bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of Patients Enrolled in a Prospective and Randomized Trial on Basis of Gestalt Assessment or ABC Score
Authors: Baird Emily W. , Lammers Daniel T. , Abraham Peter , Hashmi Zain G. , Griffin Russell L. , Stephens Shannon W. , Jansen Jan O. , Holcomb John B.
Published: February 2024

Introduction

The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial rapidly enrolled patients based on an ABC ≥ 2 score, or Physician Gestalt (PG) when ABC score was <2. The objective of this study was to describe what patients were enrolled by the two methods and whether patient outcomes differed based these enrollments. We hypothesized that there would be no differences in outcomes based on whether patients were enrolled via ABC score or PG.

Methods

Patients were enrolled with an ABC ≥ 2 or by PG when ABC was <2 by the attending trauma surgeon. We compared 1-, 3-, 6-, 12-, 18- and 24-hour mortality, 30-day mortality, time to hemostasis, emergent surgical or interventional radiology procedure and the proportion of patients who required either >10 units of blood in 24 hours or > 3 units in one hour.

Results

Of 680 patients, 438 (64%) were enrolled on the basis of an ABC score ≥ 2 and 242 (36% by PG when the ABC score was <2. Patients enrolled by PG were older (median 44, IQR 28-59, p < 0.001), more likely to be white (70.3% vs 60.3%, p = 0.014), and more likely to have been injured by blunt mechanisms (77.3% vs 37.2%, p < 0.001). They were also less hypotensive and less tachycardic than patients enrolled by ABC score (both p < 0.001). The groups had similar Injury Severity Scores in the ABC ≥ 2 and PG groups (26 and 27 respectively) and were equally represented (49.1% and 50.8% respectively) in the 1:1:1 treatment arm. There were no significant differences between the ABC score and PG groups for mortality at any point. Time to hemostasis (108 for patients enrolled on basis of Gestalt, vs. 100 mins for patients enrolled on basis of ABC score), and the proportion of patients requiring a massive transfusion (>10 units/24 h) (44.2% vs. 47.3%), or meeting the critical administration threshold (>3 unit/1 hr) (84.7% vs. 89.5%) were similar (p = 0.071)

Conclusion

Early identification of trauma patients likely to require a massive transfusion is important for clinical care, resource use, and selection of patients for clinical trials. Patients enrolled in the PROPPR trial based on PG when the ABC score was <2 represented 36% of the patients and had identical outcomes to those enrolled on the basis of an ABC score of ≥2.

Level of Evidence

Level III, Prognostic
Glymphatic system dysfunction in neurodegenerative diseases
Authors: Beschorner Natalie , Nedergaard Maiken
Published: February 2024

Purpose of review

Purpose of this review is to update the ongoing work in the field of glymphatic and neurodegenerative research and to highlight focus areas that are particularly promising.

Recent findings

Multiple reports have over the past decade documented that glymphatic fluid transport is broadly suppressed in neurodegenerative diseases. Most studies have focused on Alzheimer's disease using a variety of preclinical disease models, whereas the clinical work is based on various neuroimaging approaches. It has consistently been reported that brain fluid transport is impaired in patients suffering from Alzheimer's disease compared with age-matched control subjects.

An open question in the field is to define the mechanistic underpinning of why glymphatic function is suppressed. Other questions include the opportunities for using glymphatic imaging for diagnostic purposes and in treatment intended to prevent or slow Alzheimer disease progression.
Impact of Preoperative Weight Loss on 30-Day Complication Rate after Bariatric Surgery
Authors: Saleh Omnia S , Farag Youssef M K , Medhati Pourya , Tavakkoli Ali
Published: February 2024

BACKGROUND:

The aim of this study is to evaluate the impact of preoperative weight loss on surgical outcomes and operating room (OR) times after primary bariatric procedures, including laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (RYGB).

STUDY DESIGN:

A retrospective cohort study uses the 2021 MBSAQIP dataset. Preoperative total weight loss (TWL)% was calculated. Patients were then divided in to 4 groups: those with no weight loss, lost <0 to <5%, lost ≥5% to <10%, or lost ≥10% TWL preoperatively. These groups were then stratified into those with BMI less than 50 kg/m2 and those with BMI 50 kg/m2 or more and 30-day outcomes and OR times were compared.

RESULTS:

Analysis included 171,010 patients. For BMI less than 50 kg/m2, preoperative weight loss led to no consistent improvement in surgical outcomes. Although >0% to <5% TWL led to a decrease in intra- and postoperative occurrences after RYGB and a decrease in reoperation rates after LSG, these observations were not seen in those with higher degree of weight loss. In patients with BMI 50 kg/m2 or more, preoperative weight loss showed a consistent improvement in reintervention rates after LSG, and readmission rates after RYGB. There was no improvement in other outcomes, however, irrespective of degree of preoperative weight loss.

CONCLUSIONS:

In patients undergoing primary bariatric surgery, preoperative weight loss does not lead to a consistent improvement in outcomes or OR times. In those with BMI 50 kg/m2 or more, there may be improvement in select outcomes that is procedure-specific. Overall, these data do not support a uniform policy of preoperative weight loss, although selective use in some high-risk patients may be appropriate.
Monitoring vegetation- and geodiversity with remote sensing and traits
Authors: Lausch Angela , Selsam Peter , Pause Marion , Bumberger Jan
Published: February 2024

Geodiversity has shaped and structured the Earth's surface at all spatio-temporal scales, not only through long-term processes but also through medium- and short-term processes. Geodiversity is, therefore, a key control and regulating variable in the overall development of landscapes and biodiversity. However, climate change and land use intensity are leading to major changes and disturbances in bio- and geodiversity. For sustainable ecosystem management, temporal, economically viable and standardized monitoring is needed to monitor and model the effects and changes in vegetation- and geodiversity. RS approaches have been used for this purpose for decades. However, to understand in detail how RS approaches capture vegetation- and geodiversity, the aim of this paper is to describe how five features of vegetation- and geodiversity are captured using RS technologies, namely: (i) trait diversity, (ii) phylogenetic/genese diversity, (iii) structural diversity, (iv) taxonomic diversity and (v) functional diversity. Trait diversity is essential for establishing the other four. Traits provide a crucial interface between
in situ
, close-range, aerial and space-based RS monitoring approaches. The trait approach allows complex data of different types and formats to be linked using the latest semantic data integration techniques, which will enable ecosystem integrity monitoring and modelling in the future.

This article is part of the Theo Murphy meeting issue ‘Geodiversity for science and society’.
A test of Conserving Nature's Stage: protecting a diversity of geophysical traits can also support a diversity of species at a landscape scale
Authors: Miller Stephanie N. , Beier Paul , Suzart de Albuquerque Fabio
Published: February 2024

Conserving Nature's Stage (CNS) is a concept from conservation planning that promotes the protection of areas encompassing a broad range of enduring geophysical traits to provide long-term habitat for diverse species. The efficacy of using enduring geophysical characteristics as surrogates for biodiversity, independent of non-geophysical features and when considering finer resolution area selections, has yet to be investigated. Here, we evaluated CNS using 33 fine-scale inventories of vascular plant, non-vascular plant, invertebrate or vertebrate species from 13 areas across three continents. For each inventory, we estimated a continuous multidimensional surrogate defined from topographic and soil estimates of the surveyed plots. We assessed surrogate effectiveness by comparing the species representation of surrogate selected plots to the representation from plots picked randomly and using species information. We then used correlation coefficients to assess the link between the performance and qualities of the inventories, surroundings and surrogates. The CNS surrogate showed positive performance for 24 of the 33 inventories, and among these tests, represented 28 more species than random and 83% of the total number of species on average. We also found a small number of weak correlations between performance and environmental variability, as well as qualities of the surrogate. Our study demonstrates that prioritizing areas for a variety of geophysical characteristics will, in most cases, promote the representation of species. Our findings also point to areas for future research that might enhance CNS surrogacy.

This article is part of the Theo Murphy meeting issue ‘Geodiversity for science and society’.
Group composition and dynamics in American Crows: insights into an unusual cooperative breeder
Authors: Caffrey Carolee , Peterson Charles C.
Published: February 2024

Breeding pairs of American Crows (Corvus brachyrhynchos) in Stillwater, OK, lived with 0-10 auxil-iaries in territories distributed throughout public, campus, commercial, and residential areas. Unpaired crows moved easily among groups throughout the year, but commonly did so during the two months or so preceding the onset of nesting across the population, and the week or so preceding hatching within groups. In 2001 and 2002, pre-hatch group size ranged from 2-10 (mean = 4.5 in both years), and auxiliaries included a male sibling, social and genetic offspring, step-offspring, half-siblings, and unrelated immigrants of both sexes, ranging in age from 1 to at least five years old. Twenty nine percent of pre-hatch auxiliaries dispersed out of groups at hatch-ing (for half, only temporarily), including all females unrelated to female breeders. Post-hatch group size ranged from 2-6, with means of 3.7 in both years, and the post-hatch auxiliary popula-tion differed in composition from the pre-hatch population: whereas post-hatch male auxiliaries included a sibling, half siblings, and unrelated immigrants in addition to social and genetic sons, all post-hatch female auxiliaries were the social and genetic daughters of female breeders, and all but one (the same individual in both years) were also the social and genetic daughters of male breeders.

Crows in Stillwater delayed breeding for one or more years beyond sexual maturity, despite the availability of space and members of the opposite sex. Individual dispersal decisions by unpaired crows, and the behavior of paired territory owners, did not follow patterns described for other cooperative breeders. We found little support for extant theories regarding the formation, com-position, and maintenance of avian groups, and discuss aspects of the lives of crows that may have contributed to the complex and benign nature of this population’s society.

How to Cite: Caffrey, C. and C. C. Peterson. 2015. Group composition and dynamics in American

Crows: insights into an unusual cooperative breeder. Friesen Press.
Application of the Social Cognitive Theory amid food parenting practices of Black immigrant mothers in the US: A qualitative study
Authors: Tchoua Phoebe , Brannock Mary , Slawson Deborah
Published: February 2024

Background

Children of Black immigrant parents living in the US are at elevated risk of being overweight or obese, thus increasing their risks of morbidity and mortality as they age. Parents play a crucial role in shaping their children’s nutrition through their food parenting practices. The Social Cognitive Theory (SCT) can explain Black immigrant mother’s FPP and their children’s dietary behavior. This study aimed to assess SCT’s constructs, personal (maternal knowledge, attitudes, beliefs) and environmental factors (acculturation) in relation to the behavioral factor (food parenting practices) among a sample of Black immigrant mothers living in Metro Atlanta, Georgia.

Methods

Convenience sampling was employed to recruit 30 Black immigrant mothers who lived in seven Metro Atlanta, Georgia counties in the summer of 2022. Four focus group interviews were conducted over two weeks. The qualitative data analysis was thematic.

Results

Focus group data analysis revealed seven major themes: knowledge, attitude, belief, modeling, acculturation, coercive control, and structure, and six subthemes. Mothers discussed being intentional about encouraging healthy foods and limiting unhealthy foods for their children. Overall, acculturation influenced mothers’ food parenting practices. Since migrating to the US, some mothers’ nutrition changed in positive (e.g., eating more fruits) and negative ways (e.g., snacking more) because of schedules, cost, and access. Children ate a mixed diet, the mother’s native diet and the American diet, and the former was considered healthier and affordable by most.

Conclusion

This is the first study to look at the food parenting practices of Black immigrants in the US. By identifying key factors that influence the food parenting practices of this population and their children’s dietary habits, this study’s findings are useful to practitioners or researchers who work with this population on nutrition and obesity prevention.
Anti-diuretic hormone ITP signals via a guanylate cyclase receptor to modulate systemic homeostasis inDrosophila
Authors: Gera Jayati , Agard Marishia , Nave Hannah , Sajadi Farwa , Thorat Leena , Kondo Shu , Nässel Dick R. , Paluzzi Jean-Paul V. , Zandawala Meet
Published: February 2024

Insects have evolved a variety of neurohormones that enable them to maintain their nutrient and osmotic homeostasis. While the identities and functions of various insect metabolic and diuretic hormones have been well-established, the characterization of an anti-diuretic signaling system that is conserved across most insects is still lacking. To address this, here we characterized the ion transport peptide (ITP) signaling system inDrosophila. TheDrosophila ITPgene encodes five transcript variants which generate three different peptide isoforms: ITP amidated (ITPa) and two ITP-like (ITPL1 and ITPL2) isoforms. Using a combination of anatomical mapping and single-cell transcriptome analyses, we comprehensively characterized the expression of all three ITP isoforms in the nervous system and peripheral tissues. Our analyses reveal widespread expression of ITP isoforms. Moreover, we show that ITPa is released during dehydration and recombinantDrosophilaITPa inhibits diuretic peptide-induced renal tubule secretionex vivo, thus confirming its role as an anti-diuretic hormone. Using a phylogenetic-driven approach and theex vivosecretion assay, we identified and functionally characterized Gyc76C, a membrane guanylate cyclase, as an elusiveDrosophilaITPa receptor. Thus, knockdown of Gyc76C in renal tubules abolishes the inhibitory effect of ITPa on diuretic hormone secretion. Extensive anatomical mapping of Gyc76C reveals that it is highly expressed in larval and adult tissues associated with osmoregulation (renal tubules and rectum) and metabolic homeostasis (fat body). Consistent with this expression, knockdown of Gyc76C in renal tubules impacts tolerance to osmotic and ionic stresses, whereas knockdown specifically in the fat body impacts feeding, nutrient homeostasis and associated behaviors. We also complement receptor knockdown experiments with ITPa overexpression in ITP neurons. Interestingly, ITPa-Gyc76C pathways deciphered here are reminiscent of the atrial natriuretic peptide signaling in mammals. Lastly, we utilized connectomics and single-cell transcriptomics to identify synaptic and paracrine pathways upstream and downstream of ITP-expressing neurons. Taken together, our systematic characterization of the ITP signaling establishes a tractable system to decipher how a small set of neurons integrates diverse inputs to orchestrate systemic homeostasis inDrosophila.
Utility of an untargeted metabolomics approach using a 2D GC-GC-MS platform to distinguish relapsing and progressive multiple sclerosis
Authors: Datta Indrani , Zahoor Insha , Ata Nasar , Rashid Faraz , Cerghet Mirela , Rattan Ramandeep , Poisson Laila M , Giri Shailendra
Published: February 2024

Introduction

Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease of the central nervous system (CNS) in young adults and results in progressive neurological defects. The relapsing-remitting phenotype (RRMS) is the most common disease course in MS and may progress to the progressive form (PPMS).

Objectives

There is a gap in knowledge regarding whether the relapsing form can be distinguished from the progressive course or healthy subjects (HS) based on an altered serum metabolite profile. In this study, we performed global untargeted metabolomics with the 2D GCxGC-MS platform to identify altered metabolites between RRMS, PPMS, and HS.

Methods

We profiled 235 metabolites in the serum of patients with RRMS (n=41), PPMS (n=31), and HS (n=91). A comparison of RRMS and HS patients revealed 22 significantly altered metabolites at p<0.05 (false discovery rate [FDR]=0.3). The PPMS and HS comparisons revealed 28 altered metabolites at p<0.05 (FDR=0.2).

Results

Pathway analysis using MetaboAnalyst revealed enrichment of four metabolic pathways in both RRMS and PPMS (hypergeometric test p<0.05): 1) galactose metabolism; 2) amino sugar and nucleotide sugar metabolism; 3) phenylalanine, tyrosine, and tryptophan biosynthesis; and 4) aminoacyl-tRNA biosynthesis. The Qiagen IPA enrichment test identified the sulfatase 2 (SULF2) (p=0.0033) and integrin subunit beta 1 binding protein 1 (ITGB1BP1) (p=0.0067) genes as upstream regulators of altered metabolites in the RRMS vs. HS groups. However, in the PPMS vs. HS comparison, valine was enriched in the neurodegeneration of brain cells (p=0.05), and heptadecanoic acid, alpha-ketoisocaproic acid, and glycerol participated in inflammation in the CNS (p=0.03).

Conclusion

Overall, our study suggested that RRMS and PPMS may contribute metabolic fingerprints in the form of unique altered metabolites for discriminating MS disease from HS, with the potential for constructing a metabolite panel for progressive autoimmune diseases such as MS.
Temporal Dynamics of Cyanobacterial Bloom Community Composition and Toxin Production from Urban Lakes
Authors: Maurer Julie A. , Kim Andrew M. , Oblie Nana , Hefferan Sierra , Xie Hannuo , Slitt Angela , Jenkins Bethany D. , Bertin Matthew J.
Published: February 2024

With a long evolutionary history and a need to adapt to a changing environment, cyanobacteria in freshwater systems use specialized metabolites for communication, defense, and physiological processes. However, the role that these metabolites play in differentiating species, maintaining microbial communities, and generating niche persistence and expansion is poorly understood. Furthermore, many cyanobacterial specialized metabolites and toxins present significant human health concerns due to their liver toxicity and their potential impact to drinking water. Gaps in knowledge exist with respect to changes in species diversity and toxin production during a cyanobacterial bloom (cyanoHAB) event; addressing these gaps will improve understanding of impacts to public and ecological health. In the current project, we utilized a multi-omics strategy (DNA metabarcoding and metabolomics) to determine the cyanobacterial community composition, toxin profile, and the specialized metabolite pool at three freshwater lakes in Providence, RI during summer-fall cyanoHABs. Species diversity decreased at all study sites over the course of the bloom event, and toxin production reached a maximum at the midpoint of the event. Additionally, LC-MS/MS-based molecular networking identified new toxin congeners. This work provokes intriguing questions with respect to the use of allelopathy by organisms in these systems and the presence of emerging toxic compounds that can impact public health.

SYNOPSIS

This study reports on cyanobacterial community succession and toxin dynamics during cyanobacterial bloom events. Results show relationships and temporal dynamics that are relevant to public health.
Single Nucleotide Polymorphism (SNP) and Antibody-based Cell Sorting (SNACS): A tool for demultiplexing single-cell DNA sequencing data
Authors: Kennedy VE , Roy R , Peretz CAC , Koh A , Tran E , Smith CC , Olshen AB
Published: February 2024

Motivation

Recently, single-cell DNA sequencing (scDNA-seq) and multi-modal profiling with the addition of cell-surface antibodies (scDAb-seq) have provided key insights into cancer heterogeneity.

Scaling these technologies across large patient cohorts, however, is cost and time prohibitive. Multiplexing, in which cells from unique patients are pooled into a single experiment, offers a possible solution. While multiplexing methods exist for scRNAseq, accurate demultiplexing in scDNAseq remains an unmet need.

Results

Here, we introduce SNACS: Single-Nucleotide Polymorphism (SNP) and Antibody-based Cell Sorting. SNACS relies on a combination of patient-level cell-surface identifiers and natural variation in genetic polymorphisms to demultiplex scDNAseq data. We demonstrated the performance of SNACS on a dataset consisting of multi-sample experiments from patients with leukemia where we knew truth from single-sample experiments from the same patients. Using SNACS, accuracy ranged from 0.948 – 0.991 vs 0.552 – 0.934 using demultiplexing methods from the single-cell literature.

Availability Implementation

SNACS is available athttps://github.com/olshena/SNACS.

Abstract Figure
Mathematical Modelling Indicates Th-cell Targeted Antibody-Dependent Cellular Cytotoxic Is a Crucial Obstacle Hurdling HIV Vaccine Development
Authors: Xu Zhaobin , Zeng Qiangcheng , Yang Dongying , Sun Xiaoguang , Wei Dongqing , Demongeot Jacques , Cao Zanxia
Published: February 2024

HIV poses a significant threat to human health. Although some progress has been made in the development of an HIV vaccine, there is currently no reported success in achieving an effective and fully functional vaccine for HIV. This highlights the challenges involved in HIV vaccine development. Through mathematical modeling, we have conducted a systematic study on the impact of antibody-dependent cellular cytotoxicity (ADCC) on HIV-specific immune responses. Unlike other viral infections, the ADCC effect following HIV infection may cause significant damage to the follicular center Th cells, leading to apoptosis of follicular center cells and rapid death of effector Th cells. This impedes the generation of neutralizing antibodies and creates barriers to viral clearance, thereby contributing to long-term infection. Another challenge posed by this effect is the substantial reduction in vaccine effectiveness, as effective antigenic substances such as gp120 bind to Th cell surfaces, resulting in the apoptosis of follicular center Th cells due to ADCC, hindering antibody regeneration. To address this issue, we propose the concept of using bispecific antibodies. By genetically editing B cells to insert the bispecific antibody gene, which consists of two parts-one targeting the CD4 binding site of HIV, such as the broadly neutralizing antibody 3BNC117, and the other targeting antibodies against other viruses, such as the spike protein of SARS-CoV-2-we can simultaneously enhance the levels of two pathogen-specific antibodies through stimulation with non-HIV-antigens corresponding to the other part of the chimeric antibody, such as the spike protein. This study contributes to the elucidation of the pathophysiology of HIV, while also providing a theoretical framework for the successful development of an HIV vaccine.
A rare splice-site variant in cardiac troponin-T (TNNT2): The need for ancestral diversity in genomic reference datasets
Authors: Butters Alexandra , Thomson Kate , Harrington Franki , Henden Natasha , McGuire Karen , Byrne Alicia B. , Bryen Samantha , McGurk Kathryn A. , Leask Megan , Ackerman Michael J. , Atherton John , Bos Johan M. , Caleshu Colleen , Day Sharlene , Dunn Kyla , Hayes Ian , Juang Jimmy , McGaughran Julie , Nowak Natalie , Parikh Victoria N. , Ronan Anne , Semsarian Christopher , Tardiff Jil C. , Tiemensma Marianne , Merriman Tony R. , Ware James S. , Skinner Jonathan R. , MacArthur Daniel G. , Siggs Owen M. , Bagnall Richard D. , Ingles Jodie
Published: February 2024

The underrepresentation of different ancestry groups in large genomic datasets creates difficulties in interpreting the pathogenicity of monogenic variants. Genetic testing for individuals with non-European ancestry results in higher rates of uncertain variants and a greater risk of misclassification. We report a rare variant in the cardiac troponin T gene,TNNT2; NM_001001430.3: c.571-1G>A (rs483352835) identified via research-based whole exome sequencing in two unrelated probands of Oceanian ancestry with cardiac phenotypes.

The variant disrupts the canonical splice acceptor site, activating a cryptic acceptor and resulting in an in-frame deletion (p.Gln191del). The variant is rare in gnomAD v4.0.0 (13/780,762; 0.002%), with the highest frequency in South Asians (5/74,486; 0.007%) and has 16 ClinVar assertions (13 diagnostic clinical laboratories classify as variant of uncertain significance). There are at least 28 reported cases, many with Oceanian ancestry and diverse cardiac phenotypes. Indeed, among Oceanian-ancestry-matched datasets, the allele frequency ranges from 2.9-8.8% and is present in 2/4 (50%) Indigenous Australian alleles in Genome Asia 100K, with one participant being homozygous. With Oceanians deriving greater than 3% of their DNA from archaic genomes, we found c.571-1G>A in Vindija and Altai Neanderthal, but not the Altai Denisovan, suggesting an origin post Neanderthal divergence from modern humans 130-145 thousand years ago. Based on these data, we classify this variant as benign, and conclude it is not a monogenic cause of disease. Even with ongoing efforts to increase representation in genomics, we highlight the need for caution in assuming rarity of genetic variants in largely European datasets. Efforts to enhance diversity in genomic databases remain crucial.
AI-based differential diagnosis of dementia etiologies on multimodal data
Authors: Xue Chonghua , Kowshik Sahana S. , Lteif Diala , Puducheri Shreyas , Jasodanand Varuna H. , Zhou Olivia T. , Walia Anika S. , Guney Osman B. , Zhang J. Diana , Pham Serena T. , Kaliaev Artem , Andreu-Arasa V. Carlota , Dwyer Brigid C. , Farris Chad W. , Hao Honglin , Kedar Sachin , Mian Asim Z. , Murman Daniel L. , O’Shea Sarah A. , Paul Aaron B. , Rohatgi Saurabh , Saint-Hilaire Marie-Helene , Sartor Emmett A. , Setty Bindu N. , Small Juan E. , Swaminathan Arun , Taraschenko Olga , Yuan Jing , Zhou Yan , Zhu Shuhan , Karjadi Cody , Alvin Ang Ting Fang , Bargal Sarah A. , Plummer Bryan A. , Poston Kathleen L. , Ahangaran Meysam , Au Rhoda , Kolachalama Vijaya B.
Published: February 2024

Differential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an AI model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations, and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51, 269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a micro-averaged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the micro-averaged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two cooccurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in various clinical settings and drug trials, with promising implications for person-level management.
Retrospective Analysis of an Acute Ischemic Stroke Cohort Shows that Timing of Antidepressant Use Associated with Short-term Recovery and Functional Independence at 90-Days
Authors: Baraban Elizabeth , Lesko Alexandra , Still Kyle , Anderson Weston
Published: February 2024

Background

Little is known about how the timing of antidepressant use influences stroke outcomes. The objective of this exploratory, retrospective analysis is to examine stroke outcomes by timing of antidepressant use among patients who received stroke treatment.

Methods

12,590 eligible patients were treated for a primary or secondary diagnosis of ischemic stroke. Inpatient strokes and patients who were missing information on antidepressant use or stroke outcomes were excluded. The outcome variables were (1) a change in ambulation from pre-stroke to discharge; (2) a change in modified Rankin scale (mRS) from pre-stroke to discharge; and (3) a change in mRS from pre-stroke to 90-days post-discharge. The independent variable of interest was timing of antidepressant treatment. Logistic regression with generalized estimating equations was used, controlling for covariates.

Results

At 90-days post-discharge, patients with no history of antidepressant use or with a previous history of antidepressant use were similar to patients with current antidepressant use in terms of their return to baseline functional independence. In contrast, our model predicted that a new antidepressant prescription at discharge was associated with a ∼57% decrease in the likelihood of returning to baseline functional independence at 90-days compared to patients currently using an antidepressant (AOR:0.510, CI:0.277-0.938, p=0.03). Post-hoc analyses showed females with current antidepressant use associated with a higher predicted probability of returning to baseline functional independence at 90-days compared to females with no antidepressant use. This association was not true for males. Conversely, males with a new prescription had the lowest predicted probability of returning to baseline among all groups at 90-days post-discharge.

Conclusion

These results suggest that use of antidepressants was associated with stroke recovery, but the effects are moderated by sex. Further study is needed to determine if this relationship is causal and the mechanisms between timing of antidepressant treatment and outcomes.
WITHDRAWN: IL-17C plays a role in the pathophysiology of acute recurrent tonsillitis
Authors: Clapperton Megan , Kunanandam Tash , Florea Catalina D , Cunningham Margaret R , Douglas Catriona M , McConnell Gail
Published: February 2024

Withdrawal Statement

The authors have withdrawn their manuscript owing to an error discovered in the selection and analysis of blot data. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Impaired islet function with normal exocrine enzyme secretion is consistent across the head, body, and tail pancreas regions in type 1 diabetes
Authors: Drotar Denise M. , Mojica-Avila Ana Karen , Bloss Drew T. , Cohrs Christian M. , Manson Cameron T. , Posgai Amanda L. , Williams MacKenzie D. , Brusko Maigan A. , Phelps Edward A. , Wasserfall Clive H. , Speier Stephan , Atkinson Mark A.
Published: February 2024

Histopathological heterogeneity in human pancreas has been well documented; however, functional evidence at the tissue level is scarce. Herein we investigatedin situglucose-stimulated islet and carbachol-stimulated acinar cell secretion across the pancreas head (PH), body (PB), and tail (PT) regions in no diabetes (ND, n=15), single islet autoantibody-positive (1AAb+, n=7), and type 1 diabetes donors (T1D, <14 months duration, n=5). Insulin, glucagon, pancreatic amylase, lipase, and trypsinogen secretion along with 3D tissue morphometrical features were comparable across the regions in ND. In T1D, insulin secretion and beta-cell volume were significantly reduced within all regions, while glucagon and enzymes were unaltered. Beta-cell volume was lower despite normal insulin secretion in 1AAb+, resulting in increased volume-adjusted insulin secretion versus ND. Islet and acinar cell secretion in 1AAb+ were consistent across PH, PB and PT. This study supports low inter-regional variation in pancreas slice function and potentially, increased metabolic demand in 1AAb+.
Drug-induced cytotoxicity prediction in muscle cells, an application of the Cell Painting assay
Authors: Lambert Roman , Aparicio Pablo , Candelas Eva Serrano , Murphy Aisling , Gozalbes Rafael , Fearnhead Howard
Published: February 2024

In silicotoxicity prediction offers the chance of reducing or replacing most animal testing through the integration of large experimental assay datasets with the appropriate computational approaches. The use of Cell Painting to detect various phenotypic changes induced by chemicals is emerging as a powerful technique in toxicity prediction. However, most Cell Painting approaches use cancer cells that are less relevant for many toxicological endpoints, which may limit the usefulness of this data. In this study, a myoblast cell line is used to characterize cellular responses to a panel of 30 known myotoxicants. In place of traditional structural descriptors, here each perturbation is described by a fingerprint of calculated properties, deducted from the intensity, shape, or texture of individual cells. We show that these kinds of descriptors convey information to allow the prediction of the cellular viability and fate of cells in myoblasts and differentiated myotubes of the C2C12 cell line, and the clustering of drugs by their cytotoxicity responses.

Author Summary

Studying the toxicity of chemical compounds and drugs is crucial to avoid potentially lethal adverse effects of commercialized products, but also to detect the unsuspected toxicity of existing drugs. While these assays traditionally rely on animal models raising important ethical concerns, a need forin vitroandin silicomodels is present and increasing in recent years. We here propose a predictive model capable of predicting the values of a cell viability assay using cell morphology profiles captured with a microscopy experiment. This model predicts the healthiness of muscle cells treated with 30 compounds suspected to induce muscular damage or even myopathies in humans. We also use these profiles to find an interesting morphological similarity between two different classes of drugs: statins (used for cholesterol treatments) and tyrosine kinase inhibitors (anti-cancer drugs). This analysis opens a new perspective for understanding the mechanisms responsible for drug-induced muscular toxicity, an area of toxicology that is currently under-researched.
Network pharmacology of xylazine to understand Its health consequences and develop mechanistic based remediations
Authors: Kumar Arun HS
Published: February 2024

Background

The recent raise in xylazine use disorders (XUD) in humans is a significant cause for concern as comprehensive understanding of its molecular pathology is limited and hence the ability to reverse the potential adverse effects are lacking. To address this gap, this study evaluates the dose-dependent impact of xylazine and its interactions with various potential targets, to identify an optimal reversal strategy.

Methods

A trichotomized (Low, medium, and high) dose, volume of distribution and predicted plasma concentration of xylazine were defined. A detailed analysis of xylazine’s network protein targets and their tissue-specific expression was performed using classical pharmacoinformatic tools. Molecular docking was used to assess the drug-target affinities and identify potential reversal agents.

Results

The study categorized xylazine plasma concentrations ranging from 5-8μM, 14-20μM, and 28-40μM, as low, medium, and high respectively. Xylazine displayed preferential affinity for hydrolases, kinases, transporters, and ion channels. Xylazine’s network analysis revealed the following proteins, ABCC9, RET, RAPGEF4, ACHE, TGFBR1, PGR, KCNH2, KCNN2, and TRPM8 as its high affinity targets. The tissue-specific expression of these high-affinity targets suggested potential adverse effects on various organs, particularly skeletal and smooth muscles, and the adrenal gland. The study further explored the potential reversal of xylazine pharmacology using alpha2AR-antagonists and CNS stimulants. Prazosin emerged as the most promising candidate, exhibiting a 200 to 2000-fold superior affinity against all high-affinity targets of xylazine.

Conclusion

This study contributes to our understanding of xylazine’s molecular mechanisms and suggests that prazosin can serve as an effective therapeutic option for mitigating xylazine-induced adverse effects in XUD patients, which warrants clinical investigation.
Optical photothermal infrared spectroscopy (O-PTIR): a promising new tool for bench-top analytical palaeontology at the sub-micron scale
Authors: Loron C.C. , Borondics F.
Published: February 2024

The identification of preserved organic material within fossils is challenging. Well-established vibrational spectroscopy techniques, such as micro-FTIR (Fourier Transform Infra-Red spectroscopy), have been widely used to investigate organic fossils’ molecular composition. However, even when well-adapted to study objects several tens of micrometre across, they still suffer from limitations, notably regarding resolution and sample preparation requirements. Optical Photothermal Infrared Spectroscopy (O-PTIR), a recently developed technique, overcomes the challenges of bench-top FTIR spectroscopy. By combining an IR excitation laser with a 532 nm green probe laser, this technique allows molecular characterization at high spectral resolution (~2 cm−1) and with extremely fine spatial resolution (~500 nanometres). Additionally, problems linked with sample thickness, surface roughness and particle shape/size are mitigated when compared with FTIR or Atomic Force Microscopy-based nanoIR techniques. Here we show that O-PTIR can be used to easily and successfully map the molecular composition of small organic fossils preserved in silica matrix (chert) in petrographic thin sections. Our study reveals that O-PTIR resolves spatial heterogeneities in the preserved molecular composition of organic fossils (spores and plants) at a sub-micron scale, and that such heterogeneities occur in the cuticle in an early Devonian plant, where they suggest a structural organisation comparable to modern plants. These results on 400 million years old fossils, validate O-PTIR as a powerful and extremely promising new tool for nanoanalytical palaeontology.
Congenital T cell activation impairs transitional to follicular B cell maturation in humans
Authors: Allard-Chamard Hugues , Hillier Kirsty , Ramseier Michelle L. , Bertocchi Alice , Kaneko Naoki , Premo Katherine , Lam Tiffany , Yuen Grace , Karpel Marshall , Mahajan Vinay S. , Tsekeri Christina , Vencic Jean , Crotty Rory , Sharda Anish , Barmettler Sara , Westermann-Clark Emma , Walter Jolan E. , Ghebremichael Musie , Shalek Alex K. , Farmer Jocelyn R. , Pillai Shiv
Published: February 2024

CTLA4-deficient patients exhibit profound humoral immune dysfunction, yet the basis for the B cell defect is not known. We observed a marked reduction in transitional to follicular B cell development in CTLA4-deficient patients, correlating with decreased CTLA4 function in regulatory T cells and increased mTORC1 signaling in transitional B cells. Treatment of transitional B cells with CD40L was sufficient to induce mTORC1 signaling and inhibit follicular B cell maturationin vitro. Frequent cell-cell contacts between CD40L+T cells and naïve IgD+CD27−B cells were observed in patient lymph nodes. Follicular B cell maturation in CTLA-deficient patients was partially rescued following CTLA4 replacement therapyin vivo. We conclude that functional regulatory T cells and the containment of excessive T cell activation are required for follicular B cells to mature and attain metabolic quiescence and thus acquire a state of immunological self-tolerance.

One Sentence Summary

Congenital T cell activation in CTLA4-deficient patients impairs transitional to follicular B cell maturation and can be rescued by CTLA4 replacement therapyin vivo.
Neodymium-Doped Nanocrystals for Diffraction-limitedin vitroTemperature Sensing
Authors: Bravo M. , Yang S. , Wen D. , Krzyzowska S. , Taemaitree F. , Zaman S. , Fortuni B. , Rocha S. , Mulvaney P. , Uji-i H. , Brooke S. , Hutchison J.
Published: February 2024

Localized hyperthermia is a promising approach to cancer therapy. However, its clinical potential is limited by heterogeneous heat distribution within tumors, and advanced methods to measure temperature at the sub-micron level are therefore required. To address this challenge, luminescent nanothermometers, such as lanthanide-doped nanocrystals (Ln-NC) operating in the near-infrared (NIR), have been investigated for accurate spatiotemporal thermal monitoring. In this study, the synthesis of neodymium-doped, sodium yttrium fluoride nanocrystals (Nd-NCs) was optimized to achieve high photoluminescence (PL) intensity by adjusting the dopant concentration and by shelling with inert layers. Standard curves for luminescence-based temperature readout were developed using ratiometric analysis of the temperature-dependent PL spectra in the 850-920 nm biological window, showing excellent linearity and high thermal sensitivity. A silica shell was added to the particles and shown to confer excellent aqueous stability and biocompatibility in A549 lung cancer cells. Finally, luminescent thermal readout was demonstratedin vitroin A549 cells by spectrally resolving the diffraction-limited luminescence spots at a single-particle scale over a clinically relevant temperature range from 20-50 °C. The application of the developed nanothermometer as preclinical tools for NP-HT characterization could provide crucial information on the therapeutic temperature achieved in and around the tumor area. This could be key to optimizing NP properties and therapeutic parameters, for the development of viable hyperthermal cancer treatments.

Abstract Figure
Multimodal illumination platform for 3D single-molecule super-resolution imaging throughout mammalian cells
Authors: Nelson Tyler , Vargas-Hernández Sofía , Freire Margareth , Cheng Siyang , Gustavsson Anna-Karin
Published: February 2024

Single-molecule super-resolution imaging is instrumental for investigating cellular architecture and organization at the nanoscale. Achieving precise 3D nanometric localization when imaging structures throughout mammalian cells, which can be multiple microns thick, requires careful selection of the illumination scheme in order to optimize the fluorescence signal to background ratio (SBR). Thus, an optical platform that combines different wide-field illumination schemes for target-specific SBR optimization would facilitate more precise, 3D nanoscale studies of a wide range of cellular structures. Here we demonstrate a versatile multimodal illumination platform that integrates the sectioning and background reduction capabilities of light sheet illumination with homogeneous, flat-field epi-and TIRF illumination. Using primarily commercially available parts, we combine the fast and convenient switching between illumination modalities with point spread function engineering to enable 3D singlemolecule super-resolution imaging throughout mammalian cells. For targets directly at the coverslip, the homogenous intensity profile and excellent sectioning of our flat-field TIRF illumination scheme improves single-molecule data quality by providing low fluorescence background and uniform fluorophore blinking kinetics, fluorescence signal, and localization precision across the entire field of view. The increased contrast achieved with LS illumination, when compared with epi-illumination, makes this illumination modality an excellent alternative when imaging targets that extend throughout the cell. We validate our microscopy platform for improved 3D super-resolution imaging by two-color imaging of paxillin – a protein located in the focal adhesion complex – and actin in human osteosarcoma cells.
Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in femalemdxmice
Authors: Timpani Cara A. , Debrincat Didier , Kourakis Stephanie , Boyer Rebecca , Formosa Luke E. , Steele Joel R. , Zhang Haijian , Schittenhelm Ralf B. , Russell Aaron P. , Rybalka Emma , Lindsay Angus
Published: February 2024

Female carriers of aDuchenne muscular dystrophy(DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in femalemdxmice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT-labelling. Our study confirms that loss of estrogen in femalemdxmice reduces exercise capacity, tricarboxylic acid cycle intermediates and citrate synthase activity but that these deficits can be offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggests that estrogen mitigates dystrophinopathic features in femalemdxmice and that estrogen replacement may be a potential therapy for post-menopausal DMD carriers.