bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate
Authors: Robinson Kelsey , Mosley Trenell J. , Rivera-González Kenneth S. , Jabbarpour Christopher R. , Curtis Sarah W. , Adeyemo Wasiu Lanre , Beaty Terri H. , Butali Azeez , Buxó Carmen J. , Cutler David J. , Epstein Michael P. , Gowans Lord JJ , Hecht Jacqueline T. , Murray Jeffrey C. , Shaw Gary M. , Uribe Lina Moreno , Weinberg Seth M. , Brand Harrison , Marazita Mary L. , Lipinski Robert J. , Leslie Elizabeth J. 
Published: March 2023

AbstractOrofacial clefts (OFCs) are the most common craniofacial birth defects and are often categorized into two etiologically distinct groups: cleft lip with or without cleft palate (CL/P) and isolated cleft palate (CP). CP is highly heritable, but there are still relatively few established genetic risk factors associated with its occurrence compared to CL/P. Historically, CP has been studied as a single phenotype despite manifesting across a spectrum of defects involving the hard and/or soft palate. We performed GWAS using transmission disequilibrium tests using 435 case-parent trios to evaluate broad risks for any cleft palate (ACP, n=435), as well as subtype-specific risks for any cleft soft palate (CSP, n=259) and any cleft hard palate (CHP, n=125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p=4.24×10−8) associated with CHP. One gene at this locus, angiopoietin-like 2 (ANGPTL2), plays a role in osteoblast differentiation. It is expressed in craniofacial tissue of human embryos, as well as in the developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p<5×10−6), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios (ORs) for each of the 20 loci were most similar across all three groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either the CSP or CHP groups. We also found nominal evidence of replication (p<0.05) for 22 SNPs previously associated with cleft palate (including CL/P). Interestingly, most SNPs associated with CL/P cases were found to convey the opposite effect in those replicated in our dataset for CP only. Ours is the first study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.
Real-time Dissection and Forecast of Infection Dynamics during a Pandemic
Authors: Schulz Steven , Pastor Richard , Koyuncuoglu Cenk , Crawford Forrest W. , Zernick Detlef , Karch André , Rüdiger Sten 
Published: March 2023

AbstractPandemic preparedness requires institutions, including public health authorities and governments, to detect, survey and control outbreaks. To maintain an accurate, quantitative and up-to-date picture of an epidemic crisis is key. For SARS-CoV-2, this was mostly achieved by ascertaining incidence numbers and the effective reproductive number (Reff), which counts how many people an infected person is likely to infect on average. These numbers give strong hints on past infection dynamics in a population but fail to clearly characterize current and future dynamics as well as potential effects of pharmaceutical and non-pharmaceutical interventions. We show that, by using and combining infection surveillance and population-scale contact statistics, we can obtain a better understanding of the drivers of epidemic waves and the effectiveness of interventions. This approach can provide a real-time picture, thus saving not only many lives by quickly allowing adaptation of the health policies but also alleviating economic and other burdens if an intervention proves ineffective. We factorizeReffinto contacts and relative transmissibility: Both signals can be used, individually and combined, to identify driving forces of an epidemic, monitoring and assessing interventions, as well as projecting an epidemic’s future trajectory. Using data for SARS-CoV-2 and Influenza from 2019 onward in Germany, we provide evidence for the usefulness of our approach. In particular, we find that the effects from physical distancing and lockdowns as well as vaccination campaigns are dominant.
Examining Longitudinal Markers of Bladder Cancer Recurrence Through a Semi-Autonomous Machine Learning System for Quantifying Specimen Atypia from Urine Cytology
Authors: Levy Joshua J. , Chan Natt , Marotti Jonathan D. , Rodrigues Nathalie J. , Ismail A. Aziz O. , Kerr Darcy A. , Gutmann Edward J. , Glass Ryan E. , Dodge Caroline P. , Suriawinata Arief A. , Christensen Brock , Liu Xiaoying , Vaickus Louis J. 
Published: March 2023

AbstractUrine cytology (UC) is generally considered the primary approach for screening for recurrence of bladder cancer. However, it is currently unclear how best to use cytological exams themselves for the assessment and early detection of recurrence, beyond identifying a positive finding which requires more invasive methods to confirm recurrence and decide on therapeutic options. As screening programs are frequent, and can be burdensome, finding quantitative means to reduce this burden for patients, cytopathologists and urologists is an important endeavor and can improve both the efficiency and reliability of findings. Additionally, identifying ways to risk-stratify patients is crucial for improving quality of life while reducing the risk of future recurrence or progression of the cancer. In this study, we leveraged a computational machine learning tool, AutoParis-X, to extract imaging features from UC exams longitudinally to study the predictive potential of urine cytology for assessing recurrence risk. This study examined how the significance of imaging predictors changes over time before and after surgery to determine which predictors and time periods are most relevant for assessing recurrence risk. Results indicate that imaging predictors extracted using AutoParis-X can predict recurrence as well or better than traditional cytological / histological assessments alone and that the predictiveness of these features is variable across time, with key differences in overall specimen atypia identified immediately before tumor recurrence. Further research will clarify how computational methods can be effectively utilized in high volume screening programs to improve recurrence detection and complement traditional modes of assessment.
A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia
Authors: Koedijk Joost B. , van der Werf Inge , Penter Livius , Vermeulen Marijn A. , Barneh Farnaz , Perzolli Alicia , Meesters-Ensing Joyce I. , Metselaar Dennis S. , Margaritis Thanasis , Fiocco Marta , de Groot-Kruseman Hester A. , Moeniralam Rubina , Bang Christensen Kristina , Porter Billie , Pfaff Kathleen , Garcia Jacqueline S. , Rodig Scott J. , Wu Catherine J. , Hasle Henrik , Nierkens Stefan , Belderbos Mirjam E. , Zwaan C. Michel , Heidenreich Olaf 
Published: March 2023

AbstractBecause of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or ‘cold’ tumor microenvironment and may have a low likelihood of response to T cell-directed immunotherapies. Understanding the composition, phenotype, and spatial organization of T cells and other microenvironmental populations in the pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion mechanisms specific to pediatric AML. Here, we conducted a multidimensional analysis of the tumor immune microenvironment in pediatric AML and non-leukemic controls. We demonstrated that nearly one-third of pediatric AML cases has an immune-infiltrated BM, which is characterized by a decreased ratio of M2-to M1-like macrophages. Furthermore, we detected the presence of large T cell networks, both with and without colocalizing B cells, in the BM and dissected the cellular composition of T- and B cell-rich aggregates using spatial transcriptomics. These analyses revealed that these aggregates are hotspots of CD8+T cells, memory B cells, plasma cells and/or plasmablasts, and M1-like macrophages. Collectively, our study provides a multidimensional characterization of the BM immune microenvironment in pediatric AML and indicates starting points for further investigations into immunomodulatory mechanisms in this devastating disease.
Outcome Assessment in Neurocritical Care Trials
Authors: Fitzgerald Emily , Donaldson Lachlan , Flower Oliver , Hammond Naomi , Leung Kwan Yee , McDonald Gabrielle , Rowcliff Kirsten , Vlok Ruan , Delaney Anthony 
Published: March 2023

AbstractIntroductionThe assessment of patient reported outcomes following neurological injury remains a challenging area of neurocritical care research. Mortality amongst the neurocritical patient population remains high with a significant proportion of survivors left suffering functional, cognitive and emotional deficits, often with a reduced health-related quality of life and leaving them dependent on caregivers. Numerous instruments have been developed to assess the level of impairment patients experience following a global neurological injury. Previous systematic reviews have reported significant heterogeneity in outcome assessment in neurocritical car trials, including the outcome measure used, method of ascertainment and the timing of outcome assessment. It has been suggested that this heterogeneity in outcome assessment has complicated the design of neurocritical care clinical trials, the pooling and meta-analysis of trial data and has led to conflicting and controversial trial results. It is unclear what impact the methods of performing outcome assessment has on loss follow up rates and the validity of outcome data in neurocritical care trials.We aim to systematically review the methods of performing outcome assessment in neurocritical care trials to identify current trends in outcome assessment in this patient population and to examine loss to follow up rates and factors impacting cohort attrition. It is hoped that an understanding of the relationship between methods of outcome assessment and loss to follow up will inform future design of neurocritical care trials.Methods and analysisThis systematic review will include randomized clinical trials and large prospective observational cohort studies where the included population is adults with a diagnosis of traumatic brain injury or a subarachnoid haemorrhage and reporting at least one patient reported outcome measure. Inclusion will not be limited based on intervention nor comparator. We will limit the searches to human studies, with reports published in the English language and published within the last 10 years. We will search the Medline, EMBASE, and The Cochrane Central registry of clinical trial (CENTRAL) for eligible trials. We will manually search the reference list of relevant primary review articles, clinical registries, and abstracts from recent relevant conferencesConclusionThis systematic review and will provide clinicians with an understanding of the relationship between methods of outcome assessment and loss to follow up will inform future design of neurocritical care trials.
Spatially-resolved wastewater-based surveillance enables COVID-19 case localization across a university campus, and confirms lower SARS-CoV-2 RNA burden relative to the surrounding community
Authors: Lee Jangwoo , Acosta Nicole , Waddell Barbara J. , Du Kristine , Xiang Kevin , Van Doorn Jennifer , Low Kashtin , Bautista Maria A. , McCalder Janine , Dai Xiaotian , Lu Xuewen , Chekouo Thierry , Pradhan Puja , Sedaghat Navid , Papparis Chloe , Beaudet Alexander Buchner , Chen Jianwei , Chan Leslie , Vivas Laura , Westlund Paul , Bhatnagar Srijak , Stefani September , Visser Gail , Cabaj Jason , Achari Gopal , Clark Rhonda G. , Hrudey Steve E. , Lee Bonita E. , Pang Xiaoli , Webster Brandan , Ghali William Amin , Buret Andre Gerald , Williamson Tyler , Southern Danielle A. , Meddings Jon , Frankowski Kevin , Hubert Casey R.J. , Parkins Michael D. 
Published: March 2023

AbstractWastewater-based surveillance (WBS) has been established as a powerful tool that can guide health policy at multiple levels of government. However, this technology has not been well assessed at more granular scales, including large work sites such as University campuses. Between August 2021-April 2022, we explored the occurrence of SARS-CoV-2 RNA in wastewater from multiple complimentary sewer catchments and residential buildings spanning the University of Calgary’s campus and how this compared to levels from the municipal wastewater treatment plant servicing the campus. Concentrations of wastewater SARS-CoV-2 N1 and N2 RNA varied significantly across six sampling sites – regardless of several normalization strategies – with certain catchments consistently demonstrating values 1–2 orders higher than the others. Additionally, our comprehensive monitoring strategy enabled an estimation of the total burden of SARS-CoV-2 for the campus per capita, which was significantly lower than the surrounding community (p≤0.01). Real-time contact tracing data was used to confirm an association between wastewater SARS-CoV-2 burden and clinically confirmed cases proving the potential of WBS as a tool for disease monitoring across worksites. Allele-specific qPCR assays confirmed that variants across campus were representative of the community at large, and at no time did emerging variants first debut on campus. This study demonstrates how WBS can be efficiently applied to locate hotspots of disease activity at a very granular scale, and predict disease burden across large, complex worksites.Synopsis‘This study establishes that wastewater-based surveillance with a node-based sampling strategy can be used to passively monitor for disease, locate disease “hotspots” and approximate the burden of infected individuals’
Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomization study
Authors: Constantinescu Andrei-Emil , Bull Caroline J , Jones Nicholas , Mitchell Ruth , Burrows Kimberley , Dimou Niki , Bézieau Stéphane , Brenner Hermann , Buchanan Daniel D , D’Amato Mauro , Jenkins Mark A , Moreno Victor , Pai Rish K , Um Caroline Y , White Emily , Murphy Neil , Gunter Marc , Timpson Nicholas J , Huyghe Jeroen R , Vincent Emma E 
Published: March 2023

AbstractObservational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ∼550,000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52,775 cases and 45,940 controls) using Mendelian randomization (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4,043 incident CRC cases and 332,773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, CI(95%): 0.78-0.99,P=0.04; OR: 0.93, CI(95%): 0.88-0.98,P=0.01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, CI(95%): 0.80-0.97,P=0.01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, CI(95%): 0.76-0.93,P=6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, CI(95%): 0.93-0.99,P=0.02] and following adjustment for the other WBC subtypes [RR: 0.96, CI(95%): 0.93-0.99,P=0.001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.What is already known of this topicWhile previous observational studies have suggested a protective role for eosinophils in colorectal cancer development and implicated neutrophils, whether changes in the levels of circulating white blood cells causes colorectal cancer has not been explored.What this study addsOur study is the first to use Mendelian randomization (MR) to investigate this relationship. In parallel, for comparison, we also conduct the largest cohort study to date on the topic. We found evidence to suggest that elevated eosinophil and lymphocyte count may have a protective effect on CRC risk, adding new insights into the pathogenesis of CRC.How this study might affect research, practice or policyOur findings will encourage further mechanistic exploration to understand the biological mechanisms underpinning our findings, which may lead to new therapeutic approaches or risk reduction strategies.
Nanothermometry-enabled intelligent laser tissue soldering
Authors: Cipolato Oscar , Dosnon Lucas , Rosendorf Jachym , Sarcevic Sima , Bondi Alice , Liska Vaclav , Schlegel Andrea A. , Herrmann Inge K. 
Published: March 2023

AbstractWhile often life-saving, surgical resectioning of diseased tissues puts patients at risk for post-operative complications. Sutures and staples are well-accepted and routinely used to reconnect tissues, however, their mechanical mismatch with biological soft tissue and invasiveness contribute to wound healing complications, infections, and post-operative fluid leakage. In principle, laser tissue soldering offers an attractive, minimally-invasive alternative for seamless soft tissue fusion. However, despite encouraging experimental observations, including accelerated healing and lowered infection risk, critical issues related to temperature monitoring and control during soldering and associated complications have prevented their clinical exploitation to date. Here, we introduce intelligent laser tissue soldering (iSoldering) with integrated nanothermometry as a promising yet unexplored approach to overcoming the critical shortcomings of laser tissue soldering. We demonstrate that adding thermoplasmonic and nanothermometry nanoparticles to proteinaceous solders enables heat confinement and non-invasive temperature monitoring and control, offering a route to high-performance, leak-tight tissue sealing even at deep tissue sites. The resulting tissue seals exhibit excellent mechanical properties and resistance to chemically-aggressive digestive fluids, including gastrointestinal juice. The iSolder can be readily cut and shaped by surgeons to optimally fit the tissue defect and can even be applied using infrared light from a medically approved light source, hence fulfilling key prerequisites for application in the operating theatre. Overall, iSoldering enables reproducible and well-controlled high-performance tissue sealing, offering new prospects for its clinical exploitation in diverse fields ranging from cardiovascular to visceral and plastic surgery.TeaserIntelligent solders containing nanothermometers and thermoplasmonics offer new route to high-performance tissue sealing.
Short-chain di-carboxylates as positive allosteric modulators of the pH-dependent pentameric ligand-gated ion channel GLIC: requirement of an intact vestibular pocket
Authors: Van Renterghem Catherine , Nemecz Ákos , Delarue-Cochin Sandrine , Joseph Delphine , Corringer Pierre-Jean 
Published: March 2023

AbstractGLIC is a prokaryotic orthologue of brain pentameric neurotransmitter receptors. Using whole-cell patch-clamp electrophysiology in a host cell line, we show that short-chain di-carboxylate compounds are positive modulators of pHo 5-evoked GLIC activity, with a rank order of action fumarate > succinate > malonate > glutarate. Potentiation by fumarate depends on intracellular pH, mainly as a result of a strong decrease of the pHo 5-evoked current when intracellular pH decreases. The modulating effect of fumarate also depends on extracellular pH, as fumarate is a weak inhibitor at pHo 6 and shows no agonist action at neutral pHo. A mutational analysis of residue-dependency for succinate and fumarate effects, based on two carboxylate-binding pockets previously identified by crystallography (Fouratiet al. 2020), shows that positive modulation involves both the inter-subunit pocket, homologous to the neurotransmitter-binding orthotopic site, and the intra-subunit (also called vestibular) pocket. An almost similar pattern of mutational impact is observed for the effect of caffeate, a known negative modulator. We propose, for both di-carboxylate compounds and caffeate, a model where the inter-subunit pocket is the actual binding site, and the region corresponding to the vestibular pocket is required either for inter-subunit binding itself, or for binding-to-gating coupling during the allosteric transitions involved in pore gating modulation.Key points summaryUsing a bacterial orthologue of brain pentameric neurotransmitter receptors, we show that the orthotopic/orthosteric agonist site and the adjacent vestibular region are functionally inter-dependent in mediating compound-elicited modulation. We propose that the two sites in the extracellular domain are involved “in series”, a mechanism which may have relevance to Eukaryote receptors.We show that short-chain di-carboxylate compounds are positive modulators of GLIC. The most potent compound identified is fumarate, known to occupy the orthotopic/orthosteric site in previously published crystal structures.We show that intracellular pH modulates GLIC allosteric transitions, as previously known for extracellular pH.We report a caesium to sodium permeabilityratio(PCs/PNa) of 0.54 for GLIC ion pore.
Transdermal Electrophysiological Recordings of Diabetic Small Fiber Peripheral Neuropathy Using a Needle Electrode Array in Mice and Men
Authors: Blaszkiewicz Magdalena , Caron Lydia , Villinski Brooke , Passarelli Joshua , Towne Julia M. , Story Naeemah M. , Merchant Erin , Khan Furrukh S. , Emanetoglu Nuri , Kass Leonard , Smith Rosemary L. , Townsend Kristy L. 
Published: March 2023

AbstractDiabetic peripheral neuropathy (DPN) is a common complication of diabetes. Proactive treatment options remain limited, which is exacerbated by a lack of sensitive and convenient diagnostics, especially early in disease progression or specifically to assess small fiber neuropathy (SFN), the loss of distal small diameter axons that innervate tissues and organs. We designed, fabricated, tested, and validated a first-of-its-kind medical diagnostic device for the functional assessment of transdermal small fiber nerve activity. This device, the Detecting Early Neuropathy (DEN), is an electrically conductive needle array designed to record nerve electrical activity in the skin and subdermal tissues. DEN recordings were validated across a time course of diet-induced DPN in mice, using statistical and computational analyses compared to other SFN measures. Based on these preclinical mouse data, the device design was adapted to obtain recordings in human with a flexible printed circuit board to mold to the leg or other skin regions. The DEN successfully recorded various types of neural activity in mouse and human, with or without stimulation, including validated action potentials and electromyography signals. New functional diagnostic tools like DEN offer a promising outlook for patients needing an earlier or more sensitive diagnosis of SFN/DPN, to allow for earlier and more effective treatment options, especially as more become available in the clinic in future years.