bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kidney Function Assessment Using Cystatin C and Serum Creatinine in Heart Transplantation Recipients: Implications for Valganciclovir Dosing
Authors: Pinsino Alberto , Jennings Douglas L , Ladanyi Annamaria , Duong Phuong , Sweat Austin O , Mahoney Ian , Bohn Bruno , Demmer Ryan T , Takeda Koji , Sayer Gabriel T , Uriel Nir , Leb Jay S , Husain Syed A , Mohan Sumit , Colombo Paolo C , Yuzefpolskaya Melana 
Published: November 2023

ABSTRACTBackgroundAmong heart transplantation (HT) recipients, the accuracy of serum creatinine (sCr)-based estimated glomerular filtration rate (eGFR) may be limited by fluctuations in muscle mass. Cystatin C (cysC) is less influenced by muscle mass; however, its levels may increase with obesity and steroid use. Herein, we: i) longitudinally compared changes in eGFRcysC and eGFRsCr among HT recipients; ii) investigated the association of body mass index (BMI), steroid use and muscle mass with discrepancies between eGFRs; and iii) explored the implications of eGFRcysC use on valganciclovir (VGC) dosing.MethodscysC and sCr were measured in 294 blood samples obtained from 80 HT recipients. Intra-individual differences between eGFRs (eGFRdiffcysC-sCr) were calculated. Negative eGFRdiffcysC-sCrvalues correspond to eGFRsCr > eGFRcysC and positive values to eGFRcysC > eGFRsCr. In a patient subset (n=21), pectoralis muscle measures were derived from computed tomography scans.ResultsMarked differences between eGFRcysC and eGFRsCr were observed, particularly early post-HT (1-week post-HT, median eGFRdiffcysC-sCr−28 ml/min/1.73 m2). eGFRcysC demonstrated stability following a transient post-operative decline, while eGFRsCr decreased in the first year post-HT. Lower BMI and higher prednisone dose displayed a modest association with more negative eGFRdiffcysC-sCrvalues. Conversely, pectoralis muscle measures indicative of greater muscle mass and better tissue quality exhibited a stronger association with more positive eGFRdiffcysC-sCrvalues. eGFRcysC use would have resulted in VGC dose adjustment in 46% of samples, predominantly towards lower doses.ConclusionsAmong HT recipients, eGFRcysC and eGFRsCr markedly differ with implications for VGC dosing. The observed discrepancies may reflect changes in body composition and steroid use.
Hurricanes Pose Substantial Risk to New England Forest Carbon Stocks
Authors: Tumber-Dávila Shersingh Joseph , Lucey Taylor , Boose Emery , Laflower Danelle , León-Sáenz Agustín , Wilson Barry T. , MacLean Meghan Graham , Thompson Jonathan R. 
Published: November 2023

AbstractNature-based climate solutions are championed as a primary tool to mitigate climate change, especially in forested regions capable of storing and sequestering vast amounts of carbon. New England is one of the most heavily forested regions in the United States (>75% forested by land area), and forest carbon is a significant component of regional climate mitigation strategies. Large infrequent disturbances, such as hurricanes, are a major source of uncertainty and risk for policies that rely on forest carbon for climate mitigation, especially as climate change is projected to alter the intensity and geographic extent of hurricanes. To date, most research into disturbance impacts on forest carbon stocks has focused on fire. Here we show that a single hurricane in the region can down between 121-250 MMTCO2e or 4.6-9.4% of the total aboveground forest carbon, much greater than the carbon sequestered annually by New England’s forests (16 MMTCO2e yr-1). However, the emissions from the storms are not instantaneous; it takes approximately 19 years for the downed carbon to become a net emission, and 100 years for 90% of the downed carbon to be emitted. Using hurricane reconstructions across a range of historical and projected wind speeds, we find that an 8% and 16% increase in hurricane wind speeds leads to a 10.7 and 24.8 fold increase in the extent of high-severity damaged areas (widespread tree mortality). Increased wind speed also leads to unprecedented geographical shifts in damage; both inland and northward into heavily forested regions traditionally unaffected by hurricanes. Given that a single hurricane can emit the equivalent of 10+ years of carbon sequestered by forests in New England, the status of these forests as a durable carbon sink is uncertain. Understanding the risks to forest carbon stocks from large infrequent disturbances is necessary for decision-makers relying on forests as a nature-based climate solution.
Neurohistopathological Findings of the Brain Parenchyma After Long-Term Deep Brain Stimulation: Case Series and Systematic Literature Review
Authors: Vivanco-Suarez Juan , Woodiwiss Timothy , Fiock Kimberly L. , Hefti Marco M. , Narayanan Nandakumar S. , Greenlee Jeremy D. W. 
Published: November 2023

ABSTRACTIntroductionThe efficacy of deep brain stimulation (DBS) has been established to treat several movement and psychiatric disorders. However, several aspects, such as the mechanism of action and tissue changes after treatment are incompletely described. Hence, we aimed to describe the neurohistopathological findings of 9 patients who underwent DBS for movement disorders. Additionally, we performed a systematic literature review on postmortem studies after DBS implantation.MethodsWe performed a retrospective study of patients who underwent DBS for movement disorders between 2000-2023 and had postmortem autopsy. Demographics, clinical features, and outcomes were collected. Levodopa equivalent daily dose (LEDD) and total electrical energy delivered (TEED) were calculated. Neurohistopathological assessments were performed from autopsies. A systematic literature review was conducted to summarize the literature.ResultsPostmortem neurohistopathologic assessment of 9 patients who underwent DBS for movement disorders (8 Parkinson’s disease [multiple system atrophy was final diagnosis in 1], and 1 parkinsonism) was performed. Median age at DBS implantation was 65 years (range, 54-69), and most were male (8 patients, 89%). Most common DBS target was the subthalamic nucleus (8 patients, 89%). Median DBS duration was 65 months (range, 7-264 months). Post-DBS reduction in LEDD was found in 7/9 patients, and TEED was increased over time in 5/7 patients. No patients died due to DBS. Neurohistopathological assessment showed gliosis in 7 (78%) patients and activated microglial infiltration in 1 (11%). Additionally, postmortem findings (after DBS) of 59 patients (between 1977-2021) were identified in the literature: 26 (44%) for Parkinson’s disease, 20 (34%) for pain, and 13 (22%) for other conditions.ConclusionOur findings confirm the presence of a local tissue reaction, including gliosis and activated microglial infiltration around the implanted DBS electrodes. The effect of the local changes on the clinical efficacy of DBS is not established. Further DBS postmortem studies and standardization of tissue processing are needed.
Dose-response associations of device measured sleep regularity and duration with incident dementia in 82391 UK adults
Authors: Bian Wenxin , Biswas Raaj K. , Ahmadi Matthew N. , Bin Yu Sun , Postnova Svetlana , Phillips Andrew J.K. , Koemel Nicolas A. , Chaput Jean-Philippe , Rajaratnam Shantha M.W. , Cistulli Peter A , Stamatakis Emmanuel 
Published: November 2023

ABSTRACTObjectivesTo evaluate the associations of device-measured sleep duration and regularity with incident dementia, and to explore whether regular sleep might mitigate any association of sleep duration with dementia.MethodsThis population-based prospective cohort study of 82391 adults from the UK Biobank accelerometry subsample included adults aged 43 to 79 years old in England, Scotland, and Wales. Sleep duration (h/day) and Sleep Regularity Index (SRI, range 0-100) were calculated from the wrist-worn accelerometry data collected by participants over the course of one week. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and assess the independent associations between sleep and incident dementia after adjustment for common demographic and contextual covariates.ResultsOver a mean follow-up of 7.9 years, during which 694 incident dementia cases occurred, there was a U-shaped association between sleep duration and incident dementia. Short sleep (<7 h) was associated with increased dementia risk, while long sleep (≥ 8h) was not significantly associated with dementia risk. The median sleep duration for short sleepers (<7 h) of 6.5 hours was associated with an HR of 1.19 (95% CI 1.01, 1.40) for incident dementia. Sleep regularity was negatively associated with dementia risk in a near-linear fashion. The sample median SRI of approximately 73, compared to the reference point of 51, was associated with an HR of 0.76 (95%CI 0.61, 0.94). The SRI value where the risk reduction was 50% of the maximum observed of 66, was associated with an HR of 0.77 (95%CI 0.63, 0.95). Among individuals with sleep duration outside the optimal range (too short or too long), less regular sleep was associated with increased risk of dementia. Among those with optimal sleep duration (7-8h/day), there was no significant association between sleep regularity and dementia risk. Compared to the reference point (SRI: 51), an SRI value of 62 for non-optimal sleepers was associated with a 25% reduction in risk for dementia (HR: 0.75; 95% CI 0.63, 0.90).ConclusionsA regular sleep pattern may mitigate some adverse effects of inadequate sleep duration, suggesting that interventions aimed at improving sleep regularity may be a suitable option for people not able to achieve the recommended hours of sleep.
Sales of over the counter (OTC) codeine-containing products in the United Kingdom: a retrospective observational study
Authors: Richards Georgia C. , Martus Isabella , Aronson Jeffrey K. , Heneghan Carl 
Published: November 2023

AbstractBackgroundCodeine is a widely available opioid medicine that is on the World Health Organisation’s list of essential medicines. However, widespread access to codeine has led to its misuse, abuse, dependence, and deaths. Some countries, including France and Australia, have successfully reclassified codeine to prescription only, which is encouraging other regulators, including the UK, to reconsider the status of codeine. However, little is known about how much codeine is sold in the UK.AimTo assess national trends in sales and expenditure of codeine-containing products sold over the counter (OTC) between 2013 and 2019.MethodsWe conducted a retrospective observational study using electronic point-of-sales data from the human data science companyIQVIAand population statistics from the UK’s Office of National Statistics (ONS). Descriptive statistics were used to examine the quantity, trends over time, and types of OTC codeine-containing products sold.Results4.75 billion dosage units of codeine were sold OTC in the UK between April 2013 and March 2019, an average of 72 dosage units per UK resident. Over time, sales of codeine fell by 8%, from 12.54 dosage units per resident in 2013 to 11.48 dosage units per resident in 2019. Codeine was often sold in combination with other analgesics, amounting to 1711 tonnes of paracetamol and 96 tonnes of ibuprofen. The public spent £638 million on OTC codeine-containing products, which increased by 12% over the study period. There were 83 different types of codeine-containing products sold.ConclusionLarge volumes of codeine-containing products were purchased OTC in the UK in 2013-19. To improve the safety of opioids, OTC codeine sales data should be made accessible for public health surveillance. The trends presented in this study should inform policy for the future status of codeine availability in the UK.Principal Investigator statementThe authors confirm that the Principal Investigator for this paper is Dr Georgia Richards and that they had direct responsibility for the conduct of this study.
Longitudinal tracking of intra-breath respiratory impedance in preschool children
Authors: Wong Matthew D , Blake Tamara , Zahir Syeda Farah , Suresh Sadasivam , Hantos Zoltán , Grimwood Keith , Lambert Stephen B , Ware Robert S , Sly Peter D 
Published: November 2023

ABSTRACTBackgroundLongitudinal measurements of intra-breath respiratory impedance (Zrs) in preschool-aged children may be able to distinguish abnormal lung function trajectories in children with a history of wheezing compared to healthy ones.MethodsChildren from a prospective, longitudinal community-based cohort performed annual intra-breath oscillometry (IB-OSC) measurements from age 3-years to 7-years. IB-OSC was performed using a single 10 Hz sinusoid while clinically asymptomatic. Linear mixed-effects models were developed to explore the effects of wheezing phenotypes, growth, and sex on seven IB-OSC outcome variables over time: resistance at end-expiration (ReE), resistance at end-inspiration (ReI), the tidal change in resistance (ΔR=ReE-ReI), reactance at end-expiration (XeE), reactance at end-inspiration (XeI), the tidal change in reactance (ΔX=XeE-XeI), and ΔX normalised by tidal volume (ΔX/VT).ResultsEighty-five children produced 375 acceptable IB-OSC measurements. Subjects were classified into one of three wheeze groups: never (n=36), transient (n=35), or persistent (n=14). After adjusting for height, children with persistent wheezing, compared to those who never wheezed, had -0.669 hPa·s·L-1XeE (95% confidence interval [CI] -1.102 to -0.237, p<0.01), -0.465 hPa·s·L-1ΔX (95%CI -0.772 to -0.159, p<0.01) and +1.433 hPa·s·L-1ΔX/VT(95%CI +0.492 to +2.374, p<0.01). Increasing subject height had a significant effect on all IB-OSC resistance and reactance variables when adjusted for the effect of preschool wheezing.ConclusionsIB-OSC is feasible for tracking lung function in preschool-aged children, and intra-breath reactance outcomes may allow abnormal lung function to be identified early in asymptomatic children with a history of persistent wheeze.
RAG-17: A Novel siRNA Conjugate Demonstrating Efficacy in Late-Stage Treatment of SOD1G93AALS mice
Authors: Duan Chunling , Kang Moorim , Liu Kunshan , Gan Zubao , Li Guanlin , Chen Junnan , Schacht Ian , Place Robert F. , Li Long-Cheng 
Published: November 2023

AbstractAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by rapid progression and high mortality. With genetic mutations, particularly in the SOD1 gene, playing a significant role in ALS pathogenesis, targeted therapies have become a primary focus. This study introduces RD-12500 (RAG-17), a novel siRNA-ACO (Accessory Oligonucleotide) conjugate designed to address the challenges of delivering duplex RNAs to the central nervous system (CNS). RD-12500 exhibits remarkablein vitrostability and target specificity with minimal immunostimulation.In vivostudies demonstrate its extensive CNS biodistribution, sustained accumulation post-intrathecal administration, and a robust dose-exposure-activity correlation. Notably, RD-12500 significantly reduces cerebrospinal fluid (CSF) SOD1 protein levels, indicating potent SOD1 mRNA and protein knockdown in cynomolgus monkeys. Most notably, our study breaks new ground by demonstrating the effectiveness of RD-12500 in late-stage treatment scenarios. In SOD1G93AALS mice, post-onset administration of RD-12500 significantly delayed disease progression, improved motor function, and extended survival, marking a significant advancement over other treatments which are typically initiated pre-symptomatically in the same model mice. These findings suggest RD-12500’s potential to provide therapeutic benefits not only to pre-symptomatic but also to post-symptomatic and late-stage SOD1-ALS patients.
A bird’s eye view to the homeostatic, Alzheimer and Glioblastoma attractors
Authors: Nieves Joan , Gil Gabriel , Gonzalez Augusto 
Published: November 2023

SUMMARYAvailable data for white matter of the brain allows to locate the normal (homeostatic), Glioblastoma and Alzheimer’s disease attractors in gene expression space and to identify paths related to transitions like carcinogenesis or Alzheimer’s disease onset. A predefined path for aging is also apparent, which is consistent with the hypothesis of programmatic aging. In addition, reasonable assumptions about the relative strengths of attractors allow to draw a schematic landscape of fitness: a Wright’s diagram. These simple diagrams reproduce known relations between aging, Glioblastoma and Alzheimer’s disease, and rise interesting questions like the possible connection between programmatic aging and Glioblastoma in this tissue. We anticipate that similar multiple diagrams in other tissues could be useful in the understanding of the biology of apparently unrelated diseases or disorders, and in the discovery of unexpected clues for their treatment.Graphical abstractIn briefAging, carcinogenesis and Alzheimer’s disease onset in white matter of the brain are shown as paths or directions in gene-expression space, a simple view that allows the analysis of their mutual relations and to rise interesting questions such as whether programmatic aging could be related to avoiding the Glioblastoma.HighlightsNormal homeostatic, Glioblastoma and Alzheimer’s disease attractors are apparent in gene-expression spaceThe relative disposition of paths for carcinogenesis and Alzheimer’s disease onset reproduce known relations between these diseasesThe observed corridor for aging is consistent with programmatic agingAvoiding the fall into the huge basin of the Glioblastoma could be the subject of selection pressureAged normal samples could be captured by the weak Alzheimer’s disease attractor
Screening the MMV Pathogen Box reveals the mitochondrialbc1-complex as a drug target in matureToxoplasma gondiibradyzoites
Authors: Maus Deborah , Putrianti Elyzana , Hoffmann Tobias , Laue Michael , Seeber Frank , Blume Martin 
Published: November 2023

AbstractThe apicomplexan parasiteToxoplasma gondiiinfects 25-30% of the global human population and can cause life-threatening diseases in immunocompromised patients. The chronically infectious forms of the parasite, bradyzoites, persist within cysts in brain and muscle tissue and are responsible for its transmission and remission of the disease. Currently available treatment options are very limited and are only effective against the fast-replicating tachyzoites but fail to eradicate the chronic stages ofT. gondii. The cause of these treatment failures remains unclear. Here, we utilized our recently developed human myotube-based culture model to screen compounds from the MMV Pathogen Box against pan-resistant in vitro bradyzoites and identified multiple compounds with simultaneous activity against tachyzoites and bradyzoites. Stable isotope-resolved metabolic profiling on tachyzoites and bradyzoites identified the mitochondrialbc1-complex as a target of bradyzocidal compounds and defines their metabolic impacts on both parasite forms. Our data suggest that mature bradyzoites rely on mitochondrial ATP production.
Perceptual error based on Bayesian cue combination drives implicit motor adaptation
Authors: Zhang Zhaoran , Wang Huijun , Zhang Tianyang , Nie Zixuan , Wei Kunlin 
Published: November 2023

AbstractThe sensorimotor system can recalibrate itself without our conscious awareness, a type of procedural learning whose computational mechanism remains undefined. Recent findings on implicit motor adaptation, such as over-learning from small perturbations and fast saturation for increasing perturbation size, challenge existing theories based on sensory errors. We argue that perceptual error, arising from the optimal combination of movement-related cues, is the primary driver of implicit adaptation. Central to our theory is the increasing sensory uncertainty of visual cues with increasing perturbations, which was validated through perceptual psychophysics (Experiment 1). Our theory predicts the learning dynamics of implicit adaptation across a spectrum of perturbation sizes on a trial-by-trial basis (Experiment 2). It explains proprioception changes and their relation to visual perturbation (Experiment 3). By modulating visual uncertainty in perturbation, we induced unique adaptation responses in line with our model predictions (Experiment 4). Overall, our perceptual error framework outperforms existing models based on sensory errors, suggesting that perceptual error in locating one’s effector, supported by Bayesian cue integration, underpins the sensorimotor system’s implicit adaptation.
Predictive phage therapy forEscherichia coliurinary tract infections: cocktail selection for therapy based on machine learning models
Authors: Keith Marianne , Park de la Torriente Alba , Chalka Antonia , Vallejo-Trujillo Adriana , McAteer Sean P. , Paterson Gavin K. , Low Alison S. , Gally David L. 
Published: November 2023

AbstractThis study supports the development of predictive bacteriophage (phage) therapy: the concept of phage cocktail selection to treat a bacterial infection based on machine learning models (MLM). For this purpose, MLM were trained on thousands of measured interactions between a panel of phage and sequenced bacterial isolates. The concept was applied toEscherichia coli(E. coli) associated with urinary tract infections. This is an important common infection in humans and companion animals from which multi-drug resistant (MDR) bloodstream infections can originate. The global threat of MDR infection has reinvigorated international efforts into alternatives to antibiotics including phage therapy.E. coliexhibit extensive genome-level variation due to horizontal gene transfer via phage and plasmids. Associated with this, phage selection forE. coliis difficult as individual isolates can exhibit considerable variation in phage susceptibility due to differences in factors important to phage infection including phage receptor profiles and resistance mechanisms. The activity of 31 phage were measured on 314 isolates with growth curves in artificial urine. Random Forest models were built for each phage from bacterial genome features and the more generalist phage, acting on over 20% of the bacterial population, exhibited F1 scores of >0.6 and could be used to predict phage cocktails effective against previously untested strains. The study demonstrates the potential of predictive models which integrate bacterial genomics with phage activity datasets allowing their use on data derived from direct sequencing of clinical samples to inform rapid and effective phage therapy.Significance StatementWith the growing challenge of antimicrobial resistance there is an urgency for alternative treatments for common bacterial diseases including urinary tract infections (UTIs).Escherichia coliis the main causative agent of UTIs in both humans and companion animals with multidrug resistant strains such as the globally disseminated ST131 becoming more common. Bacteriophage (phage) are natural predators of bacteria and potentially an alternative therapy. However, a major barrier for phage therapy is the specificity of phage on target bacteria and therefore difficulty efficiently selecting the appropriate phage. Here, we demonstrate a genomics driven approach using machine learning prediction models combined with phage activity clustering to select phage cocktails based only on the genome sequence of the infecting bacterial strain.