bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.

Summary
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.

Summary
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.
Inkjet-printed transparent electrodes for electrical brain stimulation
Authors: Matta Rita , Reato Davide , Lombardini Alberto , Moreau David , O’Connor Rodney P. 
Published: September 2024

ABSTRACTElectrical 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

AbstractImmunotherapy 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

AbstractAlthough 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.SignificanceAging 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

AbstractMotivationCryogenic 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.ResultsIn 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 implementationThe 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

AbstractPurposeAlthough 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.MethodsAstrocytes 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.ResultsLC 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.ConclusionsAstrocyte 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

AbstractBackground and PurposeAnimal 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.MethodsWe 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.ResultsAll 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.ConclusionWe 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

AbstractPsilocybin 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

ABSTRACTSomatic 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.