout a building mission. The multi-robot manufacturing framework allows for autonomous three-dimensional printing under human supervision, real-time assessment of printed geometry and robot behavioural adaptation. To validate autonomous Aerial-AM based on the framework, we develop BuilDrones for depositing materials during flight and ScanDrones for measuring the print quality, and integrate a generic real-time model-predictive-control scheme with the Aerial-AM robots. In addition, we integrate a dynamically self-aligning delta manipulator with the BuilDrone to further improve the manufacturing accuracy to five millimetres for printing geometry with precise trajectory requirements, and develop four cementitious-polymeric composite mixtures suitable for continuous material deposition. We demonstrate proof-of-concept prints including a cylinder 2.05 metres high consisting of 72 layers of a rapid-curing insulation foam material and a cylinder 0.18 metres high consisting of 28 layers of structural pseudoplastic cementitious material, a light-trail virtual print of a dome-like geometry, and multi-robot simulations. Aerial-AM allows manufacturing in-flight and offers future possibilities for building in unbounded, at-height or hard-to-access locations.

Evaluation of the Pfs25-IMX313/Matrix-M malaria transmission-blocking candidate vaccine in endemic settings.

Malaria control relies heavily on the use of anti-malarial drugs and insecticides against malaria parasites and mosquito vectors. Drug and insecticide resistance threatens the effectiveness of conventional malarial interventions; alternative control approaches are, therefore, needed. The development of malaria transmission-blocking vaccines that target the sexual stages in humans or mosquito vectors is among new approaches being pursued. Here, the immunological mechanisms underlying malaria transmission blocking, status of Pfs25-based vaccines are viewed, as well as approaches and capacity for first in-human evaluation of a transmission-blocking candidate vaccine Pfs25-IMX313/Matrix-M administered to semi-immune healthy individuals in endemic settings. It is concluded that institutions in low and middle income settings should be supported to conduct first-in human vaccine trials in order to stimulate innovative research and reduce the overdependence on developed countries for research and local interventions against many diseases of public health importance.