A multidisciplinary approach on music induced-analgesia differentiated by socio-cultural background in healthy volunteers (MOSART): A cross-over randomized controlled trial protocol.

Background: Integrating music into pain treatment demonstrates significant benefits, effectively reducing subjective pain levels and perioperative opioid requirements. Currently, the relationship between the impact of specific types of music and listeners' socio-cultural background is still unclear. This is especially relevant given that sociological research indicates that these factors can have a notable influence on music preference and perception. Current evidence suggests that individuals who choose their own music may experience greater benefits. However, additional research is needed to comprehensively grasp whether the effect of (preferred) music on pain endurance remains consistent across different socio-cultural backgrounds. Methods: In this study, a collaborative effort between medical and sociological researchers aims to investigate music-induced analgesia differentiated by socio-cultural background in healthy volunteers. Participants (n = 84) will listen to self-, and researcher-chosen music and a podcast as a control condition in a cross-over study design. The primary outcome of this study is pain endurance measured by electric stimuli of increasing intensity. Detailed sociological validated questionnaires will be utilized. Considering the notable influence of educational level on music taste formation found in previous research and its crucial role as a source of socio-cultural differentiation, participants will be stratified based on their level of education. Discussion: This experimental study represents one of the first efforts to gain a socio-culturally differentiated understanding of the therapeutic potential of music. Consequently, this could pave the way to purposefully and inclusively implement personalized music in healthcare settings.

Sire: An interoperability engine for prototyping algorithms and exchanging information between molecular simulation programs.

Sire is a Python/C++ library that is used both to prototype new algorithms and as an interoperability engine for exchanging information between molecular simulation programs. It provides a collection of file parsers and information converters that together make it easier to combine and leverage the functionality of many other programs and libraries. This empowers researchers to use sire to write a single script that can, for example, load a molecule from a PDBx/mmCIF file via Gemmi, perform SMARTS searches via RDKit, parameterize molecules using BioSimSpace, run GPU-accelerated molecular dynamics via OpenMM, and then display the resulting dynamics trajectory in a NGLView Jupyter notebook 3D molecular viewer. This functionality is built on by BioSimSpace, which uses sire's molecular information engine to interconvert with programs such as GROMACS, NAMD, Amber, and AmberTools for automated molecular parameterization and the running of molecular dynamics, metadynamics, and alchemical free energy workflows. Sire comes complete with a powerful molecular information search engine, plus trajectory loading and editing, analysis, and energy evaluation engines. This, when combined with an in-built computer algebra system, gives substantial flexibility to researchers to load, search for, edit, and combine molecular information from multiple sources and use that to drive novel algorithms by combining functionality from other programs. Sire is open source (GPL3) and is available via conda and at a free Jupyter notebook server at https://try.openbiosim.org. Sire is supported by the not-for-profit OpenBioSim community interest company.

The MATRICS consensus cognitive battery for the assessment of cognitive impairment in schizotypal personality disorder.

Cognitive deficits are a core impairment across the range of schizophrenia (SZ) spectrum disorders, including schizotypal personality disorder (SPD). The MATRICS Consensus Cognitive Battery (MCCB) was developed to be a robust, specific, and valid cognitive assessment battery to assess cognition in clinical trials for treating cognitive impairments in SZ. Despite the similarity of cognitive impairments shown in SPD and SZ and the clear relevance of uniform assessment across a diagnostic spectrum, the MCCB has yet to be validated in SPD. As such, this is the first study to evaluate the sensitivity of the MCCB for the assessment of cognitive function in individuals with SPD. Participants were 30 individuals with SPD and 54 healthy controls (HC) assessed with the MCCB and supplemental neurocognitive assessments (Trails B, DOT test, Paced Auditory Serial Addition Test (PASAT), AX Continuous Performance Task (AX-CPT), and N-back). Individuals with SPD performed worse than HC participants on all MCCB subtests, as well as on converging supplemental tasks including Trails B, DOT test, PASAT, AX-CPT, and N-back. These results indicate that the MCCB was sensitive to cognitive impairment in SPD compared to controls. SPD participants demonstrate impairments similar to data of SZ participants within the literature, although to a slightly lesser degree of severity. Taken together, these results highlight the generalizability of using the MCCB across SZ spectrum diagnostic groups to assess cognition. Such findings allow for further comparison across disorders, greater understanding of the cognitive characteristics in the spectrum, and use of uniform assessment within cognitive intervention research.

Training in cognitive reappraisal normalizes whole-brain indices of emotion regulation in borderline personality disorder.

BACKGROUND: Borderline personality disorder is the prototypical disorder of emotion dysregulation. We have previously shown that borderline personality disorder patients are impaired in their capacity to engage cognitive reappraisal, a frequently-employed adaptive emotion regulation strategy. METHODS: Here we report on the efficacy of longitudinal training in cognitive reappraisal to enhance emotion regulation in borderline patients. Specifically, the training targeted psychological distancing, a reappraisal tactic whereby negative stimuli are viewed dispassionately as though experienced by an objective, impartial observer. At each of 5 sessions over 2 weeks, 22 borderline (14 Female) and 22 healthy control (13 Female) participants received training in psychological distancing and then completed a widely-used picture-based reappraisal task. Self-reported negative affect ratings and functional magnetic resonance imaging (fMRI) data were acquired at the first and fifth sessions. In addition to behavioral analyses, we performed whole-brain pattern expression analyses using independently-defined patterns for negative affect and cognitive reappraisal implementation for each session. RESULTS: Borderline patients showed a decrease in negative affect pattern expression following reappraisal training, reflecting a normalization in neural activity. They did not, however, show significant change in behavioral self-reports. CONCLUSIONS: To our knowledge, this study represents the first longitudinal fMRI examination of task-based cognitive reappraisal training. Using a brief, proof-of-concept design, the results suggest a potential role for reappraisal training in the treatment of borderline patients.

Cold-water coral energy reserves and calcification in contrasting fjord environments.

The relationship between energy reserves of cold-water corals (CWCs) and their physiological performance remains largely unknown. In addition, it is poorly understood how the energy allocation to different metabolic processes might change with projected decreasing food supply to the deep sea in the future. This study explores the temporal and spatial variations of total energy reserves (proteins, carbohydrates and lipids) of the CWC Desmophyllum dianthus and their correlation with its calcification rate. We took advantage of distinct horizontal and vertical physico-chemical gradients in Comau Fjord (Chile) and examined the changes in energy reserves over one year in an in situ reciprocal transplantation experiment (20 m vs. 300 m and fjord head vs. mouth). Total energy reserves correlated positively with calcification rates. The fast-growing deep corals had higher and less variable energy reserves, while the slower-growing shallow corals showed pronounced seasonal changes in energy reserves. Novel deep corals (transplanted from shallow) were able to quickly increase both their calcification rates and energy reserves to similar levels as native deep corals. Our study shows the importance of energy reserves in sustaining CWC growth in spite of aragonite undersaturated conditions (deep corals) in the present, and potentially also future ocean.

Postconcussive Symptoms After Early Childhood Concussion.

Importance: Research on postconcussive symptoms (PCS) following early childhood concussion has been hindered by a lack of measures suitable for this age group, resulting in a limited understanding of their evolution in young children. Objective: To document PCS in the first 3 months after early childhood concussion using a developmentally appropriate measure. Design, Setting, and Participants: This cohort study used data collected at 3 Canadian and 1 US urban pediatric emergency departments (EDs) and 8 Canadian daycares from December 2018 to December 2022 as part of the Kids' Outcomes and Long-Term Abilities (KOALA) project, a prospective, multicenter, longitudinal cohort study. Participants included children aged 6 to 72 months with early childhood concussion or orthopedic injury (OI) or uninjured children from the community to serve as controls. Data were analyzed from March 2023 to January 2024. Exposure: Concussion sustained between ages 6 and 72 months. Main Outcomes and Measures: Primary outcomes were cognitive, physical, behavioral and total PCS assessed prior to injury (retrospectively), acutely (within 48 hours), and at 10 days, 1 month, and 3 months after injury or recruitment through caregiver observations using the Report of Early Childhood Traumatic Injury Observations & Symptoms inventory. Group comparisons were analyzed using ordinal regression models. Results: The study included 303 children (mean [SD] age, 35.8 [20.2] months; 152 [50.2%] male). Of these, 174 children had a concussion (mean [SD] age, 33.3 [19.9] months), 60 children had an OI (mean [SD] age, 38.4 [19.8] months) and 69 children were uninjured controls (mean [SD] age, 39.7 [20.8] months). No meaningful differences were found between the concussion and comparison groups in retrospective preinjury PCS. Significant group differences were found for total PCS at the initial ED visit (concussion vs OI: odds ratio [OR], 4.33 [95% CI, 2.44-7.69]; concussion vs control: OR, 7.28 [95% CI, 3.80-13.93]), 10 days (concussion vs OI: OR, 4.44 [95% CI, 2.17-9.06]; concussion vs control: OR, 5.94 [95% CI, 3.22-10.94]), 1 month (concussion vs OI: OR, 2.70 [95% CI, 1.56-4.68]; concussion vs control: OR, 4.32 [95% CI, 2.36-7.92]), and 3 months (concussion vs OI: OR, 2.61 [95% CI, 1.30-5.25]; concussion vs control: OR, 2.40 [95% CI, 1.36-4.24]). Significant group differences were also found for domain-level scores (cognitive, physical, behavioral) at various time points. Conclusions and Relevance: In this early childhood cohort study, concussion was associated with more PCS than OIs or typical development up to 3 months after injury. Given the limited verbal and cognitive abilities typical of early childhood, using developmentally appropriate manifestations and behaviors is a valuable way of tracking PCS and could aid in concussion diagnosis in young children.

Benchmarking Active Learning Protocols for Ligand-Binding Affinity Prediction.

Active learning (AL) has become a powerful tool in computational drug discovery, enabling the identification of top binders from vast molecular libraries. To design a robust AL protocol, it is important to understand the influence of AL parameters, as well as the features of the data sets on the outcomes. We use four affinity data sets for different targets (TYK2, USP7, D2R, Mpro) to systematically evaluate the performance of machine learning models [Gaussian process (GP) model and Chemprop model], sample selection protocols, and the batch size based on metrics describing the overall predictive power of the model (R2, Spearman rank, root-mean-square error) as well as the accurate identification of top 2%/5% binders (Recall, F1 score). Both models have a comparable Recall of top binders on large data sets, but the GP model surpasses the Chemprop model when training data are sparse. A larger initial batch size, especially on diverse data sets, increased the Recall of both models as well as overall correlation metrics. However, for subsequent cycles, smaller batch sizes of 20 or 30 compounds proved to be desirable. Furthermore, adding artificial Gaussian noise to the data up to a certain threshold still allowed the model to identify clusters with top-scoring compounds. However, excessive noise (<1σ) did impact the model's predictive and exploitative capabilities.

Axonal excitability as an early biomarker of nerve involvement in hereditary transthyretin amyloidosis.

OBJECTIVES: The treatment of hereditary transthyretin amyloidosis polyneuropathy (ATTRv-PN) has been revolutionised by genetic therapies, with dramatic improvements in patient outcomes. Whilst the optimal timing of treatment initiation remains unknown, early treatment is desirable. Consequently, the aim of the study was to develop biomarkers of early nerve dysfunction in ATTRv-PN. METHODS: Ulnar motor and sensory axonal excitability studies were prospectively undertaken on 22 patients with pathogenic hereditary transthyretin amyloid (ATTRv) gene variants, 12 with large fibre neuropathy (LF+) and 10 without (LF-), with results compared to age- and sex-matched healthy controls. RESULTS: In motor axons we identified a continuum of change from healthy controls, to LF- and LF+ ATTRv with progressive reduction in hyperpolarising threshold electrotonus (TEh40(10-20 ms): p = 0.04, TEh40(20-40 ms): p = 0.01 and TEh40(90-10 ms): p = 0.01), suggestive of membrane depolarisation. In sensory axons lower levels of subexcitability were observed on single (SubEx) and double pulse (SubEx2) recovery cycle testing in LF+ (SubEx: p = 0.015, SubEx2: p = 0.015, RC(2-1): p = 0.04) suggesting reduced nodal slow potassium conductance, which promotes sensory hyperexcitability, paraesthesia and pain. There were no differences in sensory or motor excitability parameters when comparing different ATTRv variants. CONCLUSIONS: These progressive changes seen across the disease spectrum in ATTRv-PN suggest that axonal excitability has utility to identify early and progressive nerve dysfunction in ATTRv, regardless of genotype. SIGNIFICANCE: Axonal excitability is a promising early biomarker of nerve dysfunction in ATTRv-PN.

Serum neurofilament light chain in hereditary transthyretin amyloidosis: validation in real-life practice.

BACKGROUND: Neurofilament light chain (NfL) has emerged as a sensitive biomarker in hereditary transthyretin amyloid polyneuropathy (ATTRv-PN). We hypothesise that NfL can identify conversion of gene carriers to symptomatic disease, and guide treatment approaches. METHODS: Serum NfL concentration was measured longitudinally (2015-2022) in 59 presymptomatic and symptomatic ATTR variant carriers. Correlations between NfL and demographics, biochemistry and staging scores were performed as well as longitudinal changes pre- and post-treatment, and in asymptomatic and symptomatic cohorts. Receiver-operating analyses were performed to determine cut-off values. RESULTS: NfL levels correlated with examination scores (CMTNS, NIS and MRC; all p < .01) and increased with disease severity (PND and FAP; all p < .05). NfL was higher in symptomatic and sensorimotor converters, than asymptomatic or sensory converters irrespective of time (all p < .001). Symptomatic or sensorimotor converters were discriminated from asymptomatic patients by NfL concentrations >64.5 pg/ml (sensitivity= 91.9%, specificity = 88.5%), whereas asymptomatic patients could only be discriminated from sensory or sensorimotor converters or symptomatic individuals by a NfL concentration >88.9 pg/ml (sensitivity = 62.9%, specificity = 96.2%) However, an NfL increment of 17% over 6 months could discriminate asymptomatic from sensory or sensorimotor converters (sensitivity = 88.9%, specificity = 80.0%). NfL reduced with treatment by 36%/year and correlated with TTR suppression (r = 0.64, p = .008). CONCLUSIONS: This data validates the use of serum NfL to identify conversion to symptomatic disease in ATTRv-PN. NfL levels can guide assessment of disease progression and response to therapies.

Phase I study of peposertib and avelumab with or without palliative radiotherapy in patients with advanced solid tumors.

INTRODUCTION: We report results from a phase I, three-part, dose-escalation study of peposertib, a DNA-dependent protein kinase inhibitor, in combination with avelumab, an immune checkpoint inhibitor, with or without radiotherapy in patients with advanced solid tumors. MATERIALS AND METHODS: Peposertib 100-400 mg twice daily (b.i.d.) or 100-250 mg once daily (q.d.) was administered in combination with avelumab 800 mg every 2 weeks in Part A or avelumab plus radiotherapy (3 Gy/fraction × 10 days) in Part B. Part FE assessed the effect of food on the pharmacokinetics of peposertib plus avelumab. The primary endpoint in Parts A and B was dose-limiting toxicity (DLT). Secondary endpoints were safety, best overall response per RECIST version 1.1, and pharmacokinetics. The recommended phase II dose (RP2D) and maximum tolerated dose (MTD) were determined in Parts A and B. RESULTS: In Part A, peposertib doses administered were 100 mg (n = 4), 200 mg (n = 11), 250 mg (n = 4), 300 mg (n = 6), and 400 mg (n = 4) b.i.d. Of DLT-evaluable patients, one each had DLT at the 250-mg and 300-mg dose levels and three had DLT at the 400-mg b.i.d. dose level. In Part B, peposertib doses administered were 100 mg (n = 3), 150 mg (n = 3), 200 mg (n = 4), and 250 mg (n = 9) q.d.; no DLT was reported in evaluable patients. Peposertib 200 mg b.i.d. plus avelumab and peposertib 250 mg q.d. plus avelumab and radiotherapy were declared as the RP2D/MTD. No objective responses were observed in Part A or B; one patient had a partial response in Part FE. Peposertib exposure was generally dose proportional. CONCLUSIONS: Peposertib doses up to 200 mg b.i.d. in combination with avelumab and up to 250 mg q.d. in combination with avelumab and radiotherapy were tolerable in patients with advanced solid tumors; however, antitumor activity was limited. GOV IDENTIFIER: NCT03724890.

Markov State Models: To Optimize or Not to Optimize.

Markov state models (MSM) are a popular statistical method for analyzing the conformational dynamics of proteins including protein folding. With all statistical and machine learning (ML) models, choices must be made about the modeling pipeline that cannot be directly learned from the data. These choices, or hyperparameters, are often evaluated by expert judgment or, in the case of MSMs, by maximizing variational scores such as the VAMP-2 score. Modern ML and statistical pipelines often use automatic hyperparameter selection techniques ranging from the simple, choosing the best score from a random selection of hyperparameters, to the complex, optimization via, e.g., Bayesian optimization. In this work, we ask whether it is possible to automatically select MSM models this way by estimating and analyzing over 16,000,000 observations from over 280,000 estimated MSMs. We find that differences in hyperparameters can change the physical interpretation of the optimization objective, making automatic selection difficult. In addition, we find that enforcing conditions of equilibrium in the VAMP scores can result in inconsistent model selection. However, other parameters that specify the VAMP-2 score (lag time and number of relaxation processes scored) have only a negligible influence on model selection. We suggest that model observables and variational scores should be only a guide to model selection and that a full investigation of the MSM properties should be undertaken when selecting hyperparameters.

From Proteins to Ligands: Decoding Deep Learning Methods for Binding Affinity Prediction.

Accurate in silico prediction of protein-ligand binding affinity is important in the early stages of drug discovery. Deep learning-based methods exist but have yet to overtake more conventional methods such as giga-docking largely due to their lack of generalizability. To improve generalizability, we need to understand what these models learn from input protein and ligand data. We systematically investigated a sequence-based deep learning framework to assess the impact of protein and ligand encodings on predicting binding affinities for commonly used kinase data sets. The role of proteins is studied using convolutional neural network-based encodings obtained from sequences and graph neural network-based encodings enriched with structural information from contact maps. Ligand-based encodings are generated from graph-neural networks. We test different ligand perturbations by randomizing node and edge properties. For proteins, we make use of 3 different protein contact generation methods (AlphaFold2, Pconsc4, and ESM-1b) and compare these with a random control. Our investigation shows that protein encodings do not substantially impact the binding predictions, with no statistically significant difference in binding affinity for KIBA in the investigated metrics (concordance index, Pearson's R Spearman's Rank, and RMSE). Significant differences are seen for ligand encodings with random ligands and random ligand node properties, suggesting a much bigger reliance on ligand data for the learning tasks. Using different ways to combine protein and ligand encodings did not show a significant change in performance.

SILVR: Guided Diffusion for Molecule Generation.

Computationally generating new synthetically accessible compounds with high affinity and low toxicity is a great challenge in drug design. Machine learning models beyond conventional pharmacophoric methods have shown promise in the generation of novel small-molecule compounds but require significant tuning for a specific protein target. Here, we introduce a method called selective iterative latent variable refinement (SILVR) for conditioning an existing diffusion-based equivariant generative model without retraining. The model allows the generation of new molecules that fit into a binding site of a protein based on fragment hits. We use the SARS-CoV-2 main protease fragments from Diamond XChem that form part of the COVID Moonshot project as a reference dataset for conditioning the molecule generation. The SILVR rate controls the extent of conditioning, and we show that moderate SILVR rates make it possible to generate new molecules of similar shape to the original fragments, meaning that the new molecules fit the binding site without knowledge of the protein. We can also merge up to 3 fragments into a new molecule without affecting the quality of molecules generated by the underlying generative model. Our method is generalizable to any protein target with known fragments and any diffusion-based model for molecule generation.

Antibiotic Prescribing Practices for Urinary Tract Infection in a Pediatric Emergency Department: Is This a Problem Worth Cefix-ing?

Background: Pediatric urinary tract infection (UTI) is associated with diagnostic and therapeutic challenges. Objective: To determine the least-broad-spectrum oral antibiotic that would cover 80% of pathogens from lower (afebrile) and upper (febrile) UTIs in a Canadian pediatric emergency department (ED). Methods: This retrospective case series involved children discharged from the ED between September 2020 and February 2021 with a diagnosis of UTI and collection of a sample for urinalysis that had growth on culture. Results: Of 188 patients who met the inclusion criteria, 184 (97.9%) were discharged on antibiotics. Culture results indicated a UTI in 170 cases (92.4% of those discharged on antibiotics). The 95 urinary isolates from lower UTIs were susceptible to cephalexin (n = 81, 85.3%), cefixime (n = 78, 82.1%), nitrofurantoin (n = 76, 80.0%), trimethoprim-sulfamethoxazole (TMP-SMX) (n = 64, 67.4%), and amoxicillin (n = 55, 57.9%). The 75 urinary isolates from upper UTIs were susceptible to cefixime (n = 71, 94.7%), TMP-SMX (n = 57, 76.0%), and amoxicillin (n = 48, 64.0%). The mean prescribed duration of antibiotic therapy was 8.3 days for patients with a lower UTI and 9.1 days for those with an upper UTI (mean difference 0.80 days, 95% confidence interval 0.05-1.54). Conclusions: Empiric treatment with cephalexin or nitrofurantoin would have been successful for almost all lower UTIs. More complete reporting of cephalexin minimal inhibitory concentrations might have allowed use of this drug for most upper UTIs. Although there was a trend toward shorter duration of therapy for lower versus upper UTI, lower UTIs were always treated for longer than recommended by current guidelines.

Contexte: L'infection des voies urinaires (IVU) pédiatrique présente des défis diagnostiques et thérapeutiques. Objectif: Déterminer l'antibiotique oral à large spectre le moins élevé qui couvrirait 80 % des pathogènes des IVU inférieures (sans fièvre) et des IVU supérieures (avec fièvre) dans un service d'urgences pédiatriques canadien. Méthodes: Cette série de cas rétrospective impliquait des enfants sortis du service des urgences entre septembre 2020 et février 2021 avec un diagnostic d'IVU et la collecte d'un échantillon pour une analyse d'urine avec croissance dans la culture d'urine. Résultats: Parmi les 188 patients répondant aux critères d'inclusion, 184 (97,9 %) ont reçu des antibiotiques au moment du congé. Les résultats de la culture ont indiqué une IVU dans 170 cas (92,4 % des patients ayant reçu des antibiotiques au moment du congé). Les 95 isolats urinaires des IVU inférieures étaient sensibles à la céphalexine (n = 81, 85,3 %), au céfixime (n = 78, 82,1 %), à la nitrofurantoïne (n = 76, 80,0 %), au triméthoprime-sulfaméthoxazole (TMP-SMX) (n = 64, 67,4 %) et à l'amoxicilline (n = 55, 57,9 %). Les 75 isolats urinaires des IVU supérieures étaient sensibles au céfixime (n = 71, 94,7 %), au TMP-SMX (n = 57, 76,0 %) et à l'amoxicilline (n = 48, 64,0 %). La durée moyenne de prescription d'antibiotiques était de 8,3 jours pour les patients atteints d'une IVU inférieure et de 9,1 jours pour ceux atteints d'une IVU supérieure (différence moyenne 0,80 jours, IC à 95 % 0,05­1,54). Conclusions: Un traitement empirique avec la céphalexine ou la nitrofurantoïne aurait été efficace pour la grande majorité des infections urinaires inférieures. Un rapport plus complet des concentrations minimales inhibitrices de la céphalexine aurait peut-être permis d'utiliser ce médicament pour la plupart des infections urinaires supérieures. Bien qu'il y ait eu une tendance vers une durée de traitement plus courte pour les infections urinaires inférieures par rapport aux infections urinaires supérieures, les infections urinaires inférieures étaient toujours traitées plus longtemps que ce qui est recommandé par les lignes directrices actuelles.

Dynamic musculoskeletal ultrasound: slipping rib, muscle hernia, snapping hip, and peroneal tendon pathology.

Dynamic musculoskeletal ultrasound is an important diagnostic tool that allows the practitioner to observe soft tissue structures over a range of motion and identify pathology not diagnosed on other modalities. Familiarity with this modality allows health care practitioners to appropriately refer patients for this type of examination. This article will review several indications for dynamic ultrasound imaging, including slipping rib, muscle hernia, snapping hip, and peroneal tendon pathology. The examination technique and expected findings for common pathology in each location are discussed.

Health care impact of implementing a clinical pathway for acute care of pediatric concussion: a stepped wedge, cluster randomised trial.

OBJECTIVES: To test the effects of actively implementing a clinical pathway for acute care of pediatric concussion on health care utilization and costs. METHODS: Stepped wedge, cluster randomized trial of a clinical pathway, conducted in 5 emergency departments (ED) in Alberta, Canada from February 1 to November 30, 2019. The clinical pathway emphasized standardized assessment of risk for persistent symptoms, provision of consistent information to patients and families, and referral for outpatient follow-up. De-identified administrative data measured 6 outcomes: ED return visits; outpatient follow-up visits; length of ED stay, including total time, time from triage to physician initial assessment, and time from physician initial assessment to disposition; and total physician claims in an episode of care. RESULTS: A total of 2878 unique patients (1164 female, 1713 male) aged 5-17 years (median 11.00, IQR 8, 14) met case criteria. They completed 3009 visits to the 5 sites and 781 follow-up visits to outpatient care, constituting 2910 episodes of care. Implementation did not alter the likelihood of an ED return visit (OR 0.77, 95% CI 0.39, 1.52), but increased the likelihood of outpatient follow-up visits (OR 1.84, 95% CI 1.19, 2.85). Total length of ED stay was unchanged, but time from physician initial assessment to disposition decreased significantly (mean change - 23.76 min, 95% CI - 37.99, - 9.52). Total physician claims increased significantly at only 1 of 5 sites. CONCLUSIONS: Implementation of a clinical pathway in the ED increased outpatient follow-up and reduced the time from physician initial assessment to disposition, without increasing physician costs. Implementation of a clinical pathway can align acute care of pediatric concussion more closely with existing clinical practice guidelines while making care more efficient. TRIAL REGISTRATION: ClinicalTrials.gov NCT05095012.

ABSTRAIT: OBJECTIFS: Mettre à l'essai les effets de la mise en œuvre active d'une voie clinique pour le traitement aigu des commotions cérébrales chez les enfants sur l'utilisation et les coûts des soins de santé. MéTHODES: Essai randomisé en grappes d'une voie clinique, échelonné, mené dans cinq services d'urgence en Alberta, au Canada, du 1 février au 30 novembre 2019. Le cheminement clinique mettait l'accent sur l'évaluation normalisée du risque de symptômes persistants, la fourniture de renseignements uniformes aux patients et aux familles, et l'aiguillage vers un suivi externe. Les données administratives dépersonnalisées ont permis de mesurer six résultats : visites de retour à l'urgence; visites de suivi en clinique externe; durée du séjour à l'urgence, y compris le temps total. le temps entre le triage et l'évaluation initiale du médecin, et le temps entre l'évaluation initiale du médecin et la décision; et le nombre total de demandes de remboursement du médecin dans un épisode de soins. RéSULTATS: Un total de 2878 patients uniques (1164 femmes, 1713 hommes) âgés de 5 à 17 ans (médiane 11,00, IQR 8, 14) répondaient aux critères de cas. Ils ont effectué 3009 visites aux 5 sites et 781 visites de suivi aux soins ambulatoires, ce qui représente 2910 épisodes de soins. La mise en œuvre n'a pas modifié la probabilité d'une visite de retour à l'urgence (RC 0,77, IC à 95 %, 0,39, 1,52), mais a augmenté la probabilité de visites de suivi en clinique externe (RC 1,84, IC à 95 %, 1,19, 2,85). La durée totale du séjour à l'urgence est demeurée inchangée, mais le temps écoulé entre l'évaluation initiale du médecin et la décision a diminué considérablement (changement moyen : -23,76 minutes, IC à 95 %, -37,99, -9,52). Le nombre total de demandes de règlement de médecins a augmenté de façon significative à seulement 1 site sur 5. CONCLUSIONS: La mise en œuvre d'un cheminement clinique à l'urgence a augmenté le suivi des patients externes et réduit le temps entre l'évaluation initiale du médecin et son élimination, sans augmenter les coûts des médecins. La mise en œuvre d'un cheminement clinique peut harmoniser davantage les soins de courte durée en cas de commotion cérébrale pédiatrique avec les lignes directrices de pratique clinique existantes tout en rendant les soins plus efficaces. ENREGISTREMENT D'ESSAI: ClinicalTrials.gov NCT05095012.

What geometrically constrained models can tell us about real-world protein contact maps.

The mechanisms by which a protein's 3D structure can be determined based on its amino acid sequence have long been one of the key mysteries of biophysics. Often simplistic models, such as those derived from geometric constraints, capture bulk real-world 3D protein-protein properties well. One approach is using protein contact maps (PCMs) to better understand proteins' properties. In this study, we explore the emergent behaviour of contact maps for different geometrically constrained models and compare them to real-world protein systems. Specifically, we derive an analytical approximation for the distribution of amino acid distances, denoted asP(s), using a mean-field approach based on a geometric constraint model. This approximation is then validated for amino acid distance distributions generated from a 2D and 3D version of the geometrically constrained random interaction model. For real protein data, we show how the analytical approximation can be used to fit amino acid distance distributions of protein chain lengths ofL ≈ 100,L ≈ 200, andL ≈ 300 generated from two different methods of evaluating a PCM, a simple cutoff based method and a shadow map based method. We present evidence that geometric constraints are sufficient to model the amino acid distance distributions of protein chains in bulk and amino acid sequences only play a secondary role, regardless of the definition of the PCM.

A single-arm, multicenter, phase II trial of osimertinib in patients with epidermal growth factor receptor exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations.

BACKGROUND: For patients with stage IV non-small-cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions and exon 21 L858R mutations, osimertinib is the standard of care. Investigating the activity and safety of osimertinib in patients with EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations is of clinical interest. PATIENTS AND METHODS: Patients with stage IV non-small-cell lung cancer with confirmed EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations were eligible. Patients were required to have measurable disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients were required to be EGFR tyrosine kinase inhibitor-naive. The primary objective was objective response rate, and secondary objectives were progression-free survival, safety, and overall survival. The study used a two-stage design with a plan to enroll 17 patients in the first stage, and the study was terminated after the first stage due to slow accrual. RESULTS: Between May 2018 and March 2020, 17 patients were enrolled and received study therapy. The median age of patients was 70 years (interquartile range 62-76), the majority were female (n = 11), had a performance status of 1 (n = 10), and five patients had brain metastases at baseline. The objective response rate was 47% [95% confidence interval (CI) 23% to 72%], and the radiographic responses observed were partial response (n = 8), stable disease (n = 8), and progressive disease (n = 1). The median progression-free survival was 10.5 months (95% CI 5.0-15.2 months), and the median OS was 13.8 months (95% CI 7.3-29.2 months). The median duration on treatment was 6.1 months (range 3.6-11.9 months), and the most common adverse events (regardless of attribution) were diarrhea, fatigue, anorexia, weight loss, and dyspnea. CONCLUSIONS: This trial suggests osimertinib has activity in patients with these uncommon EGFR mutations.

Efficient Purification of Cowpea Chlorotic Mottle Virus by a Novel Peptide Aptamer.

The cowpea chlorotic mottle virus (CCMV) is a plant virus explored as a nanotechnological platform. The robust self-assembly mechanism of its capsid protein allows for drug encapsulation and targeted delivery. Additionally, the capsid nanoparticle can be used as a programmable platform to display different molecular moieties. In view of future applications, efficient production and purification of plant viruses are key steps. In established protocols, the need for ultracentrifugation is a significant limitation due to cost, difficult scalability, and safety issues. In addition, the purity of the final virus isolate often remains unclear. Here, an advanced protocol for the purification of the CCMV from infected plant tissue was developed, focusing on efficiency, economy, and final purity. The protocol involves precipitation with PEG 8000, followed by affinity extraction using a novel peptide aptamer. The efficiency of the protocol was validated using size exclusion chromatography, MALDI-TOF mass spectrometry, reversed-phase HPLC, and sandwich immunoassay. Furthermore, it was demonstrated that the final eluate of the affinity column is of exceptional purity (98.4%) determined by HPLC and detection at 220 nm. The scale-up of our proposed method seems to be straightforward, which opens the way to the large-scale production of such nanomaterials. This highly improved protocol may facilitate the use and implementation of plant viruses as nanotechnological platforms for in vitro and in vivo applications.