bluuebunny/crossref_metadata_2025 huggingface dataset:
Burlap and buddies: the effects of social enrichment (preweaning mixing) and object enrichment (burlap) on piglet performance, behavior, and welfare in the preweaning environment
Authors: Scott Ashlyn , Le Heiget Arielle , Stefanson Reyna , Ahloy-Dallaire Jamie , King Meagan
Published: April 2024

When weaned in commercial operations, piglets are not only separated from their sow but also mixed with unfamiliar pigs in an unfamiliar environment with a new diet. These abrupt changes can be stressful for piglets, often having negative welfare consequences. Our objective was to study the effects of early-life preweaning socialization and object enrichment in the preweaning environment. We compared piglet performance, behavior, and welfare across six treatments that combined multi-litter group size (1 vs. 2 vs. 4 litters) and burlap (yes vs. no). We recorded piglet behavior and lesion-scored sows and piglets. Normal conforming data, expressed per experimental unit (and behavior data were averaged over time), were analyzed by ANOVA. When given the opportunity in the sow barn, piglets in multi-litter groups socialized with other litters. Burlap use (P = 0.08) was observed in < 5% of the observations but tended to increase in mixed litter groups. Cross-sucking was observed in ~12% of the observations within mixed litter groups and tended to increase with mixed group size (P = 0.08). While there was no difference in the proportion of piglets nursing (P > 0.10), piglets were less active in the single crate groups and most active in the groups of two litters mixed (P = 0.03). Additionally, observed piglet/sow biting behaviors did not differ between treatments; however, piglet-piglet biting (P = 0.07), and pen object manipulation (P = 0.07) tended to be observed more frequently in non-enriched groups. Piglet displacements were observed more often in non-enriched groups around the pen (P = 0.03) but tended to be observed more often in enriched groups at the teat (P = 0.07). Preweaning socialization and object enrichment had no impact on the average number of piglets weaned per sow or total piglet mortality (P > 0.10). However, the proportion of laid-on piglets decreased as the number of mixed litters increased (P = 0.02). The average number of lesions per piglet did not differ between treatments. Although the final lesion scores of sow teat and udder condition did not differ between treatments (P > 0.10), sow udder scores tended to worsen more in the single litters than in the mixed litters (P = 0.08). Overall, social and object enrichment allows piglets to socialize at a younger age and to redirect their attention toward an object (burlap) which does not negatively impact piglet or sow performance, or behavior, and may improve piglet welfare around weaning.
Analgesic Effectiveness of Liposomal Bupivacaine versus Plain Local Anesthetics for Abdominal Fascial Plane Blocks: A Systematic Review and Meta-analysis of Randomized Trials
Authors: Hussain Nasir , Speer Jarod , Abdallah Faraj W.
Published: April 2024

Background

Liposomal bupivacaine is reported to prolong the duration of analgesia when used for abdominal fascial plane blocks compared to plain local anesthetics; however, evidence from randomized trials is mixed. This meta-analysis aims to compare the analgesic effectiveness of liposomal bupivacaine to plain local anesthetics in adults receiving abdominal fascial plane blocks.

Methods

Randomized trials comparing liposomal bupivacaine and plain (nonliposomal) local anesthetics in abdominal fascial plane blocks were sought. The primary outcome was area under the curve rest pain between 24 to 72 h postoperatively. Secondary outcomes included rest pain at individual timepoints (1, 6, 12, 24, 48, and 72 h); analgesic consumption at 0 to 24, 25 to 48, and 49 to 72 h; time to analgesic request; hospital stay duration; and opioid-related side effects. Data were pooled using the Hartung-Knapp-Sidik-Jonkman random effects method.

Results

Sixteen trials encompassing 1,287 patients (liposomal bupivacaine, 667; plain local anesthetics, 620) were included. The liposomal bupivacaine group received liposomal bupivacaine mixed with plain bupivacaine in 10 studies, liposomal bupivacaine alone in 5 studies, and both preparations in 1 three-armed study. No difference was observed between the two groups for area under the curve pain scores, with a standardized mean difference (95% CI) of –0.21 cm.h (–0.43 to 0.01; P = 0.058; I2 = 48%). Results were robust to subgroup analysis based on (1) potential conflict of interest and (2) mixing of plain local anesthetics with liposomal bupivacaine. The two groups were not different for any of the day 2 or day 3 secondary outcomes.

Conclusions

This systematic review and meta-analysis suggests similar analgesic effectiveness between liposomal bupivacaine and plain local anesthetics when used for fascial plane block of the abdominal wall. The authors’ analysis does not support an evidence-based preference for liposomal bupivacaine compared to plain local anesthetics for abdominal fascial plane blocks.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Biomarker-Based Risk Stratification Tool in Pediatric Acute Respiratory Distress Syndrome: Single-Center, Longitudinal Validation in a 2014–2019 Cohort
Authors: Whitney Jane E. , Johnson Grace M. , Varisco Brian M. , Raby Benjamin A. , Yehya Nadir
Published: April 2024

OBJECTIVES:

The Pediatric Acute Respiratory Distress Syndrome Biomarker Risk Model (PARDSEVERE) used age and three plasma biomarkers measured within 24 hours of pediatric acute respiratory distress syndrome (ARDS) onset to predict mortality in a pilot cohort of 152 patients. However, longitudinal performance of PARDSEVERE has not been evaluated, and it is unclear whether the risk model can be used to prognosticate after day 0. We, therefore, sought to determine the test characteristics of PARDSEVERE model and population over the first 7 days after ARDS onset.

DESIGN:

Secondary unplanned post hoc analysis of data from a prospective observational cohort study carried out 2014–2019.

SETTING:

University-affiliated PICU.

PATIENTS:

Mechanically ventilated children with ARDS.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Between July 2014 and December 2019, 279 patients with ARDS had plasma collected at day 0, 266 at day 3 (11 nonsurvivors, two discharged between days 0 and 3), and 207 at day 7 (27 nonsurvivors, 45 discharged between days 3 and 7). The actual prevalence of mortality on days 0, 3, and 7, was 23% (64/279), 14% (38/266), and 13% (27/207), respectively. The PARDSEVERE risk model for mortality on days 0, 3, and 7 had area under the receiver operating characteristic curve (AUROC [95% CI]) of 0.76 (0.69–0.82), 0.68 (0.60–0.76), and 0.74 (0.65–0.83), respectively. The AUROC data translate into prevalence thresholds for the PARDSEVERE model for mortality (i.e., using the sensitivity and specificity values) of 37%, 27%, and 24% on days 0, 3, and 7, respectively. Negative predictive value (NPV) was high throughout (0.87–0.90 for all three-time points).

CONCLUSIONS:

In this exploratory analysis of the PARDSEVERE model of mortality risk prediction in a population longitudinal series of data from days 0, 3, and 7 after ARDS diagnosis, the diagnostic performance is in the “acceptable” category. NPV was good. A major limitation is that actual mortality is far below the prevalence threshold for such testing. The model may, therefore, be more useful in cohorts with higher mortality rates (e.g., immunocompromised, other countries), and future enhancements to the model should be explored.
Reoperation following Primary Greater Occipital Nerve Decompression Surgery: Incidence, Risk Factors, and Outcomes
Authors: Remy Katya , Hazewinkel Merel H. , Mullen Connor , Hagan Robert R. , Austen William G. , Gfrerer Lisa
Published: April 2024

Background:

Although nerve decompression surgery is an effective treatment for refractory occipital neuralgia, a proportion of patients experience recurrence of pain and undergo reoperation. This study analyzes the incidence, risk factors, and outcomes of reoperation following primary greater occipital nerve (GON) decompression.

Methods:

A total of 215 patients who underwent 399 primary GON decompressions were prospectively enrolled. Data included patient demographics, medical and surgical history, reoperation rates, intraoperative findings, surgical technique, and postoperative outcomes in terms of pain frequency (days per month), duration (hours per day), intensity (scale, 0 to 10), and migraine headache index. Bivariate analyses, univariable logistic regression analysis, and multivariable logistic regression analysis, were performed.

Results:

Twenty-seven GON decompressions (6.8%) required reoperation with neurectomy at a median follow-up time of 15.5 months (range, 9.8 to 40.5 months). Cervical spine disorders on imaging that did not warrant surgical intervention (OR, 4.88; 95% CI, 1.61 to 14.79; P < 0.01) and radiofrequency ablation (OR, 4.20; 95% CI, 1.45 to 15.2; P < 0.05) were significantly associated with higher rates of reoperation. At 12 months postoperatively, patients who underwent reoperation achieved similar mean reductions in pain frequency, duration, intensity, and migraine headache index, as compared with patients who underwent only primary decompression (P > 0.05).

Conclusion:

Patients with occipital neuralgia who have a history of cervical spine disorders or radiofrequency ablation should be counseled that primary decompression has a higher risk of reoperation, but outcomes are ultimately comparable.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Characterization of the layer, direction and time-dependent mechanical behaviour of the human oesophagus and the effects of formalin preservation
Authors: Durcan Ciara , Hossain Mokarram , Chagnon Grégory , Perić Djordje , Girard Edouard
Published: April 2024

The mechanical characterization of the oesophagus is essential for applications such as medical device design, surgical simulations and tissue engineering, as well as for investigating the organ’s pathophysiology. However, the material response of the oesophagus has not been established
ex vivo
in regard to the more complex aspects of its mechanical behaviour using fresh, human tissue: as of yet, in the literature, only the hyperelastic response of the intact wall has been studied. Therefore, in this study, the layer-dependent, anisotropic, visco-hyperelastic behaviour of the human oesophagus was investigated through various mechanical tests. For this, cyclic tests, with increasing stretch levels, were conducted on the layers of the human oesophagus in the longitudinal and circumferential directions and at two different strain rates. Additionally, stress-relaxation tests on the oesophageal layers were carried out in both directions. Overall, the results show discrete properties in each layer and direction, highlighting the importance of treating the oesophagus as a multi-layered composite material with direction-dependent behaviour. Previously, the authors conducted layer-dependent cyclic experimentation on formalin-embalmed human oesophagi. A comparison between the fresh and embalmed tissue response was carried out and revealed surprising similarities in terms of anisotropy, strain-rate dependency, stress-softening and hysteresis, with the main difference between the two preservation states being the magnitude of these properties. As formalin fixation is known to notably affect the formation of cross-links between the collagen of biological materials, the differences may reveal the influence of cross-links on the mechanical behaviour of soft tissues.
Uncertainty quantification of the impact of peripheral arterial disease on abdominal aortic aneurysms in blood flow simulations
Authors: Lo Sharp C. Y. , McCullough Jon W. S. , Xue Xiao , Coveney Peter V.
Published: April 2024

Peripheral arterial disease (PAD) and abdominal aortic aneurysms (AAAs) often coexist and pose significant risks of mortality, yet their mutual interactions remain largely unexplored. Here, we introduce a fluid mechanics model designed to simulate the haemodynamic impact of PAD on AAA-associated risk factors. Our focus lies on quantifying the uncertainty inherent in controlling the flow rates within PAD-affected vessels and predicting AAA risk factors derived from wall shear stress. We perform a sensitivity analysis on nine critical model parameters through simulations of three-dimensional blood flow within a comprehensive arterial geometry. Our results show effective control of the flow rates using two-element Windkessel models, although specific outlets need attention. Quantities of interest like endothelial cell activation potential (ECAP) and relative residence time are instructive for identifying high-risk regions, with ECAP showing greater reliability and adaptability. Our analysis reveals that the uncertainty in the quantities of interest is 187% of that of the input parameters. Notably, parameters governing the amplitude and frequency of the inlet velocity exert the strongest influence on the risk factors’ variability and warrant precise determination. This study forms the foundation for patient-specific simulations involving PAD and AAAs which should ultimately improve patient outcomes and reduce associated mortality rates.
Optimization of periodic treatment strategies for bacterial biofilms using an agent-based
in silico
approach
Authors: Blee Johanna A. , Gorochowski Thomas E. , Hauert Sabine
Published: April 2024

Biofilms are responsible for most chronic infections and are highly resistant to antibiotic treatments. Previous studies have demonstrated that periodic dosing of antibiotics can help sensitize persistent subpopulations and reduce the overall dosage required for treatment. Because the dynamics and mechanisms of biofilm growth and the formation of persister cells are diverse and are affected by environmental conditions, it remains a challenge to design optimal periodic dosing regimens. Here, we develop a computational agent-based model to streamline this process and determine key parameters for effective treatment. We used our model to test a broad range of persistence switching dynamics and found that if periodic antibiotic dosing was tuned to biofilm dynamics, the dose required for effective treatment could be reduced by nearly 77%. The biofilm architecture and its response to antibiotics were found to depend on the dynamics of persister cells. Despite some differences in the response of biofilm governed by different persister switching rates, we found that a general optimized periodic treatment was still effective in significantly reducing the required antibiotic dose. As persistence becomes better quantified and understood, our model has the potential to act as a foundation for more effective strategies to target bacterial infections.
Stability of penetrative convective currents in local thermal non-equilibrium
Authors: Arnone Giuseppe , Capone Florinda , Gianfrani Jacopo Alfonso
Published: April 2024

The aim of this paper is to investigate the onset of penetrative convection in a Darcy–Brinkman porous medium under the hypothesis of local thermal non-equilibrium. For the problem at stake, the strong form of the principle of exchange of stabilities has been proved, i.e. convective motions can occur only through secondary stationary motions. We perform linear and nonlinear stability analyses of the basic state, with particular regard to the behaviour of stability thresholds with respect to the relevant physical parameters characterizing the problem. The Chebyshev-τmethod and the shooting method are employed and accurately implemented to solve the differential eigenvalue problems arising from linear and nonlinear analyses to determine critical Rayleigh numbers. Via numerical simulations, the stabilizing effect of the upper bounding plane temperature, of the Darcy number and of the interaction coefficient for the heat exchange, is demonstrated.
Blessing or curse: how the epigenetic resolution of host-transposable element conflicts shapes their evolutionary dynamics
Authors: Huang Yuheng , Lee Yuh Chwen G.
Published: April 2024

Transposable elements (TEs) are selfish genetic elements whose antagonistic interactions with hosts represent a common genetic conflict in eukaryotes. To resolve this conflict, hosts have widely adopted epigenetic silencing that deposits repressive marks at TEs. However, this mechanism is imperfect and fails to fully halt TE replication. Furthermore, TE epigenetic silencing can inadvertently spread repressive marks to adjacent functional sequences, a phenomenon considered a ‘curse’ of this conflict resolution. Here, we used forward simulations to explore how TE epigenetic silencing and its harmful side effects shape the evolutionary dynamics of TEs and their hosts. Our findings reveal that epigenetic silencing allows TEs and their hosts to stably coexist under a wide range of conditions, because the underlying molecular mechanisms give rise to copy-number dependency of the strength of TE silencing. Interestingly, contrary to intuitive expectations that TE epigenetic silencing should evolve to be as strong as possible, we found a selective benefit for modifier alleles that weaken TE silencing under biologically feasible conditions. These results reveal that the dual nature of TE epigenetic silencing, with both positive and negative effects, complicates its evolutionary trajectory and makes it challenging to determine whether TE epigenetic silencing is a ‘blessing’ or a ‘curse’.
Pooled screening for CAR function identifies novel IL13Rα2-targeted CARs for treatment of glioblastoma
Authors: Gordon Khloe S. , Perez Caleb R. , Garmilla Andrea , Lam Maxine S.Y. , Aw Joey Jy , Datta Anisha , Lauffenburger Douglas A. , Pavesi Andrea , Birnbaum Michael E.
Published: April 2024

Chimeric antigen receptor therapies have demonstrated potent efficacy in treating B cell malignancies, but have yet to meaningfully translate to solid tumors. Here, we utilize our pooled screening platform, CARPOOL, to expedite the discovery of CARs with anti-tumor functions necessary for solid tumor efficacy. We performed selections in primary human T cells expressing a library of 1.3×1063rdgeneration CARs targeting IL13Rα2, a cancer testis antigen commonly expressed in glioblastoma. Selections were performed for cytotoxicity, proliferation, memory formation, and persistence upon repeated antigen challenge. Each enriched CAR robustly produced the phenotype for which it was selected, and one enriched CAR triggered potent cytotoxicity and long-term proliferation uponin vitrotumor rechallenge. It also showed significantly improved persistence and comparable antigen-specific tumor control in a microphysiological humanin vitromodel and a xenograft model of human glioblastoma. Taken together, this work demonstrates the utility of extending CARPOOL to diseases beyond hematological malignancies and represents the largest exploration of signaling combinations in human primary cells to date.
A leg model based on anatomical landmarks to study 3D joint kinematics of walking inDrosophila melanogaster
Authors: Haustein Moritz , Blanke Alexander , Bockemühl Till , Büschges Ansgar
Published: April 2024

Walking is the most common form of how animals move on land. The model organismDrosophila melanogasterhas become increasingly popular for studying how the nervous system controls behavior in general and walking in particular. Despite recent advances in tracking and modeling leg movements of walkingDrosophilain 3D, there are still gaps in knowledge about the biomechanics of leg joints due to the tiny size of fruit flies. For instance, the natural alignment of joint rotational axes was largely neglected in previous kinematic analyses. In this study we therefore present a detailed kinematic leg model in which not only the segment lengths but also the main rotational axes of the joints were derived from anatomical landmarks, namely the joint condyles. Our model with natural oblique joint axes is able to adapt to the 3D leg postures of straight and forward walking fruit flies with high accuracy. When we compared our model to an orthogonalized version, we observed that our model showed a smaller error as well as differences in the used range of motion (ROM), highlighting the advantages of modeling natural rotational axes alignment for the study of joint kinematics. We further found that the kinematic profiles of front, middle, and hind legs differed in the number of required degrees of freedom as well as their contributions to stepping, time courses of joint angles, and ROM. Our findings provide deeper insights into the joint kinematics of walking inDrosophila, and, additionally, help to develop dynamical, musculoskeletal, and neuromechanical simulations.
Phthalates are detected in the follicular fluid of adolescents and oocyte donors with associated changes in the cumulus cell transcriptome
Authors: Gokyer Dilan , Laws Mary J. , Kleinhans Anna , Riley Joan K. , Flaws Jodi A. , Babayev Elnur
Published: April 2024

Purpose

To investigate follicular fluid (FF) phthalate levels in adolescents undergoing fertility preservation compared to oocyte donors and explore its association with ovarian reserve and cumulus cell gene expression.

Methods

20 Adolescents (16.7 ± 0.6 years old) and 24 oocyte donors (26.2 ± 0.4 years old) undergoing fertility preservation were included in the study. Patient demographics, ovarian stimulation and oocyte retrieval outcomes were analyzed for each group. FF levels of 9 phthalate metabolites were assessed individually and as molar sums representative of common compounds (all phthalates: ƩPhthalates; DEHP: ƩDEHP), exposure sources (plastics: ƩPlastic; personal care products: ƩPCP), and modes of action (anti-androgenic: ƩAA) and compared between the two groups.

Results

Follicular fluid ƩPlastic and ƩPCP levels were significantly higher in adolescents compared to oocyte donors (p<0.05). Follicular fluid ƩDEHP, ƩPlastic, ƩPCP, ƩAA, and ƩPhthalates levels were positively associated with antral follicle count (AFC) (p<0.05) in oocyte donors when adjusted for age, BMI, and race/ethnicity. RNA-seq analysis revealed 248 differentially expressed genes (DEGs) in cumulus cells of adolescents within the top quartile (n=4) of FF ƩPhthalates levels compared to the adolescents within the bottom half (n=9). Genes enriched in pathways involved in cell motility and development were significantly downregulated.

Conclusion

Adolescents undergoing fertility preservation cycles demonstrate higher levels of phthalate metabolites in their follicular fluid compared to oocyte donors. Phthalate metabolite levels in FF are associated with higher AFC levels in oocyte donors. Higher phthalate levels in FF are associated with alterations in the cumulus cells transcriptome in adolescents.

Capsule Summary

Phthalates are detected in the follicular fluid of adolescents and oocytes donors, and the levels are increased in the follicular fluid of adolescents. Higher total phthalate levels in follicular fluid are associated with altered cumulus cells transcriptome in adolescents.
Comparative specialization of intrinsic cardiac neurons in humans, mice, and pigs
Authors: Tompkins John D. , Hoover Donald B. , Havton Leif A. , Patel Janaki C. , Cho Youngjin , Smith Elizabeth H. , Biscola Natalia P. , Ajijola Olujimi A. , Shivkumar Kalyanam , Ardell Jeffrey L.
Published: April 2024

Intrinsic cardiac neurons (ICNs) play a crucial role in the proper functioning of the heart; yet a paucity of data pertaining to human ICNs exists. We took a multidisciplinary approach to complete a detailed cellular comparison of the structure and function of ICNs from mice, pigs, and humans. Immunohistochemistry of whole and sectioned ganglia, transmission electron microscopy, intracellular microelectrode recording and dye filling for quantitative morphometry were used to define the neurophysiology, histochemistry, and ultrastructure of these cells across species. The densely packed, smaller ICNs of mouse lacked dendrites, formed axosomatic connections, and had high synaptic efficacy constituting an obligatory synapse. At Pig ICNs, a convergence of subthreshold cholinergic inputs onto extensive dendritic arbors supported greater summation and integration of synaptic input. Human ICNs were tonically firing, with synaptic stimulation evoking large suprathreshold excitatory postsynaptic potentials like mouse, and subthreshold potentials like pig. Ultrastructural examination of synaptic terminals revealed conserved architecture, yet small clear vesicles (SCVs) were larger in pigs and humans. The presence and localization of ganglionic neuropeptides was distinct, with abundant VIP observed in human but not pig or mouse ganglia, and little SP or CGRP in pig ganglia. Action potential waveforms were similar, but human ICNs had larger after-hyperpolarizations. Intrinsic excitability differed; 93% of human cells were tonic, all pig neurons were phasic, and both phasic and tonic phenotypes were observed in mouse. In combination, this publicly accessible, multimodal atlas of ICNs from mice, pigs, and humans identifies similarities and differences in the evolution of ICNs.
The Cell Death Census 2024
Authors: Miari Mariam , Regnell Elsa , Aits Sonja
Published: April 2024

Cell death plays a pivotal role in many physiological processes, such as cell homeostasis, embryonic development, immune defence and in the pathophysiology of numerous diseases, such as cancer, infections and degenerative diseases. However, the lack of a comprehensive and up-to-date resource on cell death regulators poses a signiﬁcant challenge to researchers in the ﬁeld. Existing databases are often limited in scope, differ in content and are updated irregularly. This deﬁciency impedes progress in understanding the intricate molecular mechanisms governing cell death and hampers the development of targeted therapies. To address this, we have performed a census of the existing cell death databases as well as the cell death-associated entries in the UniProt and Gene Ontology databases. To ensure high quality, we have focused on manually curated entries rather than those created from automatic prediction tools. The results have been consolidated into a joint database of the known cell death regulators, including both proteins and non-coding RNAs. The Cell Death Census 2024 results and the associated python code for database parsing, cleaning and merging is publicly available athttps://github.com/Aitslab/CellDeathCensus/.
Quality of care for chronic conditions: Identifying specificities of quality aims based on scoping review and Delphi survey
Authors: Ku Grace Marie V. , van de Put Willem , Katsuva Deogratias , Ag Ahmed Mohamad Ali , Rosenberg Megumi , Meessen Bruno
Published: April 2024

Background

There is a need to implement good quality chronic care to address the ballooning burden of chronic conditions affecting all countries globally. However, to our knowledge, no systematic attempts have yet been made to define and specify aims for chronic care quality.

Objective

We conducted a scoping review and Delphi survey to establish and validate a comprehensive specification of chronic care quality aims.

Methodology

The Institute of Medicine’s (IOM) quality of care definition and aims was utilised as our base. We purposively selected scientific and grey literature that have acknowledged and unpacked the plurality of quality in chronic care and which proposed/made use of frameworks and studied their implementation or investigated minimum two IOM care quality aims and their implementation. We critically analysed the literature deductively and inductively. We validated our findings through Delphi survey involving international chronic care experts, mostly coming from/have expertise on low-and-middle-income countries.

Results

We considered the natural history of chronic conditions and the journey of a person with chronic condition to define and identify aims of chronic care quality. We noted that the six IOM aims apply but with additional meanings. We identified a seventh aim, continuity, which relates well to the issue of chronicity. Our panellists agreed with the specifications. Several provided contextualised interpretations and concrete examples.

Conclusions

Chronic conditions pose specific challenges underscoring the relevance of tailoring quality of care aims. Operationalization of this tailored definition and specified aims to improve, measure and assure quality of chronic care can be next steps.
Immune system homeostasis in people with multiple long-term conditions determines susceptibility to organ injury and mortality following cardiac surgery
Authors: Lai Florence Y , Adebayo Adewale S , Sheikh Sophia , Roman Marius , Joel-David Lathishia , Aujla Hardeep , Chad Tom , Tomkova Kristina , Ladak Shameem , Condorelli Gianluigi , Zakkar Mustafa , Solomon Charles , Woźniak Marcin J , Murphy Gavin J
Published: April 2024

Background

People with Multiple Long-Term Conditions (MLTC) experience higher rates of organ failure and death following cardiac surgery. The aim of this study was to identify disease processes in MLTC associated with increased susceptibility to organ injury post-surgery.

Methods

Unsupervised machine learning methods were applied to pre-surgery biomarkers of haematological, cardiac, liver, and renal disease from four intensively phenotyped cardiac surgery cohorts. The resulting MLTC clusters were then matched to a fifth cohort where single nuclei RNA sequencing (snRNAseq) was performed on atrial biopsies collected at surgery.

Results

K-means clustering identified two MLTC clusters. Cluster 1 had lower rates of chronic kidney disease and anaemia and increased immune system activation pre-surgery. Cluster 2 had more severe cardiorenal disease, anaemia, and elevated biomarkers of immunological ageing pre-surgery. Cluster 2 had significantly higher rates of organ injury relative to Cluster 1. The results were consistent across internal and external validation analyses.

Analysis of snRNAseq data in biopsies from Cluster 1 demonstrated enrichment for immune response genes in cardiomyocytes, naive T/B lymphocytes and progenitor cells, and activation of non-tissue resident macrophages relative to Cluster 2. Cluster 2 showed enrichment for senescent/ effector memory T cells, dysregulated activation of tissue-resident macrophages, and cardiomyocyte dedifferentiation relative to Cluster 1.

In UK Biobank, genetic modification of genes differentially expressed between the two MLTC phenotypes altered 90-day mortality post-surgery.

Conclusions

Immune system homeostasis determines susceptibility to organ injury and death in people with MLTC undergoing cardiac surgery and represents a previously unrecognised target for organ protection interventions.
Tandem RAman Microscopy (TRAM): integration of spontaneous and coherent Raman scattering offering data fusion analysis to improve optical biosensing
Authors: Brzozowski K. , Pieczara A. , Nowakowska A. , Korona W. , Orzechowska B. , Firlej J. , Wislocka-Orlowska A. , Baranska M.
Published: April 2024

We provide Tandem RAman Microscopy (TRAM), a cutting-edge multimodal microscope that integrates the methods of Stimulated Raman Scattering (SRS), Coherent anti-Stokes Raman Scattering (CARS), and spontaneous (Resonance) Raman Scattering ((R)RS). The device facilitates sequential Continuous Wave (CW) driven RS imaging to collect full spectra from every sample location and rapid pulsed-wave-driven SRS-CARS scanning at specific wavenumbers, offering a reliable and efficient analytical tool. The fingerprint spectral region can be included in the spectral imaging capabilities of CARS and SRS. Data collected from a sample area using several techniques can be integrated and analyzed, significantly increasing reliability and predictions. We analyzed thein vitromodel of nonadherent leukocytes (LC) to illustrate the capabilities of this unique system, emphasizing the benefits of measuring the same sample with three different Raman techniques without having to transfer it between microscopes. Data fusion allowed for the correct classification of two subtypes of LC based on the partial least squares (PLS) discrimination, increasing the prediction accuracy from approximately 83% in the case of textural and morphological data (SRS) to 100% when combined with spectral data (SRS and RS). We also present RRS images of LC labeled with astaxanthin, and reference data from SRS and CARS microscopy. Additionally, polystyrene beads were investigated as a non-biological material. The advantages of each Raman technique are utilized when (R)RS, SRS, and CARS are combined into a single device. This paves the way for dependable chemical characterization in a wide range of scientific and industrial fields.
Turn ‘noise’ to signal: accurately rectify millions of erroneous short reads through graph learning on edit distances
Authors: Ping Pengyao , Su Shuquan , Cai Xinhui , Lan Tian , Zhang Xuan , Peng Hui , Pan Yi , Liu Wei , Li Jinyan
Published: April 2024

Although the per-base erring rate of NGS is very low at 0.1% to 0.5%, the percentage/probability oferroneous readsin a short-read sequencing dataset can be as high as 10% to 15% or in the number of millions. Correction of these wrongly sequenced reads to retrieve their huge missing value will improve many downstream applications. As current methods correct only some of the errors at the cost of introducing many new errors, we solve this problem by turning erroneous reads into their original states, without bringing up any non-existing reads to keep the data integrity. The novelty of our method is originated in a computable rule translated from PCR erring mechanism that: a rare read is erroneous if it has a neighbouring read of high abundance. With this principle, we construct a graph to link every pair of reads of tiny edit distances to detect a solid part of erroneous reads; then we consider them as training data to learn the erring mechanisms to identify possibly remaining hard-case errors between pairs of high-abundance reads. Compared with state-of-the-art methods on tens of datasets of UMI-based ground truth, our method has made a remarkably better performance under 19 metrics including two entropy metrics that measure noise levels in a dataset. Case studies found that our method can make substantial impact on genome abundance quantification, isoform identification, SNP profiling, and genome editing efficiency estimation. For example, the abundance level of the reference genome of SARS-CoV-2 can be increased by 12% and that of Monkeypox can be boosted by 52.12% after error correction. Moreover, the number of distinct isomiRs is decreased by 31.56%, unveiling there are so many previously identified isomiRs that are actually sequencing errors.

Author summary

Detecting short-read sequencing errors and correcting the related erroneous reads is a long-standing problem in bioinformatics. Current error correction algorithms correct only small parts of the errors but simultaneously introduce thousands of non-existing sequences. We present a new method to rectify erroneous reads under 300 bp produced by PCR-involved miRNA-sequencing, small RNA sequencing, or paired-end RNA sequencing, regardless of platform or sample type. Our method is the first kind considering the PCR erring mechanism and machine learning technique to improve sequencing data quality by turning millions of erroneous short reads into their original state without bringing up any non-existing sequences into the read set. Our error correction method can make a significant impact on a wide range of cutting-edge downstream applications. The observations and advantages in the case studies lay down strong evidence to question the accuracies of current downstream research outcomes and open new avenues to conduct downstream analysis whenever short-read data are adopted.
Physiological bias governs neutrophil inflammatory threat perception
Authors: Pajonczyk Denise , Pauli Lina , Pünt Charlotte , Sternschulte Merle F. , Fehler Olesja , Vogl Thomas , Soehnlein Oliver , Bermudez Marcel , Raabe Carsten Alexander , Rescher Ursula
Published: April 2024

Background and Purpose

The functional G protein-coupled receptor (GPCR) signalling unit consists of an agonist acting on a receptor that is coupled to a G protein that transduces the signals to effectors within a complex cellular environment. While much attention is given to GPCR-agonist or GPCR-transducer relationships, the contribution of the cellular environment remains significantly unexplored.

Experimental Approach

Here, we juxtaposed the signalling responses triggered by the activation of two GPCR pattern recognition receptors, Formyl peptide receptor 1 and Formyl peptide receptor 2, in a recombinant cell system against their signalling dynamics in the native neutrophilic environment.

Key results

We observed that agonist activation leads to cell context-dependent substantial differences in the receptor signalling texture. While the impact of receptor activation onde novocAMP formation varied depending on the cell type, MAPK activation was similar in both systems. This physiological bias was conserved across species. Expression analysis unveiled the absence of the Gαi-sensitive adenylyl cyclases ADCY5 and ADCY6 in neutrophils, implying that cAMPde novosynthesis cannot be inhibited by Gαi-coupled receptors. The signalling behaviour of the Gαi-coupled LTB4 high-affinity receptor BLT1 in neutrophils corroborated our findings.

Conclusion and Implications

Our data underscore the profound impact of the specific cellular environment on GPCR signalling, causing physiological bias in GPCR signalling, thereby affecting drug efficacy and therapeutic targeting.
Harnessing molecular mechanism for precision medicine in dilated cardiomyopathy caused by a mutation in troponin T
Authors: Greenberg Lina , Stump W. Tom , Lin Zongtao , Bredemeyer Andrea L. , Blackwell Thomas , Han Xian , Greenberg Akiva E. , Garcia Benjamin A. , Lavine Kory J. , Greenberg Michael J.
Published: April 2024

Familial dilated cardiomyopathy (DCM) is frequently caused by autosomal dominant point mutations in genes involved in diverse cellular processes, including sarcomeric contraction. While patient studies have defined the genetic landscape of DCM, genetics are not currently used in patient care, and patients receive similar treatments regardless of the underlying mutation. It has been suggested that a precision medicine approach based on the molecular mechanism of the underlying mutation could improve outcomes; however, realizing this approach has been challenging due to difficulties linking genotype and phenotype and then leveraging this information to identify therapeutic approaches. Here, we used multiscale experimental and computational approaches to test whether knowledge of molecular mechanism could be harnessed to connect genotype, phenotype, and drug response for a DCM mutation in troponin T, deletion of K210. Previously, we showed that at the molecular scale, the mutation reduces thin filament activation. Here, we used computational modeling of this molecular defect to predict that the mutant will reduce cellular and tissue contractility, and we validated this prediction in human cardiomyocytes and engineered heart tissues. We then used our knowledge of molecular mechanism to computationally model the effects of a small molecule that can activate the thin filament. We demonstrate experimentally that the modeling correctly predicts that the small molecule can partially rescue systolic dysfunction at the expense of diastolic function. Taken together, our results demonstrate how molecular mechanism can be harnessed to connect genotype and phenotype and inspire strategies to optimize mechanism-based therapeutics for DCM.

Significance statement

Dilated cardiomyopathy (DCM), a leading cause of heart failure, is characterized by the inability of the heart to perfuse the body at normal filling pressures. There are multiple causes of DCM, including point mutations in sarcomeric proteins, but most patients receive similar courses of treatment, regardless of the underlying cause of the DCM. Many patients remain unserved by current therapies, and there is a need for new approaches. Here, we use multiscale experimental and computational approaches to demonstrate how knowledge of molecular mechanism can be harnessed to accurately predict the effects of a patient-specific mutation and responses to presumptive therapeutics. Our approach lays the foundation for a precision medicine approach to DCM.
Oriented Cell Dataset: efficient imagery analyses using angular representation
Authors: Kirsten LN , Angonezi AL , Oliveira FD , Faccioni JL , Cassel CB , de Sousa DC Santos , Vedovatto S , Jung CR , Lenz G
Published: April 2024

In this work, we propose a new public dataset for cell detection in bright-field microscopy images annotated with Oriented Bounding Boxes (OBBs), named Oriented Cell Dataset (OCD). We show that OBBs provide a more accurate shape representation compared to standard Horizontal Bounding Boxes (HBBs), with slight overhead of one extra click in the annotation process. Our dataset also contains a subset of images with five independent expert annotations, which allows inter-annotation analysis to determine if the results produced by algorithms are within the expected variability of human experts. We investigated how to automate cell biology microscopy images by training seven popular OBB detectors in the proposed dataset, and focused our analyses on two main problems in cancer biology: cell confluence and polarity determination, the latter not possible through HBB representation. All models achieved statistically similar results to the biological applications compared to human annotation, enabling the automation of cell biology and cancer cell biology microscopy image analysis. Our code and dataset are available athttps://github.com/LucasKirsten/Deep-Cell-Tracking-EBB.
Childhood Ocular Inflammation Sensations and Symptoms Reporting Questionnaire (ChOIR-Q): Development and assessment of a paediatric self-report tool
Authors: Solebo Ameenat L , Kellett Salomey , Rahi Jugnoo , Dick Andrew D , Ashworth Jane , Cooper Gisella , McLoone Eibhlin , Muthusamy Kirithika , Pilling Rachel , Petrushkin Harry , Tadic Valerija
Published: April 2024

We aimed to develop and assess age-appropriate child and young person, self and proxy report tools to capture and characterise eye symptoms in childhood ocular inflammatory disease.

Children and young people aged under 18 years diagnosed with inflammatory eye disease (uveitis), and their families, were recruited to a multiphase study, involving: text and pictogram items generation through focus groups and interviews (Phase 1), pre-testing face validity analysis including and discussion amongst a multidisciplinary professional panel (Phase 2), and pre-piloting (Phase 3) and piloting (Phase 4) of the instrument amongst a representative sample of the target population.

A total of 170 participants, comprising 113 children/young people and 57 parents/carers, were recruited. Phase 1 resulted in the generation of 60 items. Following phases 2 to 3, these items were developed into self-completion, and assisted self-completion tools for children aged 9 years and older, and those aged under 9 years respectively, and a proxy score, for completion by parents and carers. Correlations scores between individual item and whole domain scoring were above 0.58 for the self-completion tools and above 0.39 for the proxy completion tool. Initial Cronbach’s alpha for the tool overall was good at 0.84, with within-domain alphas of 0.81 – 0.87.

In conclusion, these instruments demonstrate the feasibility of capturing ocular sensations in children and young people, with a patient centred development approach resulting in tools with high rates of completion, and acceptable internal instrument consistency.
Influence of Anemia on Prevalence of Gestational Diabetes among Pregnant Women in Tripoli, Libya
Authors: Atia Ahmed , Elmahmoudi Hosam
Published: April 2024

Gestational diabetes mellitus (GDM) is raised globally leading to substantial maternal and foetal morbidity. This study aimed to determine the prevalence of GDM among pregnant women delivering in different private polyclinics in Tripoli, Libya. A cross-sectional study was conducted among pregnant women who were admitted to gynecology department of in different medical polyclinics, Tripoli, Libya from Jan to Dec 2022. The prevalence of GDM in pregnant women increased with increase of the gestational age to reach maximum (86%) at the third trimester of gestation. About 31% (96 patients) anemic pregnant women were observed in 312 GDM. Careful surveillance is required for these pregnancies in high-risk units for early detection and treatment of possible complications, in order to try to reduce maternal and neonatal morbidities.
Phosphate starvation stops bacteria digesting algal fucan that sequesters carbon
Authors: Xu Yi , Schultz-Johansen Mikkel , Yao Huiying , Wilkie Isabella , Klau Leesa Jane , Chen Yuerong , Orellana Luis H. , Aachmann Finn Lillelund , Farhan Mahum , Gu Bowei , Reintjes Greta , Vidal-Melgosa Silvia , Qiao Dairong , Cao Yi , Hehemann Jan-Hendrik
Published: April 2024

Algae provide a solar powered pathway to capture and sequester carbon by injecting stable fucan made from carbon dioxide into the ocean1–4. Stability of the pathway is at odds with the presence of marine bacteria with genes of enzymes that can digest fucan and release the carbon dioxide5. Biochemical explanations for stable fucan remain hypothetical6. We assembled a biological carbon cycle model and found phosphate limitation enhanced fucan synthesis by algae, stopped digestion by bacteria and thereby stabilized the fucan carbon sequestration pathway. Marine microalgaeGlossomastixsp. PLY432 increased synthesis of fucan, a part of its extracellular matrix, under nutrient-growth limiting conditions. Rate and extent of fucan digestion by a marine, isolated bacterium of theAkkermansiaceaefamily decreased with decreasing phosphate concentration. Phosphate starvation restricted bacterial growth rate, biomass yield and in turn increased the amount of stable fucan. Phosphate is universally required for growth but rare relative to glycan carbon in photosynthesis-derived ecosystems. The fact that phosphate is required for replication, transcription and translation explains why bacteria can digest gigatons of laminarin with a few enzymes, but not fucan during nutrient limited algal blooms. We conclude phosphate starvation constrains the ability of bacteria to digest fucan, which evolves to maintain stability around algal cells and consequentially also to keep carbon dioxide in the ocean.