bluuebunny/crossref_metadata_2025 huggingface dataset:
Does Free Fibular Flap Reconstruction Affect the Quality of Life in Pediatric Patients With Various Extend of Mandible Defects?
Authors: Atmodiwirjo Parintosa , Bangun Kristaninta , Rachadian Ramadan Mohamad , Tania Vika , Djohan Michael , Ralena Nadhira Anindita , Amanda Nadira Fildza
Published: June 2024

Background:

The long-term outcomes in pediatric patients with various extents of mandible defects have not been well-documented.

Methods:

A retrospective case series in which this study looked at pediatric patients under the age of 13 who had mandibular reconstruction with free fibular flap and had not received another operation in the previous 6 months. The eating, swallowing, speech function, and quality of life are evaluated with EORTC QLQ-H&N35 after the mandible growth spurt has occurred.

Results:

A total of 7 patients were included in this study with operation ages ranging from 6 years 1 month to 12 years 2 months. The etiology of malignant tumors was found in 2 patients and benign tumors in 5 patients. The mandibular defect distribution consists of 1 class Ic, 1 class II, 2 class IIc, 2 class III, and 1 class IVc. All patients reported no swallowing or speech difficulties. However, transient eating trouble was seen in 1 patient due to the extensive defect size that causes tooth loss. Only 1 patient received dental rehabilitation. The patients displayed an overall good quality of life with an average score of 2.857.

Conclusions:

Free fibular flap for mandibular reconstruction in children who have not reached their mandibular growth peak have a satisfying outcome, both in their function and quality of life.
Images of Modern Beauties in the Japanese Colonial Era of Korea (1910–1945)
Authors: Jung Sung Gyun , Hwang Kun , Hwang Young Joong
Published: June 2024

This study aimed to analyze images of the modern beauty of Korea during the Japanese colonial era. Searches were conducted on Google (www.google.com) and Naver (www.naver.com) for archives of newspapers and magazines that contained images of beauty. Beauty of the face and neck (the early 1920s): an article (1922) detailed the contemporary beauty standards. It specifies the desired characteristics of the eyes, nose, and mouth and dictates that “the cheeks ought to be plump enough to obscure the cheekbones” and “the neck and shoulders should also be full, concealing the collarbones.” Images of beauty showing balance and proportion (the late 1920s): in 1928, a magazine article introduced the concept of “the world’s beauty from a scientific perspective,” which represented Western esthetics as reflected in the “Canon” of body proportions and Vitruvian Man. From the face to the body (from the late 1920s to 1930s): in 1927, a daily newspaper established the standard for global beauty. During this period, there was an increased emphasis on maintaining the body, rather than just the face, as a crucial aspect of beauty. From the mid-1930s, the concept of a “streamlined” female body shape gained popularity. Male gaze, which fragmented and objectified women’s bodies, had been visualized and mass-produced. It is essential to understand how preferences have evolved and to possess skilled hands capable of improving the face and body. To properly sculpt the face and body, keen eyes and adept hands are needed.
Speech and Resonance Disorders in Children With Cleft Palate: Diagnostic Evaluation and Current Speech Therapy Modalities
Authors: Sommer Chelsea L. , Aljaro Karen Goldschmied , Palomares Aguilera Mirta , Yu-Quibael Veronica , Cordero Kelly
Published: June 2024

This article will provide an overview of how speech and resonance can be impacted in children with cleft palate. The authors will outline evidence-based assessment and treatment approaches commonly used for children with cleft palate and provide information on current initiatives to provide speech therapy. The methods discussed will be the use of telehealth to provide access to speech therapy for patients in areas without speech-language pathologists and the use of speech therapy camps to offer intensive, limited-duration speech therapy for groups of children due to the lack of trained providers in certain geographical regions.
Focuses, Developments, and Publication Trends in Facial Bone Aging and Related Fields: A Systematic Bibliometric Analysis (1990–2023)
Authors: Liu Ziyang , Li Xinru , Wang Zhi , Li Jie , Teng Li , Lu Jianjian
Published: June 2024

There is a current lack of bibliometric analysis in facial bone aging and relevant fields. By providing clear and intuitive references, predictions, and guidance for future research, this study aims to fill the gap in the current field, summarize the related research, and guide the researchers’ future work. Literature data were retrieved from the Web of Science Core Collection database. Results Analysis and Citation Report of Web of Science, and CiteSpace software were used to optimize the visualization results, including publication characteristics, disciplines, journals, literature, countries/regions, institutions, authors, research focuses, etc. A total of 277 publications were included after manual screening, and the overall trend of annual publications and citations was increasing. On the basis of the analysis, the characteristics of facial bone aging, aging of facial soft tissue, and facial rejuvenation have been the focuses of research in this field. As stem cell research advances and researchers, deepen their comprehension of facial bone aging, basic scientific research on facial bones has witnessed a growing trend.
Traumatic Orbital Compression Syndromes: A Comprehensive Study Into Etiologies, Intervention Strategies, and Clinical Outcomes
Authors: Dos Santos José Cleveilton , Gorla Luis Fernando de Oliveira , Moreno Roberto , Monnazzi Marcelo Silva , Pereira Filho Valfrido Antonio , Gabrielli Mário Francisco Real , Gabrielli Marisa Aparecida Cabrini
Published: June 2024

Facial fractures and their historical link to potential blindness have been well-documented, often attributed to optic canal injuries or retinal vascular occlusion. This dire consequence can result from both direct and indirect ocular trauma, including retrobulbar hemorrhage. Traumatic orbital compression can manifest in various forms, such as hematomas, fractured bone fragments, and emphysema, all posing a significant threat to vision, necessitating immediate intervention. In this study, 9 clinical cases of traumatic orbital compression are presented, each characterized by distinct etiologies. The study delves into traumatic orbital compressive syndromes, underscoring the critical imperative of early recognition and treatment to prevent vision loss. Orbital compression, whether from edema, hematoma, or emphysema, collectively culminates in elevated intraorbital pressure and the potential for optic nerve ischemia. Through the presentation of these 9 clinical cases, the article emphasizes the pressing need for timely intervention in addressing orbital compressive syndromes to avert vision loss. Various surgical techniques are elucidated, highlighting the pivotal role of expeditious medical intervention. This article offers invaluable insights into the diagnosis, management, and outcomes of traumatic orbital compressive syndromes.
Streamlining Iliac Bone Harvest for Maxillary Reconstruction With Novel Use of Arthrex Osteochondral Autograft Transfer System
Authors: Isch Emily L. , Vaile John R. , Rosado Jose A. , Caterson Edward J.
Published: June 2024

This study introduces a novel application of the Osteochondral Autograft Transfer System (OATS) for autologous bone grafting during alveolar cleft repair. Approximately 75% of patients with cleft lip and palate have an alveolar cleft, which often necessitates secondary bone grafting from common donor sites such as the iliac crest. Traditional harvesting techniques, although effective, can be labor-intensive and increase the risk of donor site injury. Here the authors describe the use of OATS, which has primarily been used in orthopedic procedures like anterior cruciate ligament reconstruction, for the first time in alveolar cleft repair. It involves a minimally invasive, single-use transfer system for harvesting osteochondral autografts from the anterior iliac crest, and thereby reduces harvest time compared with traditional open approaches. The procedure is detailed from pre-operative evaluation through long-term follow-up and highlights the technique’s benefits related to surgical time, ease of use, and maintenance of sizable autograft volumes. Similarly, the authors discuss other advantages of OATS, including its single-use and cordless nature, which is believed to contribute to a lower contamination risk and better intraoperative ergonomics.
A behaviour and disease transmission model: incorporating the Health Belief Model for human behaviour into a simple transmission model
Authors: Ryan Matthew , Brindal Emily , Roberts Mick , Hickson Roslyn I.
Published: June 2024

The health and economic impacts of infectious diseases such as COVID-19 affect all levels of a community from the individual to the governing bodies. However, the spread of an infectious disease is intricately linked to the behaviour of the people within a community since crowd behaviour affects individual human behaviour, while human behaviour affects infection spread, and infection spread affects human behaviour. Capturing these feedback loops of behaviour and infection is a well-known challenge in infectious disease modelling. Here, we investigate the interface of behavioural science theory and infectious disease modelling to explore behaviour and disease (BaD) transmission models. Specifically, we incorporate a visible protective behaviour into the susceptible–infectious–recovered–susceptible (SIRS) transmission model using the socio-psychological Health Belief Model to motivate behavioural uptake and abandonment. We characterize the mathematical thresholds for BaD emergence in the BaD SIRS model and the feasible steady states. We also explore, under different infectious disease scenarios, the effects of a fully protective behaviour on long-term disease prevalence in a community, and describe how BaD modelling can investigate non-pharmaceutical interventions that target-specific components of the Health Belief Model. This transdisciplinary BaD modelling approach may reduce the health and economic impacts of future epidemics.
Structural and functional characterization of nanobodies that neutralize Omicron variants of SARS-CoV-2
Authors: Cornish Katy , Huo Jiandong , Jones Luke , Sharma Parul , Thrush Joseph W. , Abdelkarim Sahar , Kipar Anja , Ramadurai Siva , Weckener Miriam , Mikolajek Halina , Liu Sai , Buckle Imogen , Bentley Eleanor , Kirby Adam , Han Ximeng , Laidlaw Stephen M. , Hill Michelle , Eyssen Lauren , Norman Chelsea , Le Bas Audrey , Clarke John , James William , Stewart James P. , Carroll Miles , Naismith James H. , Owens Raymond J.
Published: June 2024

The Omicron strains of SARS-CoV-2 pose a significant challenge to the development of effective antibody-based treatments as immune evasion has compromised most available immune therapeutics. Therefore, in the ‘arms race’ with the virus, there is a continuing need to identify new biologics for the prevention or treatment of SARS-CoV-2 infections. Here, we report the isolation of nanobodies that bind to the Omicron BA.1 spike protein by screening nanobody phage display libraries previously generated from llamas immunized with either the Wuhan or Beta spike proteins. The structure and binding properties of three of these nanobodies (A8, H6 and B5-5) have been characterized in detail providing insight into their binding epitopes on the Omicron spike protein. Trimeric versions of H6 and B5-5 neutralized the SARS-CoV-2 variant of concern BA.5 both
in vitro
and in the hamster model of COVID-19 following nasal administration. Thus, either alone or in combination could serve as starting points for the development of new anti-viral immunotherapeutics.
Amyloidogenic regions in beta-strands II and III modulate the aggregation and toxicity of SOD1 in living cells
Authors: McAlary Luke , Nan Jeremy R. , Shyu Clay , Sher Mine , Plotkin Steven S. , Cashman Neil R.
Published: June 2024

Mutations in the protein superoxide dismutase-1 (SOD1) promote its misfolding and aggregation, ultimately causing familial forms of the debilitating neurodegenerative disease amyotrophic lateral sclerosis (ALS). Currently, over 220 (mostly missense) ALS-causing mutations in the SOD1 protein have been identified, indicating that common structural features are responsible for aggregation and toxicity. Using
in silico
tools, we predicted amyloidogenic regions in the ALS-associated SOD1-G85R mutant, finding seven regions throughout the structure. Introduction of proline residues into β-strands II (I18P) or III (I35P) reduced the aggregation propensity and toxicity of SOD1-G85R in cells, significantly more so than proline mutations in other amyloidogenic regions. The I18P and I35P mutations also reduced the capability of SOD1-G85R to template onto previously formed non-proline mutant SOD1 aggregates as measured by fluorescence recovery after photobleaching. Finally, we found that, while the I18P and I35P mutants are less structurally stable than SOD1-G85R, the proline mutants are less aggregation-prone during proteasome inhibition, and less toxic to cells overall. Our research highlights the importance of a previously underappreciated SOD1 amyloidogenic region in β-strand II (
15
QGIINF
20
) to the aggregation and toxicity of SOD1 in ALS mutants, and suggests that β-strands II and III may be good targets for the development of SOD1-associated ALS therapies
STEP: extraction of underlying physics with robust machine learning
Authors: Alaa El-Din Karim K. , Forte Alessandro , Kasim Muhammad Firmansyah , Miniati Francesco , Vinko Sam M.
Published: June 2024

A prevalent class of challenges in modern physics are inverse problems, where physical quantities must be extracted from experimental measurements. End-to-end machine learning approaches to inverse problems typically require constructing sophisticated estimators to achieve the desired accuracy, largely because they need to learn the complex underlying physical model. Here, we discuss an alternative paradigm: by making the physical model auto-differentiable we can construct a neural surrogate to represent the unknown physical quantity sought, while avoiding having to relearn the known physics entirely. We dub this process surrogate training embedded in physics (STEP) and illustrate that it generalizes well and is robust against overfitting and significant noise in the data. We demonstrate how STEP can be applied to perform dynamic kernel deconvolution to analyse resonant inelastic X-ray scattering spectra and show that surprisingly simple estimator architectures suffice to extract the relevant physical information.
Emergence of collective behaviours from local Voronoi topological perception
Authors: Gonzalez Ivan , Tisdell Jack , Choksi Rustum , Nave Jean-Christophe
Published: June 2024

This article addresses how diverse collective behaviours arise from simple and realistic decisions made entirely at the level of each agent’s personal space in the sense of the Voronoi diagram. We present a discrete-time model in two dimensions in which individual agents are aware of their local Voronoi environment and may seek static target locations. In particular, agents only communicate directly with their Voronoi neighbours and make decisions based on the geometry of their own Voronoi cells. With two effective control parameters, it is shown numerically to capture a wide range of collective behaviours in different scenarios. Further, we show that the Voronoi topology facilitates the computation of several novel observables for quantifying discrete collective behaviours. These observables are applicable to all agent-based models and to empirical data.
Modelling hepatitis C infection acquired from blood transfusions in the UK between 1970 and 1991 for the Infected Blood Inquiry
Authors: Hayes Sarah , McCabe Ruth , De Angelis Daniela , Donnelly Christl A. , Evans Stephen J. W. , Medley Graham F. , Spiegelhalter David J. , Bird Sheila M.
Published: June 2024

The Statistics Expert Group was convened at the request of the Infected Blood Inquiry to provide estimates of the number of infections and deaths from blood-borne infections including hepatitis B virus, human immunodeficiency virus, hepatitis C virus (HCV) and variant Creutzfeldt Jakob disease, as a direct result of contaminated blood and blood products administered in the United Kingdom of Great Britain and Northern Ireland (UK). In the absence of databases of HCV infections and related deaths for all nations of the UK, a statistical model was required to estimate the number of infections and subsequent deaths from HCV acquired from blood transfusions from January 1970 to August 1991. We present this statistical model in detail alongside the results of its application to each of the four nations in the UK. We estimated that 26 800 people (95% uncertainty interval 21 300–38 800) throughout the UK were chronically infected with HCV because of contaminated blood transfusions between January 1970 and August 1991. The number of deaths up to the end of 2019 that occurred as a result of this chronic infection is estimated to be 1820 (95% uncertainty interval 650–3320).
Cardenolides in the defensive fluid of adult large milkweed bugs have differential potency on vertebrate and invertebrate predator Na
+
/K
+
-ATPases
Authors: Rubiano-Buitrago P. , Pradhan S. , Aceves A. A. , Mohammadi S. , Paetz C. , Rowland H. M.
Published: June 2024

Aposematic animals rely on diverse secondary metabolites for defence. Various hypotheses, such as competition, life history and multifunctionality, have been posited to explain defence variability and diversity. We investigate the compound selectivity hypothesis using large milkweed bugs,
Oncopeltus fasciatus
, to determine if distinct cardenolides vary in toxicity to different predators. We quantify cardenolides in the bug’s defensive secretions and body tissues and test the individual compounds against predator target sites, the Na
+
/K
+
-ATPases, that are predicted to differ in sensitivity. Frugoside, gofruside, glucopyranosyl frugoside and glucopyranosyl gofruside were the dominant cardenolides in the body tissues of the insects, whereas the two monoglycosidic cardenolides—frugoside and gofruside—were the most abundant in the defensive fluid. These monoglycosidic cardenolides were highly toxic (IC
50
 < 1 μM) to an invertebrate and a sensitive vertebrate enzyme, in comparison to the glucosylated compounds. Gofruside was the weakest inhibitor for a putatively resistant vertebrate predator. Glucopyranosyl calotropin, found in only 60% of bugs, was also an effective inhibitor of sensitive vertebrate enzymes. Our results suggest that the compounds sequestered by
O. fasciatus
probably provide consistency in protection against a range of predators and underscore the need to consider predator communities in prey defence evolution.
Aggressive interactions influence cognitive performance in Western Australian magpies
Authors: Speechley Elizabeth M. , Ashton Benjamin J. , Thornton Alex , King Stephanie L. , Simmons Leigh W. , Woodiss-Field Sarah L. , Ridley Amanda R.
Published: June 2024

Extensive research has investigated the relationship between the social environment and cognition, suggesting that social complexity may drive cognitive evolution and development. However, evidence for this relationship remains equivocal. Group size is often used as a measure of social complexity, but this may not capture intraspecific variation in social interactions. Social network analysis can provide insight into the cognitively demanding challenges associated with group living at the individual level. Here, we use social networks to investigate whether the cognitive performance of wild Western Australian magpies (
Gymnorhina tibicen dorsalis
) is related to group size and individual social connectedness. We quantified social connectedness using four interaction types: proximity, affiliative, agonistic and vocal. Consistent with previous research on this species, individuals in larger groups performed better on an associative learning task. However, social network position was also related to cognitive performance. Individuals receiving aggressive interactions performed better, while those involved in aggressive interactions with more group members performed worse. Overall, this suggests that cognitive performance is related to specific types of social interaction. The findings from this study highlight the value of considering fine-grained metrics of sociality that capture the challenges associated with social life when testing the relationship between the social environment and cognition.
Seasonal patterns and processes of migration in a long-distance migratory bird: energy or time minimization?
Authors: Hedenström Anders , Hedh Linus
Published: June 2024

Optimal migration theory prescribes adaptive strategies of energy, time or mortality minimization. To test alternative hypotheses of energy- and time-minimization migration we used multisensory data loggers that record time-resolved flight activity and light for positioning by geolocation in a long-distance migratory shorebird, the little ringed plover,
Charadrius dubius
. We could reject the hypothesis of energy minimization based on a relationship between stopover duration and subsequent flight time as predicted for a time minimizer. We found seasonally diverging slopes between stopover and flight durations in relation to the progress (time) of migration, which follows a time-minimizing policy if resource gradients along the migration route increase in autumn and decrease in spring. Total flight duration did not differ significantly between autumn and spring migration, although spring migration was 6% shorter. Overall duration of autumn migration was longer than that in spring, mainly owing to a mid-migration stop in most birds, when they likely initiated moult. Overall migration speed was significantly different between autumn and spring. Migratory flights often occurred as runs of two to seven nocturnal flights on adjacent days, which may be countering a time-minimization strategy. Other factors may influence a preference for nocturnal migration, such as avoiding flight in turbulent conditions, heat stress and diurnal predators.
Comprehensive Druggable Genome-Wide Mendelian Randomization Reveals Therapeutic Targets for Kidney Diseases
Authors: Su Zhihang , Wan Qijun
Published: June 2024

Background

Kidney diseases, including membranous nephropathy (MN), IgA nephropathy (IgAN), and chronic kidney disease (CKD), pose significant global health challenges due to their high prevalence and severe outcomes. There is still an urgent need to discover new targets for treating kidney diseases. Mendelian randomization (MR) has been widely used to repurpose licensed drugs and discover novel therapeutic targets. Thus, we aimed to identify novel therapeutic targets for Kidney diseases and analyze their pathophysiological mechanisms and potential side effects.

Methods

Integrated with currently available druggable genes, Summary-data-based MR (SMR) analysis was conducted to estimate the causal effects of blood expression quantitative trait loci (eQTLs) on kidney diseases. A study was replicated using distinct blood eQTL and diseases genome-wide association study (GWAS) data sources to validate the identified genes. The eQTL data was obtained from eQTLGen and GTEx v8.0, with sample sizes of 31,684 and 15,201, respectively. The data on kidney diseases was sourced from the Kiryluk Lab, CKDgen, and the Finngen consortium, with sample sizes ranging from 7,979 to 412,181. Subsequently, reverse two-sample MR and colocalization analysis were employed for further validation. Finally, the potential side effects of the identified key genes in treating kidney diseases were assessed using phenome-wide MR and mediation MR.

Results

After correcting for the false discovery rate, a total of 20, 23, and 6 unique potential genes were found to have causal relationships with MN, IgAN, and CKD, respectively. Among them, MN showed validated associations with one gene (HCG18), IgAN demonstrated associations with four genes (AFF3, CYP21A2, DPH3, HLA-DRB5), and chronic kidney disease (CKD) displayed an association with one gene (HLA-DQB1-AS1). Several of these key genes are druggable genes. Further phenome-wide MR analysis revealed that certain genes may be associated with diabetes, fat metabolism, and infectious diseases, suggesting that these factors could potentially serve as mediators.

Conclusions

This study presents genetic evidence that supports the potential therapeutic benefits of targeting these key genes for treating kidney diseases. This is significant in prioritizing the development of drugs for kidney diseases.
Protective Effects of Butyrate on Retinal Neovascularization in Preclinical Retinopathy of Prematurity Models
Authors: Oxenrider Allston , Bui Tommy , Lester John , Thounaojam Menaka C. , Martin Pamela M. , Jadeja Ravirajsinh N.
Published: June 2024

Retinopathy of prematurity (ROP) remains a leading cause of childhood blindness worldwide, necessitating new therapeutic strategies. Current interventions targeting advanced disease stages often fail to prevent long-term visual impairment. This study investigates the potential of sodium butyrate (NaB), an orally administered short-chain fatty acid, in preclinical models of ROP. Using the oxygen-induced retinopathy (OIR) mouse model, we demonstrate that daily oral NaB supplementation significantly protects against pathological angiogenesis, impacting not only vascular but also neuronal and microglial pathology in the inner retina. Notably, NaB shows efficacy in early-phase ROP intervention, as evidenced by studies in post-natal day 9 (P9) OIR mice and a novel hyperglycemia-associated retinopathy (HAR) model, which mimics the hyperglycemic conditions of many premature infants. These findings highlight NaB as a promising alternative or adjunct therapy to current anti-VEGF treatments, offering protection across multiple retinal cell types and stages of ROP development. The study underscores the need for further research to elucidate the specific mechanisms of NaB’s action, paving the way for its potential clinical application in ROP management. This research marks the first exploration of butyrate as a preventative and therapeutic agent for ROP, setting the stage for additional preclinical evaluations and optimization.

Highlights

Sodium butyrate (NaB) shows significant protection against pathological angiogenesis in the oxygen-induced retinopathy (OIR) mouse model.

NaB impacts not only vascular but also neuronal and microglial pathology in the inner retina.

The study highlights NaB’s potential as an early-phase intervention therapy for retinopathy of prematurity (ROP).

This research is the first to investigate butyrate as a preventative and therapeutic agent for ROP.
Student self-assessment: feasibility, advantages and limitations Example of a workshop for trainee surgeons using a suture score
Authors: Riquin Elise , Le Nerzé Thomas , Goulin Jeanne , Rony Louis , Boucher Sophie , Martin Ludovic , Schmitt Françoise
Published: June 2024

Introduction

Evaluating skills requires developing relevant grading tools that could potentially be used for self-assessments. The goal of our study was to assess the relevance of a self-assessment (SA) grid used for a skin suture exercise as compared to an evaluation carried out at the same time by an expert (EE), while also identifying any factors likely to influence it.

Materials and methods

Between 2018 and 2022, an assessment grid for a skin suture exercise was used during skills assessment sessions with first-year trainee surgeons. The students were given a self-assessment grid to fill out at the same time. The results of the SA and the EE in this grid were analyzed and compared, then set against the anxiety scores of the trainees based on the STAI Y-A. A comparative analysis of trainees with a tendency to over- or underestimate themselves was carried out to identify the factors that could contribute to them misjudging their skills.

Findings

The data for 70 trainee doctors was analyzed. The mean of the difference in score between the SA and the EE was 2 points lower for SA than EE (p < 0.001). The mean score for the STAI Y-A was 36.2 +/- 8.9 and the learner’s anxiety had no effect on the EE but did affect the SA. When learners showed low self-confidence, they underestimated themselves, but examiners also had a tendency to give them lower grades. In multivariate analysis, the less experience a learner had, the more they tended to overestimate their abilities.

Conclusion

Anxiety and self-confidence affect self-assessment, but external assessment does not seem to be affected by the learner’s stress levels. Formative self-reflection based on the use of SA grids should be introduced during medical studies so as to adjust the level of technical skill perceived by trainees and to make simulation-based training more effective.
Reproducibility and Robustness of Localized Mortality Prediction
Authors: Nitch-Griffin Evelyn , Peterson Amy , Skaf Yara , Brunson Jason Cory
Published: June 2024

Background

While localized modeling—the use of predictive models to perform the adaptation step in case-based reasoning—has been evaluated in several experimental settings, its reported successes have infrequently been independently and externally validated.

Objective

We aimed to extend and validate an experimental study of mortality prediction in a critical care population and to assess the importance of several methodological factors to predictive performance.

Methods

We reproduced the workflow of Lee, Maslove, and Dubin (2015) using an updated database. We evaluated performance as area under the receiver operating characteristic curve and under the precision–recall curve and calibration as weakness of evidence in Hosmer– Lemeshow tests. We compared the effects of several modeling choices, including how relevance is quantified, and how relevance cohorts are retrieved, and the choice of model. We compared ours to previous results and used linear regression to quantify the role of each modeling choice on performance.

Results

Overall performance and its relationship to cohort size validated previous results. These relationships varied by model family as expected, though we observed no advantage of decision trees over a model-free approach and poor performance by random forests. An alternate choice of unlearned similarity measure yielded marginal and inconsistent performance differences. Denominating cohorts by similarity threshold rather than by cardinality yielded marginal but consistent performance losses. A temporal validation exercise enabled by a change of information system before the recent upgrade corroborated performance estimates from cross-validation. In all, cohort denomination mattered more to performance than any other methodological choice.

Discussion

The greater impact of retrieval than of adaptation suggests a weakness with the strategy of localized modeling. Additional research to deconstruct the varieties of this approach and quantify the relative benefits of its components is needed to resolve this question.
Clinical prediction with localized modeling using similarity-based cohorts: A scoping review
Authors: Cohen Adi , McCall-Junkin Patti , Brunson Jason Cory
Published: June 2024

Background

Applications of classical case-based reasoning (CBR) have given rise to a family of techniques we call “localized models”, in which a statistical model is fitted to a neighborhood of labeled cases matched by similarity to a target case. We aim to describe clinical and health applications of localized models to date and propose a general framework for their design and evaluation.

Methods

We searched four bibliographic platforms during 2021 July 19–22, updated 2024 January 24. We set four eligibility criteria to identify applications of localized models to clinical and health tasks. Two authors divided title/abstract screening and reviewed screened entries for inclusion. We discussed settings, tasks, and tools; identified and tabulated themes; and synthesized the methods into a general framework.

Results

Of 1,657 search results, 360 were reviewed, then combined with 43 publications that seeded the review and 1 obtained by citation tracking. 27 were included, published 1997–2022. The specificity of search terms was poor, and inter-rater reliability was low. Almost all models were predictive, the most common tasks being prognosis and diagnosis. Most studies used clinical, occasionally laboratory and image, data. Several addressed memory and runtime costs. A general technique that specializes to most of those reviewed involved matching, retrieval, fitting, and evaluation steps that could optionally be supervised, optimized, or recursively performed.

Conclusions

Localized models have potential to improve the performance of clinical decision support tools while maintaining interpretability, but rigorous comparisons to competing methods must be conducted and computational hurdles must be overcome. We hope that our review will spur future work on efficiency, reproducibility, and user needs.
Association of Endovascular Thrombectomy Volume and Outcomes in Acute Ischemic Stroke: A National Inpatient Sample Study
Authors: Fry Lane , Brake Aaron , Heskett Cody , De Stefano Frank A. , Williams Ari , Majo Nashaat , Lei Catherine , Alkiswani Abdul-Rahman , Le Kevin , Rouse Adam G. , Peterson Jeremy , Ebersole Koji
Published: June 2024

Background

Previous studies have reported a positive relationship between higher hospital endovascular thrombectomy (EVT) volume and shorter procedures, higher revascularization rates, and improved functional outcomes. We investigated the association between hospital EVT volume and clinical outcomes using the National Inpatient Sample (NIS) database from 2016-2020.

Methods

A cross-sectional analysis of the NIS examining the relationship of hospital EVT volume and outcomes was performed. All relevant clinical and demographic information was collected. The outcomes were favorable functional outcome (home without assistance), inpatient mortality, and intracerebral hemorrhage (ICH). Centers were classified as high-volume if they were in the top quintile of annual EVT volume. We performed univariate, multivariate, nearest neighbor matched analysis, and an exploratory annual case volume cutoff analysis.

Results

There were 114,640 patients who underwent EVT included in the sample. Of these, 24,415 (21.3%) were in the high-volume group. High-volume centers had higher rates of favorable functional outcome in univariate (OR 1.20, p < 0.001), multivariate (aOR 1.19, p = 0.003), and matched analysis (OR 1.14, p = 0.028). Prior to matching, lower rates of inpatient mortality (OR 0.83, p < 0.001). However, in univariate and matched analysis there were no differences between high and low-volume centers. There were no differences in ICH across all analyses. Functional benefit was first noted at ≥ 50 EVTs, but centers performing ≥ 175 EVTs had substantially higher functional benefit (aOR 1.42, p = 0.002).

Conclusions

Our analysis demonstrates increased hospital case volume is associated with a modest improvement in favorable functional outcomes in patients undergoing EVT for AIS. Attempts to identify procedural cut off values reveal likely improved functional outcomes beginning at 50 EVT per year, while this benefit seems to increase with increasing case volumes. These higher levels of case volumes do not lead to higher rates of inpatient mortality or ICH.
Noncanonical roles of chemokine regions in CCR9 activation revealed by structural modeling and mutational mapping
Authors: Pinheiro Ines De Magalhaes , Dawson John R.D. , Calo Nicolas , Paolini-Bertrand Marianne , Akondi Kalyana Bharati , Tan Gavin , Handel Tracy M. , Kufareva Irina , Hartley Oliver
Published: June 2024

The G protein-coupled CC chemokine receptor 9 (CCR9) plays a major role in inflammatory bowel disease and has been implicated in cancer. Despite its importance as a drug target, there is limited mechanistic understanding of how CCR9 engages and is activated by its endogenous chemokine agonist CCL25. Here, by combining structural modeling with multimodal pharmacological assessment of receptor mutants, we generated a functional map of the CCR9-CCL25 interaction interface and delineated key determinants of binding, agonism, constitutive activity, and G protein vs arrestin signaling. In contrast to all complexes studied to date, where chemokines drive receptor activation through their N-termini, we determined that CCL25 activates CCR9 via a distinct region, its 30s loop. In support of this non-canonical mechanism, CCR9 signaling is tolerant to alanine mutations in the N-terminus of CCL25 but strongly affected by modifications to the 30s loop. Through molecular evolution of the CCL25 N-terminus, we identified chemokine analogs with enhanced binding properties. However, in contrast to other receptor-chemokine systems, these analogs remained full agonists, consistent with the localization of CCL25 signaling determinants outside of the N-terminus. The non-canonical signature of CCR9 activation provides new insights to aid CCR9 drug discovery and may also inform structure-based design of drugs targeting other chemokine receptors.
Nonsymmetric formation of Δ1-piperideine from lysine in plants via a bacterial-like PLP-dependent enzyme
Authors: Wood Catharine X. , Daza Oriana Serna , Newling Katherine , James Sally , Unsworth William P. , Lichman Benjamin R.
Published: June 2024

Piperidine alkaloids in plants derive from lysine via Δ1-piperideine. We investigated the alkaloid biosynthesis inFlueggea suffruticosa, a plant that produces diverse piperidine alkaloids, including securinine. Until now, pathways leading to the formation of Δ1-piperideine have involved two enzymatic steps: a decarboxylase and an oxidase, proceeding via free cadaverine. We discovered Δ1-piperideine synthase (PS), a PLP-dependent enzyme that forms Δ1-piperideine directly from lysine via an oxidative deamination. We demonstrate that PS catalyses this transformation in a non-symmetric manner, and show it is positioned within the group III decarboxylase family, which is typically associated with prokaryotes. We also identified a paralog gene exhibiting decarboxylase activity. This work delineates the first enzymatic step in the biosynthesis of securinine as an unprecedented oxidative deamination of lysine. It also marks the identification of the first eukaryotic group III decarboxylase and resolves the longstanding question of non-symmetric nitrogen incorporation in piperidine alkaloids.
Imperfect hairpins formed by CTG trinucleotide repeats are heteroduplex DNA molecules in living cells
Authors: Viterbo David , Dupaigne Pauline , Kaminski Pierre Alexandre , Dejardin François , Petres Stéphane , Cam Eric Le , Richard Guy-Franck
Published: June 2024

There are over fifty microsatellite expansion disorders, often neurodegenerative pathologies, due to large expansions of tandem repeat sequences. These microsatellites vary in motif composition, size and copy number in the genome. The ability of these repeats to form secondary structuresin vitrois strongly suspected to trigger the expansion process and therefore, the pathology. However, there is no formal proof that similar structures are formedin vivo, in living and replicating cells.

We are focused on the CTG trinucleotide repeat whose expansion is responsible for myotonic dystrophy type 1 (DM1 or Steinert disease), affecting 1 in 8,000 people worldwide.

A series of llama nanobodies (VHH) were selected to bind to the secondary structure formed by a synthetic imperfect CTG hairpin. Yeast one-hybrid was used to identify VHH that were able to activate a reporter genein vivo. One of them was shown to be very specific since it binds a CTG hairpin but not a CAG hairpin or a GC-rich sequence. This nanobody also bind to long CTG trinucleotide repeats carried by plasmidic or genomic DNAs, proportionally to the number of repeats, suggesting that longer repeats tend to form more frequently imperfect hairpins. Finally, the VHH was bound to a protein G column and used to selectively enrich structure-containing DNA molecules, that were further observed by electron microscopy. They exhibit different kinds of structures in which only one strand is folded into an imperfect hairpin.

Our results unambiguously show that alternative DNA structures are transiently formed by CTG trinucleotide repeats in living bacterial and yeast cells and suggest that imperfect CTG hairpins mainly existin vivomainly as heteroduplex DNA molecules.
Binocular combination in the autonomic nervous system
Authors: Segala Federico G. , Bruno Aurelio , Martin Joel T. , Morsi Anisa Y. , Wade Alex R. , Baker Daniel H.
Published: June 2024

Pupil diameters are regulated by the autonomic nervous system, which combines light signals across the eyes independently of the visual cortex. Distinct classes of retinal photoreceptor are involved in this process, with cones and rods driving the initial constriction and intrinsically photosensitive retinal ganglion cells maintaining diameter over prolonged time periods. We investigated binocular combination by targeting different photoreceptor pathways using a novel binocular multiprimary system to modulate the input spectra via silent substitution. At the first harmonic of the modulation frequency, light flux and S-cone responses showed strong binocular facilitation, and weak interocular suppression. Melanopsin responses were invariant to the number of eyes stimulated. Notably, the L-M pathway involved binocular inhibition, whereby responses to binocular stimulation were weaker than for monocular stimulation. The second harmonic involved strong interocular suppression in all pathways, but with some evidence of binocular facilitation. Our results are consistent with a computational model of binocular signal combination (implemented in a Bayesian hierarchical framework), in which the weight of interocular suppression differs across pathways. We also find pathway differences in response phase, consistent with different lag times for phototransduction. This work demonstrates for the first time the algorithm governing binocular combination in the autonomic nervous system.
CircPVT1 sponges miR-33a-5p unleashing the c-MYC/GLS1 metabolic axis in breast cancer
Authors: Palcau Alina Catalina , Pulito Claudio , De Pascale Valentina , Casadei Luca , Valerio Maria Cristina , Sacconi Andrea , Rutigliano Daniela , Donzelli Sara , Auciello Romana Francesca , Pimpinelli Fulvia , Muti Paola , Botti Claudio , Strano Sabrina , Blandino Giovanni
Published: June 2024

Altered metabolism is one of the cancer hallmarks. The role of circRNAs in cancer metabolism is still unexplored. Herein, we initially found that the expression of circPVT1 was significantly higher in tumoral tissues than in non-tumoral breast tissues. Basal like breast cancer patients with higher levels of circPVT1 exhibited shorter disease-free survival compared to those with lower expression. CircPVT1 ectopic expression rendered fully transformed MCF-10A immortalized breast cells and increased tumorigenicity of TNBC cell lines. Depletion of endogenous circPVT1 reduced tumorigenicity of SUM-159PT and MDA-MB-468 cells. 1H-NMR spectroscopy metabolic profiling of circPVT1 depleted breast cancer cell lines revealed reduced glycolysis and glutaminolitic fluxes. Conversely, MCF-10A cells stably overexpressing circPVT1 exhibited increased glutaminolysis. Mechanistically, circPVT1 sponges miR-33a-5p, a well know metabolic microRNA, which in turn releases c-MYC activity which promotes transcriptionally glutaminase, which converts glutamine to glutamate. CircPVT1 depletion synergizes with GLS1 inhibitors BPTES or CB839 to reduce cell viability of breast cancer cell lines and breast cancer-derived organoids. In aggregate, our findings unveil the circPVT1/miR-33a-5p/Myc/GLS1 axis as a pro-tumorigenic metabolic event sustaining breast cancer transformation with potential therapeutic implications.
The dominance of global phase dynamics in human cortex, from delta to gamma
Authors: Alexander David M. , Dugué Laura
Published: June 2024

The organization of the phase of electrical activity in the cortex is critical to inter-site communication, but the balance of this communication across macroscopic (>15cm), mesoscopic (1 to 15cm) and microscopic (<1cm) ranges is an open question. Traveling waves in the cortex are spatial phase gradients, such that phase values change smoothly through the cortical sheet over time. Macroscopic cortical traveling waves have been understudied compared to micro- or mesoscopic waves. The spatial frequencies (i.e., the characteristic scales) of cortical waves have been characterized in the grey-matter for micro- and mesoscopic scales of cortex and show decreasing spatial power with increasing spatial frequency. This research, however, has been limited by the size of the measurement array, thus excluding macroscopic traveling waves. Obversely, poor spatial resolution of extra-cranial measurements prevents incontrovertible macroscopic estimates of spatial power via electroencephalogram and magnetoencephalogram. We apply a novel method to estimate the spatial frequency spectrum of phase dynamics in order to quantify the uncertain macroscopic scale. Stereotactic electroencephalogram is utilized to leverage measurements of local-field potentials within the grey matter, while also taking advantage of the sometimes large extent of spatial coverage. Irregular sampling of the cortical sheet is offset by use of linear algebra techniques to empirically estimate the spatial frequency spectrum. We find the spatial power of the phase is highest at the lowest spatial frequencies (longest wavelengths), consistent with the power spectra ranges for micro- and meso-scale dynamics, but here shown up to the size of the measurement array (15-25cm), i.e., approaching the entire extent of cortex. Low spatial frequencies dominate the cortical phase dynamics. This has important functional implications as it means that the phase measured at a single contact in the grey-matter is more strongly a function of global phase organization than local. This result arises across a wide range of temporal frequencies, from the delta band (2Hz) through to the high gamma range (100Hz).
Machine learning guided rational design of a non-heme iron-based lysine dioxygenase improves its total turnover number
Authors: Wilson R. Hunter , Damodaran Anoop R. , Bhagi-Damodaran Ambika
Published: June 2024

Highly selective C-H functionalization remains an ongoing challenge in organic synthetic methodologies. Biocatalysts are robust tools for achieving these difficult chemical transformations. Biocatalyst engineering has often required directed evolution or structure-based rational design campaigns to improve their activities. In recent years, machine learning has been integrated into these workflows to improve the discovery of beneficial enzyme variants. In this work, we combine a structure-based machine-learning algorithm with classical molecular dynamics simulations to down select mutations for rational design of a non-heme iron-dependent lysine dioxygenase, LDO. This approach consistently resulted in functional LDO mutants and circumvents the need for extensive study of mutational activity before-hand. Our rationally designed single mutants purified with up to 2-fold higher yields than WT and displayed higher total turnover numbers (TTN). Combining five such single mutations into a pentamutant variant, LPNYI LDO, leads to a 40% improvement in the TTN (218±3) as compared to WT LDO (TTN = 160±2). Overall, this work offers a low-barrier approach for those seeking to synergize machine learning algorithms with pre-existing protein engineering strategies.