bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved predictive diagnosis of diabetic macular edema based on hybrid models: an observational study
Authors: Hughes-Cano JA , Quiroz-Mercado H , Hernández-Zimbrón LF , García-Franco R , Mijangos JF Rubio , López-Star E , García-Roa M , Lansingh VC , Olivares-Pinto U , Thébault SC 
Published: April 2023

AbstractDiabetic Macular Edema (DME) is the most common sight-threatening complication of type 2 diabetes. Our goal was to develop an alternative method to optical coherence tomography (OCT) for DME diagnosis by introducing spectral information derived from spontaneous electroretinogram (ERG) signals as a single input or combined with eye fundus. To this end, an observational study was completed (n = 233 participants). Basal ERGs were used to generate scalograms and spectrograms via Wavelet and Fourier transforms, respectively. Using transfer learning, distinct Convolutional Neural Networks (CNN) were trained as classifiers for DME using OCT, scalogram, spectrogram, and fundus images. Input data were randomly split into training and test sets with a proportion of 80 % to 20 %, respectively. The top performers for each input type were selected, OpticNet-71 for OCT and DenseNet-201 for fundus and non-evoked ERG-derived scalograms, to generate a combined model by assigning different weights for each of the selected models. Model validation was performed using a dataset alien to the training phase of the models. None of the models powered by non-evoked ERG-derived input performed well. Metrics of the best hybrid models were all above 0.81 for fundus combined with non-evoked ERG-derived information; and above 0.85 for OCT combined with non-evoked ERG-derived scalogram images. These data show that the spontaneous ERG-based model improves all the performance metrics of the fundus and OCT-based models, with the exception of sensitivity for the OCT model, to predict DME. Combining non-evoked ERG with OCT represents an improvement to the existing OCT-based models, and combining non-evoked ERG with fundus is a reliable and economical alternative for the diagnosis of DME in underserved areas where OCT is unavailable.Author summaryProviding an alternative diagnostic method to those that already exist for diabetic macular edema (DME) that is reliable and physically and economically accessible is needed in places where optical coherence tomography (OCT) is unavailable. In this work, we combined artificial intelligence (AI) classifying techniques with information from a newly introduced signal that can be captured in a non-invasive manner, the spontaneous oscillations of the electroretinogram (ERG). We found that if these signals alone are ineffective in diagnosing DME cases, they improve the performance of AI models based on either eye fundus or OCT in the prediction of DME. We therefore conclude that combining spontaneous ERG with fundus, which is a basic optometric test even in underserved areas, represents a reliable alternative to OCT for the diagnosis of DME. Also, combining OCT with spontaneous ERG signals will help ameliorate the diagnosis of DME.
Comparative Effectiveness of mRNA-1273 and BNT162b2 COVID-19 Vaccines in Immunocompromised Individuals: A Systematic Review and Meta-Analysis Using the GRADE Framework
Authors: Wang Xuan , Haeussler Katrin , Spellman Anne , Phillips Leslie E. , Ramiller Allison , Bausch-Jurken Mary T. , Sharma Pawana , Krivelyova Anna , Vats Sonam , Van de Velde Nicolas 
Published: April 2023

ABSTRACTIntroductionDespite representing only 3% of the US population, immunocompromised (IC) individuals account for nearly half of the COVID-19 breakthrough hospitalizations. IC individuals generate a lower immune response following vaccination in general, and the US CDC recommended a third dose of either mRNA-1273 or BNT162b2 COVID-19 vaccines as part of their primary series. Influenza vaccine trials have shown that increasing dosage could improve effectiveness in IC populations. The objective of this systematic literature review and pairwise meta-analysis was to evaluate the clinical effectiveness of mRNA-1273 (50 or 100 mcg/dose) versus BNT162b2 (30 mcg/dose) in IC populations using the GRADE framework.MethodsThe systematic literature search was conducted in the World Health Organization COVID-19 Research Database. Studies were included in the pairwise meta-analysis if they reported comparisons of mRNA-1273 and BNT162b2 in IC individuals ≥18 years of age; outcomes of interest were SARS-CoV-2 infection, hospitalization due to COVID-19, and mortality due to COVID-19. Risk ratios (RR) were pooled across studies using random-effects meta-analysis models. Outcomes were also analyzed in subgroups of patients with cancer, autoimmune disease, and solid organ transplant. Risk of bias was assessed for randomized and observational studies using the Risk of Bias 2 tool and the Newcastle-Ottawa Scale, respectively. Evidence was evaluated using the GRADE framework.ResultsOverall, 22 studies were included in the pairwise meta-analysis. Compared with BNT162b2, mRNA-1273 was associated with significantly reduced risk of SARS-CoV-2 infection (RR 0.87, 95% CI 0.79–0.96;P=0.0054;I2=61.9%), COVID-19–associated hospitalization (RR 0.83, 95% CI 0.76–0.90;P<0.0001;I2=0%), and COVID-19–associated mortality (RR 0.62, 95% CI 0.43–0.89;P=0.011;I2=0%) in IC populations. Results were consistent across subgroups. Because of sample size limitations, relative effectiveness of COVID-19 mRNA vaccines in IC populations cannot be studied in randomized trials and evidence certainty among comparisons was type 3 (low) and 4 (very low), reflecting potential biases in observational studies.ConclusionThis GRADE meta-analysis based on a large number of consistent observational studies showed that the mRNA-1273 COVID-19 vaccine is associated with improved clinical effectiveness in IC populations compared with BNT162b2.
Association Between the Degree of Vertebrobasilar Stenosis, Location, Infarction Pattern and QMRA Flow State
Authors: Ballout Ahmad A. , Huang Brendan , Oh Seok Yoon , Black Karen , Sideras Panagiotis , Arora Rohan , Yaghi Shadi , Katz Jeffrey M. , Libman Richard B. 
Published: April 2023

ABSTRACTBackground and PurposeThe relationship between the degree and location of vertebrobasilar stenosis and QMRA distal-flow status is uncertain. Our aim was to investigate the relationship between QMRA distal-flow status with degree and location of vertebrobasilar stenosis.MethodsWe retrospectively reviewed patients who presented with acute ischemic stroke, had neurovascular imaging demonstrating ≥50% stenosis of extracranial or intracranial vertebral or basilar arteries, and QMRA performed within one year of stroke, between 2009 and 2021. Standardized methods were used to measure the degree of stenosis and to dichotomize vertebrobasilar distal-flow status. Patients were grouped based on the involved artery and the location and severity of disease. P-values were calculated using chi-squared analysis and Fisher exact test with statistical significance defined as p <0.05.ResultsSixty-nine patients met study inclusion, consisting of 31 with low distal-flow and 38 with normal distal-flow states. Low distal-flow states were found exclusively in patients with severe stenosis or occlusion; however, severe stenosis or occlusion was poorly predictive of distal-flow status as nearly half of these patients had normal flow states (47%). Bilateral vertebral disease was significantly associated with low distal-flow states compared to patients with unilateral vertebral (70.8% versus 14.3%; p = 0.01), isolated basilar (70.8% versus 28.6%; p = 0.01), or mixed (71.4% versus 47.1%; p = 0.01) disease.ConclusionsSevere stenosis of ≥70% may mark the minimal threshold required to cause hemodynamic insufficiency in the posterior circulation, but nearly half of these patients may remain hemodynamically sufficient. The presence of bilateral vertebral stenosis resulted in a five-fold increase in the probability of QMRA low distal-flow status compared to unilateral vertebral disease. Our findings may have implications for the design of future treatment trials of endovascular versus medical management that may use hemodynamic markers as inclusion criteria.
Planning optimal sequence for arteriovenous fistula creation in hemodialysis patients, using quality-of-life adjusted access patency
Authors: Kumar Manoj , Usulumarty Deepa , Brahmbhatt Ravi , Rangaraj Narayan , Noronha Santosh , Billa Viswanath 
Published: April 2023

AbstractObjectiveThe study proposes a decision strategy for the choice of arm for placement of an arteriovenous fistula (AVF) in patients with kidney failure who undergo hemodialysis (HD). The possible surgical sites for placement of the AVF are located in the arm and at two locations in each arm, the wrist (distal AVF) and the elbow (proximal AVF). Recommendations are made for the location of the first AVF and subsequent ones, as needed.MethodA retrospective analysis of AVFs created between 2015 and 2022 in patients at five HD centers was performed. The study uses qualityadjusted survival, parametric, and nonparametric survival methods. We conducted two surveys to assess the HD patient’s quality of life. In addition, the Cox proportional hazard model is used to suggest a patient-specific strategy. The survival functions are compared using the log-rank and Tarone-Ware tests.ResultsThe results of the multivariate analysis showed that placing AVFs on the non-dominant arm leads to superior patient quality of life compared to the dominant arm. The quality-adjusted survival was also found to be better when AVFs were located on the non-dominant arm. Considering both these aspects and also clinical constraints on the sequence, the optimal sequence is found to be non-dominant distal followed by non-dominant proximal locations, followed by a similar sequence on the dominant hand if required.ConclusionThe study identifies criteria for data-driven decision-making as to good locations for AVFs for Hemodialysis and supports clinical experience and practice in this matter.
Linezolid population pharmacokinetic model in plasma and cerebrospinal fluid among patients with tuberculosis meningitis
Authors: Abdelgawad Noha , Wasserman Sean , Abdelwahab Mahmoud Tareq , Davis Angharad , Stek Cari , Wiesner Lubbe , Black John , Meintjes Graeme , Wilkinson Robert J. , Denti Paolo 
Published: April 2023

ABSTRACTBackgroundLinezolid is being evaluated in novel treatment regimens for tuberculous meningitis (TBM). The pharmacokinetics of linezolid have not been characterized in this population, particularly in cerebrospinal fluid (CSF) where exposures may be affected by changes in protein concentration and rifampicin co-administration.MethodsThis was a sub-study of a phase 2 clinical trial of intensified antibiotic therapy for adults with HIV-associated TBM. Participants in the intervention groups received high-dose rifampicin (35 mg/kg) plus linezolid 1200 mg daily for 28 days followed by 600 mg daily until day 56. Plasma was intensively sampled, and lumbar CSF was collected at a single timepoint in a randomly allocated sampling window, within 3 days after enrolment. Sparse plasma and CSF samples were also obtained on day 28. Linezolid concentrations were analyzed using non-linear mixed effects modelling.Results30 participants contributed 247 plasma and 28 CSF linezolid observations. Plasma PK was best described by a one-compartment model with first-order absorption and saturable elimination. The typical value of maximal clearance was 7.25 L/h. Duration of rifampicin co-treatment (compared on day 3 versus day 28) did not affect linezolid pharmacokinetics. Partitioning between plasma and CSF correlated with CSF total protein concentration up to 1.2 g/L where the partition coefficient reached a maximal value of 37%. The equilibration half-life between plasma and CSF was estimated at ∼3.5 hours.ConclusionLinezolid was readily detected in CSF despite co-administration of the potent inducer rifampicin at high doses. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults.
Histone Deacetylases (HDACs) maintain expression of the pluripotent gene network via recruitment of RNA polymerase II to coding and non-coding loci
Authors: Kelly RDW , Stengel KR , Chandru A , Johnson LC , Hiebert SW , Cowley SM 
Published: April 2023

ABSTRACTHistone acetylation is a dynamic modification regulated by the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Deacetylation of histone tails results in chromatin tightening and therefore HDACs are generally regarded as transcriptional repressors. Counterintuitively, simultaneous deletion ofHdac1andHdac2in embryonic stem cells (ESC) reduced expression of pluripotent transcription factors,Oct4, Sox2andNanog(OSN). By shaping global histone acetylation patterns, HDACs indirectly regulate the activity of acetyl-lysine readers, such as the transcriptional activator, BRD4. We used inhibitors of HDACs and BRD4 (LBH589 and JQ1 respectively) in combination with precision nuclear run-on and sequencing (PRO-seq) to examine their roles in defining the ESC transcriptome. Both LBH589 and JQ1 caused a marked reduction in the pluripotent network. However, while JQ1 treatment induced widespread transcriptional pausing, HDAC inhibition caused a reduction in both paused and elongating polymerase, suggesting an overall reduction in polymerase recruitment. Using enhancer RNA (eRNA) expression to measure enhancer activity we found that LBH589-sensitive eRNAs were preferentially associated with super-enhancers and OSN binding sites. These findings suggest that HDAC activity is required to maintain pluripotency by regulating the OSN enhancer network via the recruitment of RNA polymerase II.
ARecql5mutant enables complex chromosomal engineering of mouse zygotes
Authors: Iwata Satoru , Nagahara Miki , Iwamoto Takashi 
Published: April 2023

SummaryComplex chromosomal rearrangements (CCRs) are often observed in clinical samples from patients with cancer and congenital diseases but are difficult to induce experimentally. For generating animal models, these CCRs must be induced as desired, otherwise they cause profound genome instability and/or result in cell death. Here, we report the first success in establishing animal models for CCRs. The disruption ofRecql5, which degrades RAD51 during DNA repair, successfully induces CRISPR/Cas9-mediated CCRs, establishing a mouse model containing triple fusion genes and megabase-sized inversions. Notably, some of these structural features of individual chromosomal rearrangements use template switching and microhomology-mediated break-induced replication mechanisms and are reminiscent of the newly described phenomenon “chromoanasynthesis.” Whole-genome sequencing analysis revealed that the structural variants in these mice caused only target-specific rearrangements. Thus, these data show that Recql5-deficient mice would be a novel powerful tool for analyzing the pathogenesis of CCRs, particularly chromoanasynthesis, whose underlying mechanisms are poorly understood.
High-THCCannabissmoke impairs working memory capacity in spontaneous tests of novelty preference for objects and odors in rats
Authors: Barnard Ilne L. , Onofrychuk Timothy J. , Toderash Aaron D. , Patel Vyom N. , Glass Aiden E. , Adrian Jesse C. , Laprairie Robert. B. , Howland John G. 
Published: April 2023

AbstractWorking memory (WM) is an executive function that orchestrates the use of a limited amount of information, referred to as working memory capacity (WMC), in cognitive functions. In humans,Cannabisexposure impairs WM; however, it is unclear ifCannabisfacilitates or impairs rodent WM. Existing literature also fails to address the effects ofCannabisexposure on rodent WMC using exposure paradigms that closely mirror patterns of human use. In the present study, WMC of rats was inferred by novelty preference after a short delay in spontaneous recognition-based tests. Either object or odor-based stimuli were used in different variations of the tests that present identical (IOT) and different (DOT) sets of stimuli (3 or 6) for low-and high-cognitive loads, respectively. Additionally, we present a human-machine hybrid (HYB) behavioral quantification approach which supplements stopwatch-based scoring with supervised machine learning (SML)-based classification, enabling behavioral data to be made publicly available. After validating the spontaneous tests, 6-item IOT and DOT tests with the HYB method were used to evaluate the impact of acute exposure to high-THC or high-CBDCannabissmoke on novelty preference. Under control conditions, rats showed novelty preference in all test variations. We found that high-THC, but not high-CBD,Cannabissmoke exposure impaired novelty preference for objects under a high-cognitive load. Odor-based recognition deficits were seen under both low-, and high-cognitive loads only following high-THC smoke exposure. Ultimately, these data show thatCannabissmoke exposure impacts novelty preference in a load-dependent, and stimuli-specific manner.Significance StatementWorking memory (WM) capacity is the limited amount of information that can be utilized by WM to orchestrate processes like learning and memory. Using object-and odor-based spontaneous recognition tests, the impact of high-THC or high-CBDCannabissmoke on novelty preference was evaluated. Behavioral measurements were generated using a combination of open-source analysis software and traditional stopwatch scoring to form a human-machine hybrid (HYB) scoring method. We show novelty preference deficits under high-cognitive loads in object-based tests, while impacting novelty preference under both high-and low-cognitive loads in the odor-based tests. Ultimately, we show thatCannabissmoke exposure affects cognitive functions that underly WM in rats, which has broad implications for human use.
TheAchromobacterType 3 secretion system drives pyroptosis and immunopathology via independent activation of NLRC4 and NLRP3 inflammasomes
Authors: Turton Keren , Parks Hannah , Zarodkiewicz Paulina , Hamad Mohamad A. , Dwane Rachel , Parau Georgiana , Ingram Rebecca J. , Coll Rebecca C. , Bryant Clare E. , Valvano Miguel A. 
Published: April 2023

AbstractAchromobacterspecies are newly recognized opportunistic, pro-inflammatory Gram-negative pathogens in immunocompromised individuals, but how they interact with the innate immune system to drive inflammation is poorly understood. We createdsctV(Type 3 Secretion System baseplate) mutants in threeAchromobacterclinical isolates from two species and showed that all three required the T3SS to induce cell death in human macrophages. Mutating other critical T3SS components also abolished cell death, which was restored by genetic complementation. Cell death ofAchromobacter-infected macrophages was contact-dependent, enhanced by bacterial internalisation, and caused by inflammasome-dependent pyroptosis (typified by Gasdermin-D cleavage and IL-1β secretion). Macrophages deficient in the inflammasome sensors NLRC4 or NLRP3 underwent pyroptosis upon bacterial internalization but those deficient in both NLRC4 and NLRP3 did not, suggesting either sensor can mediate pyroptosis induction in a T3SS-dependent manner. Detailed analysis of the intracellular trafficking of one isolate indicated that the intracellular bacteria reside in an acidic LAMP-1/dextran-positive membrane compartment. Using an intranasal mouse infection model, we observed thatAchromobacterdamages lung structure and causes severe illness, contingent on a functional T3SS. Together, we demonstrate thatAchromobacterspecies can survive phagocytosis by macrophages and promote macrophage cell death and inflammation by redundant mechanisms of pyroptosis induction.
A Rapid, Functional sgRNA Screening Method for Generating Murine RET and NTRK1 Fusion Oncogenes
Authors: Schubert Laura , Le Anh T. , Hinz Trista K. , Navarro Andre , Nelson-Taylor Sarah K. , Nemenoff Raphael A. , Heasley Lynn E. , Doebele Robert C. 
Published: April 2023

AbstractCRISPR/Cas9 gene editing technology is an indispensable and powerful tool in the field of cancer biology. To conduct successful CRISPR-based experiments, it is crucial that sgRNAs generate their designed alterations. Here, we describe a simple and efficient sgRNA screening method for validating sgRNAs that generate oncogenic gene rearrangements. We used IL3-independence in Ba/F3 cells as an assay to identify sgRNA pairs that generate fusion oncogenes involving theRetandNtrk1tyrosine kinases. We confirmed these rearrangements with PCR or RT-PCR as well as sequencing. Ba/F3 cells harboringRetorNtrk1rearrangements acquired sensitivity to RET and TRK inhibitors, respectively. Adenoviruses encoding Cas9 and sgRNAs that catalyze theKif5b-RetandTrim24-Retrearrangements were intratracheally instilled into mice and yielded lung adenocarcinomas. A cell line (TR.1) was established from aTrim24-Retpositive tumor that exhibited highin vitrosensitivity to RET-specific TKIs. Moreover, orthotopic transplantation of TR.1 cells into the left lung yielded well-defined tumors that shrank in response to LOXO-292 treatment. The method offers an efficient means to validate sgRNAs that successfully target their intended loci for the generation of novel murine oncogene-driven tumor models.
SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in mice
Authors: Alhammad Yousef M. , Parthasarathy Srivatsan , Ghimire Roshan , O’Connor Joseph J. , Kerr Catherine M. , Pfannenstiel Jessica J. , Chanda Debarati , Miller Caden A. , Unckless Robert L. , Zuniga Sonia , Enjuanes Luis , More Sunil , Channappanavar Rudragouda , Fehr Anthony R. 
Published: April 2023

ABSTRACTSeveral coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies for COVID-19. Included in this set of proteins is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical for both murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV virulence. However, as a potential drug target, it is imperative to understand how a complete Mac1 deletion impacts the replication and pathogenesis of different CoVs. To this end, we created recombinant bacterial artificial chromosomes (BACs) containing complete Mac1 deletions (ΔMac1) in MHV, MERS-CoV, and SARS-CoV-2. While we were unable to recover infectious virus from MHV or MERS-CoV ΔMac1 BACs, SARS-CoV-2 ΔMac1 was readily recovered from BAC transfection, indicating a stark difference in the requirement for Mac1 between different CoVs. Furthermore, SARS-CoV-2 ΔMac1 replicated at or near wild-type levels in multiple cell lines susceptible to infection. However, in a mouse model of severe infection, ΔMac1 was quickly cleared causing minimal pathology without any morbidity. ΔMac1 SARS-CoV-2 induced increased levels of interferon (IFN) and interferon-stimulated gene (ISG) expression in cell culture and mice, indicating that Mac1 blocks IFN responses which may contribute to its attenuation. ΔMac1 infection also led to a stark reduction in inflammatory monocytes and neutrophils. These results demonstrate that Mac1 only minimally impacts SARS-CoV-2 replication, unlike MHV and MERS-CoV, but is required for SARS-CoV-2 pathogenesis and is a unique antiviral drug target.SIGNIFICANCEAll CoVs, including SARS-CoV-2, encode for a conserved macrodomain (Mac1) that counters host ADP-ribosylation. Prior studies with SARS-CoV-1 and MHV found that Mac1 blocks IFN production and promotes CoV pathogenesis, which has prompted the development of SARS-CoV-2 Mac1 inhibitors. However, development of these compounds into antivirals requires that we understand how SARS-CoV-2 lacking Mac1 replicates and causes diseasein vitroandin vivo. Here we found that SARS-CoV-2 containing a complete Mac1 deletion replicates normally in cell culture but induces an elevated IFN response, has reduced viral loadsin vivo, and does not cause significant disease in mice. These results will provide a roadmap for testing Mac1 inhibitors, help identify Mac1 functions, and open additional avenues for coronavirus therapies.