bluuebunny/crossref_metadata_2025 huggingface dataset:
Platelet transfusion
Authors: Mo Allison , Wood Erica , McQuilten Zoe
Published: September 2024

Purpose of review

Platelet transfusions, used as prophylaxis or treatment for bleeding, are potentially life-saving. In many countries, demand for platelet transfusion is rising. Platelets are a limited and costly resource, and it is vital that they are used appropriately. This study will explore the evidence behind platelet transfusions in different contexts, in particular recent and important research in this area.

Recent findings

Recent randomized clinical trials demonstrate the efficacy of platelet transfusions in some contexts but potential detrimental effects in others. Platelet transfusions also carry risk of transfusion reactions, bacterial contamination and platelet transfusion refractoriness. Observational and clinical studies, which highlight approaches to mitigate these risks, will be discussed. There is growing interest in cold-stored or cryopreserved platelet units, which may improve platelet function and availability. Clinical trials also highlight the efficacy of other supportive measures such as tranexamic acid or thrombopoietin receptor agonists in patients with bleeding.

Although platelet transfusions are beneficial in many patients, there remain many settings in which the optimal use of platelet transfusions is unclear, and some situations in which they may have detrimental effects. Future clinical trials are needed to determine optimal use of platelet transfusions in different patient populations.
Characterization of Human Pancreatic Islet Cells Using a Single-Cell Western Blot Platform
Authors: Lenz Gal , Miao Lynn , Lenz Ayelet , Mares Jacob , Quijano Janine , Zook Heather N. , Komatsu Hirotake , Garcia Pablo , Ferreri Kevin , Ku Hsun Teresa , Kandeel Fouad
Published: September 2024

Objective

Islet transplantation is an effective treatment for type 1 diabetes. However, transplant success depends on quick islet assessment because islets deteriorate 2–3 days after isolation. A new tool, single-cell western blot (scWestern), offers results within 1 day. In this study, we aimed to test the suitability of scWestern to detect protein markers for beta (insulin), alpha (glucagon), and delta (somatostatin) cells, the 3 major endocrine cell types in islets.

Materials and Methods

We characterized the antibody specificity, signal intensity, and cell identification on the scWestern platform and then compared the islet cell composition analysis between scWestern and immunohistochemistry performed by the Integrated Islet Distribution Program.

Results

Islet cell composition is comparable for alpha and beta cells, but not delta cells. Protein expression levels of insulin, glucagon, and somatostatin in individual islet cells varied greatly, highlighting cell type heterogeneity. Surprisingly, scWestern revealed double-hormonal cells (~1%), co-expressing insulin and somatostatin or insulin and glucagon, in nondiabetic and nonobese adult human islets, which was confirmed by confocal immunofluorescence microscopy.

Conclusions

These results demonstrate that each alpha, beta, and delta cells express varying levels of peptide hormones, and a small subpopulation co-expresses double hormones in normal human islets. The scWestern platform will enable timely assessment of beta cell mass in isolated islets before clinical transplantation.
Spectral transmission of commercially available high-energy visible light–filtering spectacle lenses
Authors: Rampersad Nishanee , Carlson Anthony
Published: September 2024

SIGNIFICANCE

High-energy visible (HEV) light–filtering spectacle lenses are being widely promoted despite limited evidence to support their use. The spectral transmission properties of commercially available lenses varied, particularly in the HEV light region, and they do not perform in the same way for transmission of ultraviolet (UV)-A and HEV light.

PURPOSE

Although HEV light is important for several visual and nonvisual functions, there are concerns over the potential adverse effects of increased HEV light exposure. High-energy visible light–filtering spectacle lenses are being widely marketed to promote ocular health and improve sleep by reducing exposure to HEV light. This study reports on the spectral transmission characteristics of commercially available HEV light–filtering spectacle lenses based on the recommendations of the Spectral Bands Task Force technical report.

METHODS

The spectral transmission of light through nine afocal plastic lenses, including eight commercially available HEV light–filtering lenses and one clear uncoated control lens, was evaluated using a Cary 5000 UV-Vis-NIR spectrophotometer (Agilent Technologies, Johannesburg, South Africa) for wavelengths 250 to 780 nm. The percentage transmission values are reported for UV radiation and visible light, with emphasis for HEV light (380 to 500 nm) and the three subbands therein.

RESULTS

All lenses blocked UV-C and UV-B radiation (250 to 315 nm). For UV-A radiation (315 to 380 nm), six lenses showed optimal 100% absorption, whereas three lenses allowed ≤12%. The transmission values for the HEV light–filtering lenses ranged from 55 to 90% and 75 to 95% for HEV light of wavelengths 400 to 455 nm and 455 to 500 nm, respectively. In contrast, the control lens showed 92 (400 to 455 nm) and 93% (455 to 500 nm) transmission.

CONCLUSIONS

The HEV light–filtering spectacle lenses varied in their transmission properties and do not necessarily perform in the same way for transmission of UV-A and HEV light. Optometric personnel should consider these transmission properties, particularly for HEV light, when making recommendations to patients about HEV light–filtering spectacle lenses.
Running the enrollment numbers on ophthalmic clinical trials in the United States
Authors: Pucker Andrew D. , Derthick Nicole , Scott Lanita
Published: September 2024

SIGNIFICANCE

This is one of the first reports to summarize the enrollment metrics for ophthalmology trials completed in the United States (US).

PURPOSE

This study aimed to describe US ophthalmology clinical trial enrollment metrics to facilitate planning and budgeting of US Food and Drug Administration–regulated ophthalmological drugs trials.

METHODS

A GlobalData PLC search was conducted on or before February 27, 2024, to evaluate the clinical trial landscape for completed ophthalmology clinical trials conducted in the US. The primary search contained only the term “ophthalmology,” which was restricted to trials that were completed and were conducted within the US. Trials were classified as multicenter when trials included three sites or more, and when the enrollment search resulted in ≥30 multicenter trials for an individual indication, enrollment data were further broken down by Food and Drug Administration trial phase.

RESULT

The search yielded 2229 trials, which analyzed 980 different drugs produced by 854 different sponsors. The most common indications evaluated in US trials were macular degeneration, glaucoma, macular edema, allergies, and keratoconjunctivitis. Multicenter trials by indication had an overall median enrollment period range of 4.8 to 35.1 months; number of subjects enrollment, range of 36 to 518 subjects; number of sites utilized, range of 4 to 74 sites; and enrollment rate, range of 0.11 to 4.04 subjects/sites per month. There were 17 indications with ≥30 multicenter trials, which allowed for enrollment metric calculation by trial phase.

CONCLUSIONS

This study provides sponsors with an understanding of the number of subjects and sites needed to complete a trial while also setting realistic enrollment timelines. Although this work represents the US market, more work is needed to better understand other countries given that country-specific guidelines and subject beliefs may impact enrollment metrics.
A scoping review and evaluation of open-source transtibial amputation musculoskeletal models for female populations
Authors: Carswell Tess M. R. , Hasan Misha , Giles Joshua W.
Published: September 2024

Musculoskeletal modeling is often used to study people with transtibial amputations. Females in this population are of particular interest as they are underrepresented in research, experience unique challenges, and demonstrate gait biomechanics distinct from males. Because generic models often neglect innate variations between populations, it is important to determine whether data used to develop a model are representative of the population studied. The objective of this study was to review and analyze existing transtibial amputation musculoskeletal models, establish a database from the information compiled, and use the database to select the model most relevant for studying female populations. A scoping search was performed and a database was created based on data detailing the eligible models. Models were evaluated through a weighted decision process based on criteria of their representation of females with transtibial amputations, prosthetic functionality, development transparency, overall functionality, and experimental validation methods. The scoping review identified 3 studies, Willson et al., LaPrè et al., and Miller and Esposito. A database detailing these models was established. The Willson model scored highest on all criteria except overall functionality, where the LaPrè model outscored it. Based on the established weightings, the Willson model was classed most appropriate for the stated goals. The created database can be used by other researchers to guide their own modeling studies, irrespective of the population of focus. Of the 3, the Willson model was found most relevant for studying females with transtibial amputations. This model will be used in future work investigating and addressing challenges of females with transtibial amputations.
The role of sulbactam-durlobactam in treating carbapenem-resistant Acinetobacter infections
Authors: Bassetti Matteo , Giacobbe Daniele Roberto , Castaldo Nadia , Vena Antonio
Published: September 2024

Purpose of review

Infections caused by multidrug-resistant Acinetobacter baumannii present a significant global health challenge. Available treatment options are limited and frequently constrained by unfavourable safety and pharmacokinetic profiles. Sulbactam-durlobactam is a novel β-lactamase inhibitors combination specifically developed to target A. baumannii, including carbapenem-resistant strains. The purpose of this review is to assess the current evidence supporting the role of sulbactam-durlobactam in the management of A. baumannii infections.

Recent findings

We summarize the available evidence regarding the pharmacokinetic and pharmacodynamic profiles of sulbactam-durlobactam from key in-vitro and in-vivo studies. Additionally, efficacy results from the Phase III randomized controlled trial and real-world data on sulbactam-durlobactam's use against severe A. baumannii infections are also discussed.

Sulbactam-durlobactam is a promising addition to the treatment options for carbapenem-resistant A. baumannii infections. Ongoing research and vigilance are essential to monitor the development of in-vivo resistance, assess effectiveness across diverse patient populations, and explore potential synergistic combinations with other antimicrobials. Careful stewardship and comprehensive clinician education will be crucial to optimizing the clinical use of sulbactam-durlobactam.
Reassessment of the role of combination antifungal therapy in the current era
Authors: Neoh Chin Fen , Slavin Monica A.
Published: September 2024

Purpose of review

Given the high mortality and morbidity associated with invasive fungal diseases (IFDs), the use of combination antifungal therapies is often considered despite the dearth of data. This review aims to summarize the current state of literature of combination antifungal therapies, discussing the potential roles of newer antifungal combinations and key considerations for their clinical use.

Recent findings

In infections other than cryptococcal meningitis or in the setting of empirical treatment for suspected azole-resistant Aspergillus infections, the utility of the combination antifungal approaches remains controversial given the paucity of well designed randomized controlled trials. Data on potential combined antifungal treatments have been primarily limited to in-vitro studies, animal models, case reports and/or observational studies. With availability of novel antifungal agents (e.g. ibrexafungerp, fosmanogepix), combination therapy to treat mould infections should be re-visited. A phase 2 clinical trial of ibrexafungerp combined with voriconazole to treat invasive pulmonary aspergillosis is on-going.

There is a need to investigate the use of combination antifungal agents. This includes delineating the indication of these combined antifungal therapies and determining how to use them most appropriately in the clinical setting.
Diagnostic Performance of Surgical Indication for Branch-duct or Mixed-type Intraductal Papillary Mucinous Neoplasms of the Revised International Association of Pancreatology (IAP) 2023 Guidelines
Authors: Jung Hye-Sol , Han Youngmin , Chae Yoon Soo , Yun Won-Gun , Cho Young Jae , Seo Younsoo , Choi Go Won , Kim Haeryoung , Lee Kyoung Bun , Lee Dong Ho , Kwon Wooil , Park Joon Seong , Jang Jin-Young
Published: September 2024

Objective:

To evaluate the diagnostic performance of surgical indications of the revised International Association of Pancreatology (IAP) 2023 guidelines compared to the IAP 2017 and European 2018 guidelines.

Summary Background Data:

The revised IAP guidelines for surgical indications for branch duct (BD) intraductal papillary mucinous neoplasms (IPMN) include the presence of at least two worrisome features without mandatory endoscopic ultrasound.

Methods:

Among 663 patients who underwent resection for pathologically confirmed IPMN in a tertiary hospital between 2013 and 2023, 556 patients with BD or mixed-type IPMN were retrospectively reviewed. Diagnostic performances of the three guidelines for predicting high-grade dysplasia or IPMN with invasive carcinoma were compared. The primary outcome was the malignancy rate. Clinicopathological and radiological imaging data were analyzed.

Results:

A total of 540, 451, and 490 patients met the surgical indications of the IAP, 2017, 2023, and European guidelines, respectively. Malignant IPMN was observed in 229 (41.2%) patients (high-grade dysplasia, n=99; invasive carcinoma, n=130). Surgical indication by the IAP 2023 guidelines showed higher specificity (29.1 vs. 4.9%, P<0.001), positive predictive value (48.6 vs. 42.4%, P=0.031), and accuracy (55.5 vs. 44.1%, P<0.001) than the IAP 2017 guidelines. It also had higher specificity than the European guidelines (18.7%, P=0.024). The IAP 2023 guidelines showed a superior AUC of surgical indication (0.623 vs. 0.582 for the European guidelines, P<0.001; and 0.524 for the IAP guidelines, P=0.008).

Conclusions:

The IAP 2023 guidelines showed better malignancy prediction than the IAP 2017 and European guidelines, potentially reducing unnecessary surgeries.
Karl Pearson’s (1857–1936) patterns of publishing
Authors: Kiladi Maria , Cain Joe
Published: September 2024

Karl Pearson (1857–1936) was elected FRS in 1896 based on his contributions to applied mathematics. His contributions to biometry, eugenics, and other areas of applied statistics largely came later. This research note describes patterns in Pearson’s publishing behaviour: which venues he chose for his work, and how these choices compare with choices made by peers of similar standing at the same institution. This note quantifies patterns in choice for publishing venues for Pearson, both for his whole bibliography and for the subset of his bibliography associated with biometry and eugenics. This analysis indicates that Pearson relied to a high degree on publishing through venues either solely or primarily under his own editorial control. That pattern of publishing is a significant outlier compared with our sample of peers of similar local standing in the University of London. These results suggest the considerable potential for more detailed studies of publishing patterns by senior university researchers.
Spatiotemporal evidence accumulation through saccadic sampling for object recognition
Authors: Zheng Zhihao , Hu Jiaqi , Okazawa Gouki
Published: September 2024

Visual object recognition has been extensively studied under fixation conditions, but our natural viewing involves frequent saccadic eye movements that scan multiple local informative features within an object (e.g., eyes and mouth in a face image). These saccades would contribute to object recognition by subserving the integration of sensory information across local features, but mechanistic models that explain human behavior during natural object recognition have yet to be established due to the presumed complexity of the interactions between the visual and oculomotor systems. Here, we employ a framework of perceptual decision making and show that human face and object categorization behavior with saccades can be quantitatively explained by a model that simply accumulates the sensory evidence available at each moment. Our model can fit human object-recognition behavior even under conditions in which people freely make saccades to scan local features, departing from past studies that required controlled eye movements to test trans-saccadic integration. Moreover, further experimental results confirmed that active saccade commands (efference copy) do not substantially contribute to behavioral performance. Therefore, we propose that object recognition with saccades can be approximated by a parsimonious decisionmaking model without assuming complex interactions between the visual and oculomotor systems.
Inkjet-printed transparent electrodes for electrical brain stimulation
Authors: Matta Rita , Reato Davide , Lombardini Alberto , Moreau David , O’Connor Rodney P.
Published: September 2024

Electrical stimulation is a powerful tool for investigating and modulating brain activity, as well as for treating neurological disorders. However, understanding the precise effects of electrical stimulation on neural activity has been hindered by limitations in recording neuronal responses near the stimulating electrode, such as stimulation artifacts in electrophysiology or obstruction of the field of view in imaging. In this study, we introduce a novel stimulation device fabricated from conductive polymers that is transparent and therefore compatible with optical imaging techniques. The device is manufactured using a combination of microfabrication and inkjet printing techniques and is flexible, allowing better adherence to the brain’s natural curvature. We characterized the electrical and optical properties of the electrode and evaluated its performance in the brain of an anesthetized mouse. Furthermore, we combined experimental data with a finite-element model of the in-vivo experimental setup to estimate the maximum electric field that the highly transparent device can generate in the mouse brain. Our findings indicate that the device can generate an electric field as high as 300 V/m, demonstrating its potential for studying and manipulating neural activity using a range of electrical stimulation techniques relevant to human applications. Overall, this work presents a promising approach for developing versatile new tools to apply and study electrical brain stimulation.
Simulating CD8 T Cell Exhaustion: A Comprehensive Approach
Authors: Manrique-Rincón Andrea J. , Foster Ben , Horswell Stuart , Goulding David A. , Adams David J. , Speak Anneliese O.
Published: September 2024

Immunotherapy has revolutionised the treatment of multiple cancer types, however, these treatments only work for a proportion of patients and biomarkers to predict response are lacking. One correlate of response is the reinvigoration of a subset of CD8 T cells that have an exhausted phenotype and impaired functionality. In order to develop new therapies, reproducible models are required to identify candidate target genes that enables the reversal of key hallmarks of T cell exhaustion. Here we describe the development of anin vitromodel by chronically stimulating T cells with their cognate antigen and performed an in depth temporal phenotypic characterisation. This model recapitulates many of the critical hallmarks of exhaustion, including increased expression of canonical exhaustion surface markers, impaired proliferation, reduced cytokine production, decreased release of cytotoxic granules, and metabolic alterations, including dysfunctional mitochondria. These exhaustion hallmarks were validated using anin vivomodel and a gene signature identified which robustly define the sharedin vitroandin vivoexhausted state. Critically, this signature is also observed in tumour infiltrating T cells from multiple human tumour types, validating the translational potential of this model for discovering and triaging new therapies.
Regulation of Age-Related Lipid Metabolism in Ovarian Cancer
Authors: Feng Jihua , Rouse Clay Douglas , Coogan Isabella , Byrd Olivia , Nguyen Ethan , Taylor Lila , Garcia Santiago , Lee Hannah , Berchuck Andrew , Murphy Susan K. , Huang Zhiqing
Published: September 2024

Although a lot of effort has been dedicated to ovarian cancer (OC) research, the mortality rate is still among the highest in female gynecologic malignancies. The effects of the aged tumor microenvironment are still being undermined despite age being the highest risk factor in ovarian cancer development and progression. In this study, we have conducted RNA sequencing and lipidomics analysis of gonadal adipose tissues from young and aged rat xenografts before and after ovarian cancer formation. We have found significantly higher tumor formation rates and volumes in aged OC xenograft rat models compared to their young counterparts (p<0.05), suggesting the aged adipose microenvironment (AME) is more susceptible to OC outgrowth. We have revealed significant shifts in the gene expression enrichment from groups of young vs. aged ratsbeforetumor formation, groups of young vs. aged ratswhenthe tumor formed, and groups of aged ratsbefore and aftertumor formation. We also observed shifts in the lipid components of the gonadal adipose tissues between young and aged rat xenografts when tumors were generated.

Additionally, we found that the aged AME was associated with age-related changes in the immune cell composition, especially inflammation-related cells. The top hits showing the most differences between aged and young adipose tissues were eight genes including S100a8, S100a9, Il1rl1, Lcn2, C3, Hba-a1, Fcna, and Pnpla3, 22 lipids including multiple isoforms of free fatty acids (FFA) and triglyceride (TG), as well as four immune cells including neutrophil, myeloid dendritic cell, T cell CD4+ (non-regulatory), and mast cell activation. The functional correlation among S100a8, S100a9, neutrophil, and FFA (18:3) was also determined. Furthermore, FFA (18:3), which was shown to be downregulated in aged xenograft rats, was capable of inhibiting OC cell proliferation. In conclusion, our study suggested that aging promoted OC proliferation through changes in genes/pathways, lipid metabolism, and immune cells. Targeting the aging adipose microenvironment, particularly lipid metabolism reprogramming, holds promise as a therapeutic strategy for OC, which warrants further investigation.

Significance

Aging microenvironment of OC may be regulated by S100a8 and S100a9 secreted by adipocytes, preadipocytes, or neutrophils through affecting the lipid metabolism, such as FFA (18:3).
CryoTEN: Efficiently Enhancing Cryo-EM Density Maps Using Transformers
Authors: Selvaraj Joel , Wang Liguo , Cheng Jianlin
Published: September 2024

Motivation

Cryogenic Electron Microscopy (cryo-EM) is a core experimental technique used to determine the structure of macromolecules such as proteins. However, the effectiveness of cryo-EM is often hindered by the noise and missing density values in cryo-EM density maps caused by experimental conditions such as low contrast and conformational heterogeneity. Although various global and local map sharpening techniques are widely employed to improve cryo-EM density maps, it is still challenging to efficiently improve their quality for building better protein structures from them.

Results

In this study, we introduce CryoTEN - a three-dimensional U-Net style transformer to improve cryo-EM maps effectively. CryoTEN is trained using a diverse set of 1,295 cryo-EM maps as inputs and their corresponding simulated maps generated from known protein structures as targets. An independent test set containing 150 maps is used to evaluate CryoTEN, and the results demonstrate that it can robustly enhance the quality of cryo-EM density maps. In addition, the automatic de novo protein structure modeling shows that the protein structures built from the density maps processed by CryoTEN have substantially better quality than those built from the original maps. Compared to the existing state- of-the-art deep learning methods for enhancing cryo-EM density maps, CryoTEN ranks second in improving the quality of density maps, while running>10 times faster and requiring much less GPU memory than them.

Availability and implementation

The source code and data is freely available athttps://github.com/jianlin-cheng/cryoten
Morphological comparison of astrocytes in the lamina cribrosa and glial lamina
Authors: Waxman Susannah , Schilpp Hannah , Linton Ashley , Jakobs Tatjana C. , Sigal Ian A.
Published: September 2024

Purpose

Although the mechanisms underlying glaucomatous neurodegeneration are not yet well understood, cellular and small animal models suggest that LC astrocytes undergo early morphologic and functional changes, indicating their role as early responders to glaucomatous stress. These models, however, lack the LC found in larger animals and humans, leaving thein situmorphology of LC astrocytes and their role in glaucoma initiation underexplored. In this work, we aimed to characterize the morphology of LC astrocytesin situand determine differences and similarities with astrocytes in the mouse glial lamina (GL), the analogous structure in a prominent glaucoma model.

Methods

Astrocytes in the LCs of twenty-two eyes from goats, sheep, and pigs were stochastically labeled via Multicolor DiOlistics and imagedin situusing confocal microscopy. 3D models of DiOlistically-labeled LC astrocytes and hGFAPpr-GFP mouse GL astrocytes were constructed to quantify morphological features related to astrocyte functions. LC and GL astrocyte cross-pore contacts, branching complexity, branch tortuosity, and cell and branch span were compared.

Results

LC astrocytes displayed distinct spatial relationships with collagen, greater branching complexity, and higher branch tortuosity compared to GL astrocytes. Despite substantial differences in their anatomical environments, LC and GL astrocytes had similar cell and branch spans.

Conclusions

Astrocyte morphology in the LC was characterized through Multicolor DiOlistic labeling. LC and GL astrocytes have both distinct and shared morphological features. Further research is needed to understand the potentially unique roles of LC astrocytes in glaucoma initiation and progression.
Safety and Outcomes of Valproic Acid in Subarachnoid Hemorrhage Patients: A Retrospective Study
Authors: Cobler-Lichter Matthew , Suchdev Kushak , Tatro Hayley , Cascone Ava , Yang Joanna , Weinberg Janice , Abdalkader Mohamad K , Dasenbrock Hormuzdiyar H , Ong Charlene J , Cervantes-Arslanian Anna , Greer David , Nguyen Thanh N , Daneshmand Ali , Chung David Y
Published: September 2024

Background and Purpose

Animal studies have suggested that valproic acid (VPA) is neuroprotective in aneurysmal subarachnoid hemorrhage (SAH). Potential mechanisms include an effect on cortical spreading depolarizations (CSD), apoptosis, blood-brain barrier integrity, and inflammatory pathways. However, the effect of VPA on SAH outcomes in humans has not been investigated.

Methods

We conducted a retrospective analysis of 123 patients with nontraumatic SAH. Eighty-seven patients had an aneurysmal source and 36 patients did not have a culprit lesion identified. We used stepwise logistic regression to determine the association between VPA and the following: delayed cerebral ischemia (DCI), radiographic vasospasm, and discharge modified Rankin Scale (mRS) score > 3.

Results

All 18 patients who received VPA underwent coil embolization of their aneurysm. VPA use did not have a significant association with DCI on adjusted analysis (Odds Ratio, OR = 1.07, 95% CI: 0.20 – 5.80). The association between VPA use and vasospasm was OR = 0.64 (0.19 – 1.98) and discharge mRS > 3 was OR = 0.45 (0.10 – 1.64). Increased age (OR = 1.04, 1.01 - 1.07) and Hunt and Hess (HH) grade > 3 (OR = 14.5, 4.31 – 48.6) were associated with an increased likelihood for poor discharge outcome (mRS > 3). Younger age (OR = 0.96, 0.93 - 0.99), mFS score = 4 (OR = 4.14, 1.81 – 9.45), and HH grade > 3 (OR = 2.92, 1.11 – 7.69) were all associated with subsequent development of radiographic vasospasm. There were no complications associated with VPA administration.

Conclusion

We did not observe an association between VPA and the rate of DCI. There may have been a protective association on discharge outcome and radiographic vasospasm that did not reach statistical significance. We found that VPA use was safe and is plausible to be used in a population of SAH patients who have undergone endovascular treatment of their aneurysm. Larger, prospective studies are needed to determine the effect of VPA on outcome after SAH.
Psilocybin alters brain activity related to sensory and cognitive processing in a time-dependent manner
Authors: Nikolic Marek , Mediano Pedro , Froese Tom , Reydellet David , Palenicek Tomas
Published: September 2024

Psilocybin is a classic psychedelic and a novel treatment for mood disorders. Psilocybin induces dose-dependent transient (4-6 hours) usually pleasant changes in perception, cognition, and emotion by non-selectively agonizing the 5-HT2Areceptors and negatively regulating serotonin reuptake, and long-term positive antidepressant effect on mood and well-being. Long-term effects are ascribed to the psychological quality of the acute experience, increase in synaptodensity and temporary (1-week) down-regulation of 5-HT2Areceptors. Electroencephalography, a non-invasive neuroimaging tool, can track the acute effects of psilocybin; these include the suppression of alpha activity, decreased global connectivity, and increased brain entropy (i.e. brain signal diversity) in eyes-closed resting-state. However, few studies investigated how these modalities are affected together through the psychedelic experience. The current research aimed to evaluate the psilocybin intoxication temporal EEG profile. 20 healthy individuals (10 women) underwent oral administration of psilocybin (0.26mg/kg) as part of a placebo-controlled cross-over study, resting-state 5-minute eyes closed EEG was obtained at baseline and 1, 1.5, 3, 6, and 24 hours after psilocybin administration. Absolute power, relative power spectral density (PSD), power envelope global functional connectivity (GFC), Lempel-Ziv complexity (LZ), and a Complexity via State-Space Entropy Rate (CSER) were obtained together with measures of subjective intensity of experience. Absolute power decreased in alpha and beta band, but increased in delta and gamma frequencies. 24h later was observed a broadband decrease. The PSD showed a decrease in alpha occipitally between 1 and 3 hours and a decrease in beta frontally at 3 hours, but power spectra distribution stayed the same 24h later. The GFC showed decrease acutely at 1, 1.5, and 3 hours in the alpha band. LZ and showed an increase at 1 and 1.5 hours. Decomposition of CSER into functional bands shows a decrease in alpha band but increase over higher frequencies. Further, complexity over a source space showed opposing changes in the Default Mode Network (DMN) and visual network between conditions, suggesting a relationship between signal complexity, stimulus integration, and perception of self. In an exploratory attempt, we found that a change in gamma GFC in DMN correlates with oceanic boundlessness. Psychological effects of psilocybin may be wrapped in personal interpretations and history unrelated to underlying neurobiological changes, but changes to perception of self may be bound to perceived loss of boundary based on whole brain synchrony with the DMN in higher frequency bands.
Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy
Authors: Vanner Robert J. , Bansal Suraj , Buttigeig Marco M. , Zeng Andy G.X. , Rondeau Vincent , Chan Darryl Y. , Chan-Seng-Yue Michelle , Jin Liqing , McLeod Jessica , Donato Elisa , Stelmach Patrick , Vlasschaert Caitlyn , Yang Yitong , Gupta Aarushi , Genta Sofia , Sanz Garcia Enrique , Shlush Liran , Ribeiro Mauricio , Butler Marcus O. , Abelson Sagi , Minden Mark , Chan Steven M. , Rauh Michael J. , Trumpp Andreas , Dick John E
Published: September 2024

Somatic mutations inactivatingTET2are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In our mouse model, hematopoieticTet2mutation enhanced immune checkpoint blockade (ICB) response. Enhanced ICB response withTet2mutation required phagocytes, CD4 and CD8 T cells. Mechanistically, inTet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially induced anti-tumor states and restricted cell states linked to tumor progression.Tet2-mutant monocytes activated costimulatory programs, whileTet2-mutant T cells showed enhanced T cell memory signatures, lesser exhaustion and decreased regulatory phenotype. Our murine data was clinically relevant, since we found that melanomas from patients withTET2driver mutation-CH (TET2-CH) showed enhanced immune infiltration, T cell activation, and T cell memory programs. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, our data establishes that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.
Surgeon Factors and Their Association With Operating Room Turnover Time
Authors: Pandit Kshitij , Wang Luke , Rosenberg Joel , Goldhaber Nicole , Buckley Jill C. , Ramamoorthy Sonia , Mekeel Kristin L. , Bagrodia Aditya
Published: September 2024

Introduction

Operating room (OR) turnover time (TT), defined as the interval between the completion of one surgery and the start of the next, is a critical measure of OR efficiency impacting healthcare costs, patient outcomes, and surgical staff well-being. Previous research has identified various contributors to TT, such as surgical team dynamics, OR preparation, and interdisciplinary workflows. However, the influence of surgeon-specific factors like gender, administrative roles, and experience on TT remains underexplored. This study aims to address this gap by examining how these individual surgeon characteristics impact OR efficiency.

Methods

We conducted a retrospective study at the UC San Diego School of Medicine, a tertiary academic medical center. We analysed 12,820 surgical case entries from January 2022 to July 2023, sourced from the electronic health record system. Surgeons were categorized by gender, ethnicity, years of experience, training at UCSD, academic rank, and administrative roles. We utilized Mann-Whitney U test for binary variables and Kruskal-Wallis H test for variables with more than two categories. Multivariable linear regression was applied, adjusting for multiple comparisons using Holm correction. A p-value of less than 0.05 was considered statistically significant. All data analysis was performed using IBM SPSS version 29.

Results

Our analysis of 12,820 surgical cases revealed that surgeons in administrative roles and those with over ten years of experience demonstrated significantly shorter turnover times (TT). Specifically, administrators demonstrated a TT of 27 minutes, compared to 35 minutes for non-administrators (p<0.001) (Table 2). Surgeons with more than ten years of experience had a TT of 31 minutes, versus 37 minutes for those with less experience (p<0.001). Multivariable linear regression confirmed these associations, with significant reductions in TT linked to administrative roles (beta: - 7.2; 95% confidence interval (CI): -8.2 to -6.2, p<0.001) and surgeon experience (beta: -4.7, 95% CI: -5.9 to -3.5, p< 0.001).

Conclusion

We recommend efforts focusing on building a standardized environment for surgeons regardless of their background. This could lead to not only an equitable. OR culture but also an overall increase in the institution efficiency and patient outcomes.
Border control strategies for reducing importation risk of Clade Ib Mpox
Authors: Jin Shihui , Guan Tong , Endo Akira , Gan Gregory , Janhavi A. , Hu Gang , Ejima Keisuke , Lim Jue Tao , Dickens Borame L
Published: September 2024

Background

The Clade Ib monkeypox virus (MPXV), newly identified in the ongoing 2024 mpox outbreak, can be more transmissible through non-sexual routes compared to the previous Clade IIb strain. With imported cases sporadically reported globally, concerns have emerged about the potential of widespread transmission in the general community after importation events. Border control measures, such as screening and quarantining of arriving travellers, may help mitigate this risk and prevent localized outbreaks in the event of global spread.

Methods

We proposed nine border control strategies and evaluated their effectiveness in reducing importation risk using 10,000 microsimulations of individual infection profiles and PCR testing results under scenarios with varying disease prevalence levels (0.01%, 0.05%, and 0.1%) in the country of origin.

Results

The proposed border-control measures would reduce missed cases by 40.1% (39.1%–41.0%), 49.8% (48.8%–50.8%), and 58.1% (57.1%–59.0%) for predeparture, on-arrival, and both tests, respectively. Replacing the on-arrival test with a seven-day quarantine and post-quarantine testing would lower the count to 21.8% (20.9%–22.6%). Quarantine-only strategies showed a linear increase in effectiveness against duration, reaching a 90.4% (89.8%–91.0%) reduction with a 28-day quarantine. Disparities in distributions of missed case counts across strategies would become more pronounced at higher prevalence levels, with stringent approaches like quarantining followed by post-quarantine screening and 28-day quarantine keeping counts below two per 10,000 travellers, even at 0.1% prevalence.

Conclusions

When disease prevalence in the country of origin is low (0.01%), less restrictive approaches such as single on-arrival testing or a 14-day quarantine can maintain very low imported case counts of one or below. At higher prevalences, seven-day quarantining followed by post-quarantine testing, or 28-day quarantining is required to maintain similar effects. Decision makers will face balancing importation risk management and the negative impacts of such interventions to maintain safe international travel.
Learning to read transforms phonological into phonographic representations: Evidence from a Mismatch Negativity study
Authors: Pattamadilok Chotiga , Wang Shuai , Bolger Deidre , Dubarry Anne-Sophie
Published: September 2024

Learning to read changes the nature of speech representation. One possible change consists in transforming phonological representations into phonographic ones. However, evidence for such transformation remains surprisingly scarce. Here, we used a novel word learning paradigm to address this issue. During a learning phase, participants were exposed to unknown words in both spoken and written forms. Following this phase, the impact of spelling knowledge on spoken input perception was assessed at two time points through an unattended oddball paradigm, while the Mismatch Negativity component was measured by high density EEG. Immediately after the learning phase, no influence of spelling knowledge on the perception of the spoken input was found. Interestingly, one week later, this influence emerged, making similar sounding words with different spellings more distinct than similar sounding words that also share the same spelling. Our finding provides novel neurophysiological evidence of an integration of phonological and orthographic representations that occurs once newly acquired knowledge has been consolidated. These novel phonographic representations may characterize how known words are stored in literates’ mental lexicon.
Development of a competition assay to assess thein vitrofitness of dengue virus serotypes using an optimized serotype-specific qRT-PCR
Authors: Griffon Anne-Fleur , Rault Loeïza , Simon-Lorière Etienne , Dupont-Rouzeyrol Myrielle , Inizan Catherine
Published: September 2024

Background

Comparing thein vitrofitness of dengue virus (DENV) isolates is a pivotal approach to assess the contribution of DENV strains’ replicative fitness to epidemiological contexts, including serotype replacements. Competition assays are the gold standard to compare thein vitroreplicative fitness of viral strains. Implementing competition assays between DENV serotypes requires an experimental setup and an appropriate read-out to quantify the viral progeny of strains belonging to different serotypes.

Results

In the current study, we optimized an existing serotyping qRT-PCR by adapting primer/probe design and multiplexing the serotype-specific qRT-PCR reactions, allowing to accurately detect and quantify all four DENV serotypes. The qRT-PCR was specific, had a limit of detection of at least 5.08×101, 5.16×101, 7.14×101and 1.36 x101genome copies/µL, an efficiency of 1.993, 1.975, 1.902, 1.898 and a linearity (R²) of 0.99975, 0.99975, 0.9985, 0.99965 for DENV-1, -2, -3 and -4 respectively. Challenge of this multiplex serotype-specific qRT-PCR on mixes of viral supernatants containing known concentrations of strains from two serotypes evidenced an accurate quantification of the amount of genome copies of each serotype. We next developed anin vitroassay to compare the replicative fitness of two DENV serotypes in the human hepatic cell line HuH7: quantification of the viral progeny of each serotype in the inoculum and the supernatant using the serotype-specific multiplex qRT-PCR unveiled an enrichment of the supernatant in DENV-1 genome copies, uncovering the enhanced replicative fitness of this DENV-1 isolate.

Conclusions

This optimized qRT-PCR combined to a relevant cellular model allowed to accurately quantify the viral progeny of two DENV strains belonging to two different serotypes in a competition assay, allowing to determine which strain had a replicative advantage. This reliable experimental setup is adaptable to the comparative study of the replicative fitness of any DENV serotypes.
Sheltered load in fungal mating-type chromosomes revealed by fitness experiments
Authors: Guyot Lou , Chahine Elizabeth , De Filippo Elsa , Lalanne Christophe , Brun Sylvain , Hartmann Fanny E. , Giraud Tatiana
Published: September 2024

Sex chromosomes and mating-type chromosomes can carry large regions with suppressed recombination. As a result of a lower efficacy of selection, recessive deleterious mutations are expected to accumulate in these non-recombining regions. Multiple genomic analyses have indirectly inferred the presence of deleterious mutations in sex and mating-type chromosomes, but direct experimental evidence remains scarce. Here, we performed fitness assays in fungi with megabase-large and young non-recombining regions around the mating-type locus, using three Sordariales species, to test whether heterokaryons (diploid-like, heterozygous at the mating-type locus) exhibited a fitness advantage over homokaryons (haploid-like, with a single mating-type allele), in terms of spore germination dynamics or mycelium growth speed, under different conditions of light and temperature. We found a faster growth of heterokaryons compared to one of the homokaryons forPodospora anserinaat 18°C and forSchizothecium tetrasporumandSchizothecium tritetrasporumat 22°C under light. These findings suggest the presence of a sheltered load, i.e. recessive deleterious mutations at the heterozygous state in or near non-recombining regions. Genomic analyses indeed confirmed that strains in these selfing species are highly homozygous beyond the regions around the mating-type locus. We also checked that the difference in growth rates did not result from different numbers or densities of nuclei between homokaryons and heterokaryons. Leveraging the experimental assets of fungi, allowing cultivating separately haploid-like and diploid-like life stages, our experiments provided one of the rare direct experimental evidence of sheltered load around mating-compatibility loci, which is crucial for our understanding of sex-related chromosome evolution.
Ancient DNA Clarifies the Identity and Geographic Origin of the holotype of the genusCtenomys
Authors: Maestri Renan , Gonçalves Gislene Lopes , Nicolas-Colin Violaine , Bryjova Anna , Fornel Rodrigo , Coissac Eric , Taberlet Pierre , Moreira Gilson Rudinei Pires , de Freitas Thales Renato Ochotorena
Published: September 2024

CtenomysBlainville 1826 ranks among the top ten most diverse mammal genera in terms of species richness. However, the taxonomic history ofCtenomys brasiliensisBlainville,1826, the corresponding type species, has long been obscured by a dearth of information regarding the collection data of the type material, compounded by an elusive geographic origin. Here, employing ancient DNA methodology, we sequenced the complete mitogenome of the remaining type specimen and conducted an extensive historical investigation to correlate originally described locality names with present-day locales in South America. Our analysis unequivocally confirms that the type specimen corresponds to the species currently designated asCtenomys minutusNehring, 1887. This resolution lays to rest a century-old debate surrounding the provenance of the type specimen, rejecting prior hypotheses that placed its collection site in southeastern Brazil or Uruguay. Instead, our evidence suggests it was likely obtained from a third location in southernmost Brazil. Previous analyses overlooked this new location due to confusion surrounding geographic nomenclature and labeling errors, issues rectified by our combined mitogenomic and historical approach. Furthermore, quantitative morphological analyses boost our findings, demonstrating a closer affinity betweenC. brasiliensisandC. minutuswithin the same species group. Accordingly, we validateC. brasiliensisand proposeC. minutusas its junior synonym. Our study underscores the importance of robust DNA analyses in confirming the identity and geographic origins of type specimens, especially forCtenomysspecies with similar phenotypes, and specimens collected centuries ago.