bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammatory biomarkers and nanotechnology: new insights in pancreatic cancer early detection
Authors: Caputo Damiano , Quagliarini Erica , Coppola Alessandro , La Vaccara Vincenzo , Marmiroli Benedetta , Sartori Barbara , Caracciolo Giulio , Pozzi Daniela
Published: June 2023

Background:

Poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is mainly due to the lack of effective early-stage detection strategies. Even though the link between inflammation and PDAC has been demonstrated and inflammatory biomarkers proved their efficacy in predicting several tumors, to date they have a role only in assessing PDAC prognosis. Recently, the studies of interactions between nanosystems and easily collectable biological fluids, alone or coupled with standard laboratory tests, have proven useful in facilitating PDAC diagnosis. Notably, tests based on magnetic levitation (MagLev) of biocoronated nanosystems have demonstrated high diagnostic accuracy in compliance with the criteria stated by World Health Organization. Herein, we developed a synergistic analysis that combines a user-friendly Maglev-based approach and common inflammatory biomarkers for discriminating PDAC subjects from healthy ones.

Materials and Methods:

Plasma samples from 24 PDAC subjects and 22 non-oncological patients (NOPs) have been collected and let to interact with Graphene Oxide (GO) nanosheets.

Biomolecular corona formed around GO nanosheets have been immersed in a Magnetic Levitation- (Maglev) platform to study the levitation profiles.

Inflammatory biomarkers such as NLR, dNLR and PLR have been calculated and combined with results obtained by the Maglev platform.

Results:

Maglev profiles resulted significantly different between NOPs and PDAC and allowed to identify a Maglev fingerprint for PDAC. Four inflammatory markers were significantly higher in PDAC subjects: neutrophils (P=0.04), NLR (P=4.7 ×10-6), dNLR (P=2.7 ×10-5) and PLR (P=0.002). Lymphocytes were appreciably lower in PDACs (P=2.6 ×10-6).

Combining the MagLev fingerprint with dNLR and NLR returned global discrimination accuracy for PDAC of 95.7% and 91.3% respectively.

Conclusions:

The multiplexed approach discriminated PDAC patients from healthy volunteers in up to 95% of cases. If further confirmed in larger-cohort studies, this approach may be used for PDAC detection.
Proportion of early extubation and short-term outcomes after esophagectomy: a retrospective cohort study
Authors: Hirano Yuki , Konishi Takaaki , Kaneko Hidehiro , Itoh Hidetaka , Matsuda Satoru , Kawakubo Hirofumi , Uda Kazuaki , Matsui Hiroki , Fushimi Kiyohide , Daiko Hiroyuki , Itano Osamu , Yasunaga Hideo , Kitagawa Yuko
Published: June 2023

Background:

The proportion of early extubation after esophagectomy varies among hospitals; however, the impact on clinical outcomes is unclear. The aim of this retrospective study was to evaluate associations between the proportion of early extubation in hospitals and short-term outcomes after esophagectomy. Because there is no consensus regarding the optimal timing for extubation, we considered that hospitals’ early extubation proportion reflects the hospital-level extubation strategy.

Materials and methods:

Data of patients who underwent oncologic esophagectomy (July 2010–March 2019) were extracted from a Japanese nationwide inpatient database. The proportion of patients who underwent early extubation (extubation on the day of surgery) at each hospital was assessed and grouped by quartiles: very low- (<11%), low- (11–37%), medium- (38–83%), and high-proportion (≥84%) hospitals. The primary outcome was respiratory complications; secondary outcomes included reintubation, anastomotic leakage, other major complications, and hospitalization costs. Multivariable regression analyses were performed, adjusting for patient demographics, cancer treatments, and hospital characteristics. Restricted cubic spline analysis was also performed for the primary outcome.

Results:

Among 37,983 eligible patients across 545 hospitals, early extubation was performed in 17,931 (47%) patients. Early extubation proportions ranged from 0–100% across hospitals. Respiratory complications occurred in 10,270 patients (27%). Multivariable regression analyses showed that high- and medium-proportion hospitals were significantly associated with decreased respiratory complications (odds ratio, 0.46 [95% confidence interval, 0.36–0.58] and 0.43 [0.31–0.60], respectively), reintubation, and hospitalization costs when compared with very low-proportion hospitals. The risk of anastomotic leakage and other major complications did not differ among groups. The restricted cubic spline analysis demonstrated a significant inverse dose-dependent association between the early extubation proportion and risk of respiratory complications.

Conclusion:

A higher proportion of early extubation in a hospital was associated with a lower occurrence of respiratory complications, highlighting a potential benefit of early extubation after esophagectomy.
Novel techniques for assessment of bone tissue material properties
Authors: Rao Ajay D.
Published: June 2023

Purpose of review

The purpose of this review will be to shed light on novel techniques for assessment of bone tissue material properties.

Recent findings

Recently there has been an increase in modalities to investigate bone tissue material properties. Historically, clinicians treating patients with bone disorders have relied upon the use of bone mineral density (BMD) as assessed by dual-energy X-ray absorptiometry (DXA). Although DXA provides an ability to screen at a large-scale population level, it only explains about 60% of the fracture risk. Recent advances include the use of imaging modalities, responses to load, and novel infrared (IR) techniques.

These newer techniques have not reached a point for population level screening; however, they may inform the science of bone biology further and help discern various bone disease states.
Reducing Medication Math Anxiety of Prelicensure Nursing Students Using Social Media Tutorials
Authors: Gaffney Mary Kathryn
Published: June 2023

Background:

First-semester prelicensure nursing students commonly report experiencing math anxiety that negatively affects academic performance and triggers fear of causing patient harm. Students often turn to social media platforms to supplement their learning experience.

Purpose:

To explore the feasibility of using Instagram tutorials to reduce math anxiety of first-semester prelicensure nursing students.

Methods:

A quasi-experimental descriptive survey design was used to evaluate the utility of posting supplemental math tutorials on Instagram and examined the effect of tutorials on math anxiety levels. A convenience sample of 20 students used the tutorials. Math anxiety levels were evaluated using the Single-Item Math Anxiety Scale.

Results:

A statistically significant inverse relationship was observed between math anxiety levels and tutorial use. The Instagram platform was familiar to students and simple to access. Brief tutorials appealed to audio-visual learners.

Conclusions:

Using Instagram-based tutorials is feasible and appears effective in reducing medication math anxiety.
99mTc-MDP Bone Scan Findings of Recurrent Langerhans Cell Histiocytosis in an Adult Involving Femur After Joint Replacement
Authors: Xu Tingting , Cen Bing , Li Hongmei , Wang Yudi , Chen Yue
Published: June 2023

Langerhans cell histiocytosis (LCH) is a rare proliferative histiocytic disorder. It mainly occurs in children and is rare in adults. We reported99mTc-MDP bone scan findings of recurrent LCH in an adult, which involved the right femur after right-side total hip arthroplasty. This case emphasizes that the possibility of LCH should be considered in osteolytic lesions in adults, especially after joint replacement. In addition, LCH should be included in the differential diagnosis of prosthetic joint pain and abnormal 3-phase bone scan after prosthesis arthroplasty.
Harnessing the power of endogenous pain control mechanisms for novel therapeutics: how might innovations in neuroimaging help?
Authors: Howard Matthew A. , Lawn Timothy , Kowalczyk Olivia S.
Published: June 2023

Purpose of review

This review explores the potential of using novel imaging approaches to deepen our understanding of descending modulatory mechanisms in pain, focussing on functional magnetic resonance imaging (fMRI) of the spinal cord and novel approaches to combining molecular and fMRI data. This review sheds light on the neural processes involved in pain modulation, paving the way for the development of targeted treatments.

Recent findings

The reviewed literature demonstrates significant advancements in pain research. Recent studies show the potential of using fMRI to investigate the spinal cord’s role in pain modulation. Furthermore, novel analytical approaches integrating molecular and fMRI data show promise in elucidating the complex neurobiological processes underlying pain regulation. The main themes explored here include the identification of neurochemical markers associated with pain modulation and the characterisation of neural circuits involved in descending pain control.

A comprehensive understanding of descending modulatory mechanisms in pain can inform the development of novel treatments, targeting dysfunction of these key pathways. By leveraging spinal fMRI and integrating molecular data into brain fMRI, researchers can identify potential therapeutic targets throughout the neuraxis. These advances may contribute to the development of personalised medicine approaches, allowing for tailored interventions based on individual pain profiles.
Temperament and character dimensions explain self-reported resilience deficits in patients with affective disorders
Authors: Tsigkaropoulou Evdoxia , Michopoulos Ioannis , Porichi Evgenia , Dafnas Konstantinos , Serretti Alessandro , Ferentinos Panagiotis
Published: June 2023

This is the first study exploring how temperament and character personality dimensions impact self-reported resilience in major depressive disorder (MDD) and bipolar disorder (BD). We included 130 euthymic patients with affective disorders (AFD; 66 MDD and 64 BD) and 134 healthy controls (HC). Connor and Davidson resilience scale and Temperament and Character Inventory (TCI-140) were administered. Multiple linear regressions and interaction analyses were performed. Mediation analyses examined if personality dimensions explained group differences in resilience. Resilience was lower in MDD and BD vs. HC and in MDD vs. BD, adjusting for sex, age and education. Higher resilience was predicted by lower harm avoidance (HA) and higher persistence (P) in AFD and MDD, lower HA in BD and higher P and self-directedness (SD) in HC. However, only HA and P had a group-specific effect on resilience in AFD vs. HC. In mediation analyses, specific TCI dimensions at least partially explained differences in resilience: HA, P and SD in AFD or MDD vs. HC; SD in BD vs. HC; P in BD vs. MDD. Concludingly, two temperament traits (HA, P) and a character trait (SD) predict resilience in AFD. Focusing on personality could identify sources of compromised resilience as potential treatment targets.
Reproductive and Child Health Indicators at Primary Health Centers: A Trend of last four years and their comparison with National And State averages
Authors: Desai Dev , Shukla Aparajita
Published: June 2023

Background

Large amount of data is gathered by Community health centers but remain unanalyzed resulting in poor resource allocation and subsequent poor health outcomes.

objectives

to study RCH indicators and compare them with NFHS and SFHS

Methods

A record based study for 2017–2021 was carried out among all urban and rural primary health centers of Ahmedabad. RCH indicators were compiled and compared with NFHS and SFHS to draw conclusions about the performance of these centers.

Results

in all selected centers, in last 4 years, almost all women who registered pregnancy have come for ANC visits; home deliveries, Health Centre based Cesarean-section, Vasectomy and malnutrition along with Severe Acute Malnutrition has decreased. Female sterilization has remained same. Immunizations has remained satisfactorily. Newborn Mortality Rate, Neonatal Mortality Rate, Infant Mortality Rates, Under-5 Mortality Rate and Maternal Mortality rates all have decreased. This results are similar in both Rural and Urban areas and are along the lines of recent NFHS and SFHS. It was particularly found that Data Management at various levels is faulty and there are mistakes in Data Collection, Data Gathering, Data Analysis and Data preserving. There is a visible difference between how Rural data is managed versus how Urban data is managed.

Conclusions

Valuable information is generated which can be utilized by local governing bodies. Better methodology and techniques are now a necessity for quality Data Recording, Management and Safe-keeping. Use of technology can reduce these limitations in the field and improve decision making.
Rapid nanopore metagenomic sequencing and predictive susceptibility testing of positive blood cultures from intensive care patients with sepsis
Authors: Harris Patrick N. A. , Bauer Michelle J. , Lüftinger Lukas , Beisken Stephan , Forde Brian M. , Balch Ross , Cotta Menino , Schlapbach Luregn , Raman Sainath , Shekar Kiran , Kruger Peter , Lipman Jeff , Bialasiewicz Seweryn , Coin Lachlan , Roberts Jason A. , Paterson David L. , Irwin Adam D.
Published: June 2023

Background

Direct metagenomic sequencing from positive blood culture (BC) broths, to identify bacteria and predict antimicrobial susceptibility, has been previously demonstrated using Illumina-based methods, but is relatively slow. We aimed to evaluate this approach using nanopore sequencing to provide more rapid results.

Methods

Patients with suspected sepsis in 4 intensive care units were prospectively enrolled. Human-depleted DNA was extracted from positive BC broths and sequenced using nanopore (MinION). Species abundance was estimated using Kraken2, and a cloud-based artificial intelligence (AI) system (AREScloud) providedin silicoantimicrobial susceptibility testing (AST) from assembled contigs. These results were compared to conventional identification and phenotypic AST.

Results

Genus-level agreement between conventional methods and metagenomic whole genome sequencing (MG-WGS) was 96.2% (50/52), but increased to 100% in monomicrobial infections. In total, 262 high quality AREScloud AST predictions across 24 samples were made, exhibiting categorical agreement (CA) of 89.3%, with major error (MA) and very major error (VME) rates of 10.5% and 12.1%, respectively. Over 90% CA was achieved for some taxa (e.g.Staphylococcus aureus), but was suboptimal forPseudomonas aeruginosa(CA 50%). In 470 AST predictions across 42 samples, with both high quality and exploratory-only predictions, overall CA, ME and VME rates were 87.7%, 8.3% and 28.4%. VME rates were inflated by false susceptibility calls in a small number of species / antibiotic combinations with few representative resistant isolates. Time to reporting from MG-WGS could be achieved within 8-16 hours from blood culture positivity.

Conclusions

Direct metagenomic sequencing from positive BC broths is feasible and can provide accurate predictive AST for some species and antibiotics, but is sub-optimal for a subset of common pathogens, with unacceptably high VME rates. Nanopore-based approaches may be faster but improvements in accuracy are required before it can be considered for clinical use. New developments in nanopore sequencing technology, and training of AI algorithms on larger and more diverse datasets may improve performance.
Next-Generation Phenotyping: Introducing PhecodeX for Enhanced Discovery Research in Medical Phenomics
Authors: Shuey MM , Stead WW , Aka I , Barnado AL , Bastarache JA , Brokamp E , Campbell Joseph MS , Carroll RJ , Goldstein JA , Lewis A , Malow BA , Mosley JD , Osterman T , Padovani-Claudio DA , Ramirez A , Roden DM , Schuler BA , Siew E , Sucre J , Thomsen I , Tinker RJ , Van Driest S , Walsh C , Warner JL , Wells QS , Wheless L , Bastarache L
Published: June 2023

Phecodes are widely-used and easily adapted phenotypes based on International Classification of Diseases (ICD) codes. The current version of phecodes (v1.2) was designed primarily to study common/complex diseases diagnosed in adults. Here we present phecodeX, an expanded version of phecodes with a revised structure and 1,761 new codes. PhecodeX adds granularity to phenotypes in key disease domains that are under-represented in the current phecode structure-including infectious disease, pregnancy, congenital anomalies, and neonatology- and is a more robust representation of the medical phenome for global use in discovery research.

Availability and implementation

phecodeX is available athttps://github.com/PheWAS/phecodeX.

Contact

lisa.bastarache@vumc.org

Supplementary information

Supplemental Tables 1-4, Bastarache_bioRxiv_20220907.pdf

WC-1999
The genetic drivers of juvenile, young, and early-onset Parkinson’s Disease in India
Authors: Andrews Shan V , Kukkle Prashanth L , Menon Ramesh , Geetha Thenral S , Goyal Vinay , Kandadai Rukmini Mridula , Kumar Hrishikesh , Borgohain Rupam , Mukherjee Adreesh , Wadia Pettarusp M , Yadav Ravi , Desai Soaham , Kumar Niraj , Joshi Deepika , Murugan Sakthivel , Biswas Atanu , Pal Pramod K , Oliver Merina , Nair Sandhya , Kayalvizhi Anbu , Samson Praveena L , Deshmukh Manjari , Bassi Akshi , Sandeep Charugulla , Mandloi Nitin , Davis Oliver B , Roberts Melissa A , Leto Dara E , Henry Anastasia G , Di Paolo Gilbert , Muthane Uday , Das Shymal K , Peterson Andrew S , Sandmann Thomas , Gupta Ravi , Ramprasad Vedam L ,   Parkinson Research Alliance of India (PRAI)
Published: June 2023

Background

Recent studies have advanced our understanding of the genetic drivers of Parkinson’s Disease (PD). Rare variants in more than 20 genes are considered causal for PD, and the latest PD GWAS study identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused.

Objectives

To identify genetic risk factors for PD in a South Asian population.

Methods

674 PD subjects predominantly with age of onset ≤ 50 years (encompassing juvenile, young, or early-onset PD) were recruited from 10 specialty movement disorder centers across India over a 2-year period. 1,376 control subjects were selected from the reference population GenomeAsia, Phase 2. We performed various case-only and case-control genetic analyses for PD diagnosis and age of onset.

Results

A genome-wide significant signal for PD diagnosis was identified in theSNCAregion, strongly colocalizing withSNCAregion signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. Gene burden studies of rare, predicted deleterious variants identifiedBSN, encoding the presynaptic protein Bassoon that has been previously associated with neurodegenerative disease.

Conclusions

This study constitutes the largest genetic investigation of PD in a South Asian population to date. Future work should seek to expand sample numbers in this population to enable improved statistical power to detect PD genes in this understudied group.
An explainable machine learning-based phenomapping strategy for adaptive predictive enrichment in randomized controlled trials
Authors: Oikonomou Evangelos K , Thangaraj Phyllis M. , Bhatt Deepak L , Ross Joseph S , Young Lawrence H , Krumholz Harlan M , Suchard Marc A , Khera Rohan
Published: June 2023

Randomized controlled trials (RCT) represent the cornerstone of evidence-based medicine but are resource-intensive. We propose and evaluate a machine learning (ML) strategy of adaptive predictive enrichment through computational trial phenomaps to optimize RCT enrollment. In simulated group sequential analyses of two large cardiovascular outcomes RCTs of (1) a therapeutic drug (pioglitazone versus placebo; Insulin Resistance Intervention after Stroke (IRIS) trial), and (2) a disease management strategy (intensive versus standard systolic blood pressure reduction in the Systolic Blood Pressure Intervention Trial (SPRINT)), we constructed dynamic phenotypic representations to infer response profiles during interim analyses and examined their association with study outcomes. Across three interim timepoints, our strategy learned dynamic phenotypic signatures predictive of individualized cardiovascular benefit. By conditioning a prospective candidate’s probability of enrollment on their predicted benefit, we estimate that our approach would have enabled a reduction in the final trial size across ten simulations (IRIS: – 14.8% ± 3.1%,pone-sample t-test=0.001; SPRINT: –17.6% ± 3.6%,pone-sample t-test<0.001), while preserving the original average treatment effect (IRIS: hazard ratio of 0.73 ± 0.01 for pioglitazone vs placebo, vs 0.76 in the original trial; SPRINT: hazard ratio of 0.72 ± 0.01 for intensive vs standard systolic blood pressure, vs 0.75 in the original trial; all withpone-sample t-test<0.01). This adaptive framework has the potential to maximize RCT enrollment efficiency.
A Novel Autosomal Dominant Childhood-Onset Disorder Associated with Pathogenic Variants inVCP
Authors: Mah-Som Annelise Y. , Daw Jil , Huynh Diana , Wu Mengcheng , Creekmore Benjamin C. , Burns William , Skinner Steven A. , Holla Øystein L. , Smeland Marie F. , Planes Marc , Uguen Kevin , Redon Sylvia , Bierhals Tatjana , Scholz Tasja , Denecke Jonas , Mensah Martin A. , Sczakiel Henrike L. , Tichy Heidelis , Verheyen Sarah , Blatterer Jasmin , Schreiner Elisabeth , Thies Jenny , Lam Christina , Spaeth Christine , Pena Loren , Ramsey Keri , Narayanan Vinodh , Seaver Laurie H. , Rodriguez Diana , Afenjar Alexandra , Burglen Lydie , Lee Edward B. , Chou Tsui-Fen , Weihl Conrad C. , Shinawi Marwan S.
Published: June 2023

Valosin-containing protein (VCP) is an AAA+ ATPase that plays critical roles in multiple ubiquitin-dependent cellular processes. Dominant pathogenic variants inVCPare associated with adult-onset multisystem proteinopathy (MSP) that presents with myopathy, bone disease, dementia, and/or motor neuron disease. Through GeneMatcher, we identified 13 unrelated individuals who carry novel heterozygousVCPvariants (12de novo, 1 inherited) associated with a childhood-onset disorder characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly. Trio exome sequencing or multigene panel identified nine missense variants, two in-frame deletions, one frameshift, and one splicing variant. We performedin vitrofunctional studies andin silicomodelling to investigate the impact of these variants on protein function. In contrast to MSP variants, most missense variants had decreased ATPase activity, and one caused hyperactivation. Other variants were predicted to cause haploinsufficiency, suggesting a loss-of-function mechanism. This is the first description ofVCP-related neurodevelopmental disease presenting in childhood.
Different indicators of stress-induced hyperglycemia and poor outcomes after spontaneous intracerebral hemorrhage
Authors: Song Xintong , Zhang Jia , Wang Wenjuan , Wang Anxin , Zhang Xiaoli , Li Sijia , Wang Chuanying , Zhao Xingquan , Zhang Qian
Published: June 2023

Background

This study aimed to compare the predictive value of metrics unique to stress-induced hyperglycemia (SIH) with fasting blood on poor functional outcomes of spontaneous intracerebral hemorrhage (sICH).

Methods

This investigation included 528 patients from a multicenter, observational, prospective cohort study. Poor functional outcomes were defined as modified Rankin Scale(mRS) ≥ 3. Logistic regression analyses were used to assess the relationship between indicators of SIH, including fasting blood glucose (FBG), two definitions of the stress hyperglycemia ratio [SHR, the fast blood glucose concentration/estimated average glucose (SHR1) and the ratio of glucose to HbA1c(SHR2)], and glycemic gap (GG), and poor functional outcomes at 30-day, 90-day, and 1-year.

Results

Higher values of all these indicators for SIH (e.g., FBG, GG, SHR1, and SHR2) were independently related to poor outcomes at 30-day, 90-day, and 1-year in patients with sICH (p < 0.05 for all models). Compared with the area under the curve (AUC), all these indicators performed greater AUC in predicting poor prognosis at 1-year (FBG: AUC=0.710; GG: AUC=0.741; SHR1: AUC=0.743) than 30-day and 90-day. And SHR2 has the highest predictive value among these indicators (AUC=0.748). Finally, diabetes had no statistical effect on the correlation between these indicators and poor functional outcomes at 30-day, 90-day, and 1-year in subgroup analysis (p for interaction >0.05).

Conclusions

Patients with higher FBG, GG, SHR1, and SHR2 values were more likely to have a poor functional outcome. SHR2 has the highest predictive value for poor outcomes at 30-day, 90-day and 1-year.
Portable Arbitrary Pulse Generator for Driving μCoils for Micromagnetic Neurostimulation
Authors: Bloom Robert P. , Saha Renata , Sanger Zachary , Benally Onri J. , Wu Kai , Girolamo Arturo di , Low Walter C. , Netoff Theoden I. , Wang Jian-Ping
Published: June 2023

Micromagnetic stimulation (μMS) is a promising branch of neurostimulation technologies. Microcoil (μcoil) based magnetic stimulation uses micrometer sized coils that generate a time-varying magnetic field which as per Faraday’s Laws of Electromagnetic Induction induces an electric field on a conductive surface. This method of stimulation has the advantage of not requiring electrical contact with tissue, however these μcoils are not easy to operate. Large currents are required to generate the required magnetic field. These currents are too large for standard test equipment to provide, and additional power amplifiers are needed. To aid in the development and application of micromagnetic stimulation devices, we have created a compact single unit test setup for driving these devices called the μCoil Driver. This unit is designed to drive small inductive loads up to ±8 V at 5 A and 10 kHz.
Dual proteomic signature of immune cells andYersinia pestisupon blood infection
Authors: Lê-Bury Pierre , Douché Thibaut , Gianetto Quentin Giai , Matondo Mariette , Pizarro-Cerdá Javier , Dussurget Olivier
Published: June 2023

Emerging and reemerging infectious diseases represent major public health concerns. The urgent need for infection control measures requires deep understanding of molecular pathogenesis. Global approaches to study biological systems such as mass-spectrometry based proteomics benefited from groundbreaking physical and bioinformatical technological developments over recent years. However, dual proteomic study of highly pathogenic microorganisms and their hosts in complex matrices encountered during infection remains challenging due to high protein dynamic range of samples and requirements imposed in biosafety level 3 or 4 laboratories. Here, we constructed a dual proteomic pipeline ofYersinia pestisin human blood and plasma, mirroring bacteremic phase of plague. We provide the most completeY. pestisproteome revealing a major reshaping of important bacterial path-ways such as methionine biosynthesis and iron acquisition in human plasma. Remarkably, proteomic profiling in human blood highlights a greaterYersiniaouter proteins intoxication of monocytes than neutrophils. Our study unravels global expression changes and points to a specific pathogenic signature during infection, paving the way for future exploration of proteomes in the complex context of host-pathogen interactions.

Subject Categories

Microbiology, Virology and Host Pathogen Interaction, Proteomics
CellStitch: 3D Cellular Anisotropic Image Segmentation via Optimal Transport
Authors: Liu Yining , Jin Yinuo , Azizi Elham , Blumberg Andrew J.
Published: June 2023

Background

Spatial mapping of transcriptional states provides valuable biological insights into cellular functions and interactions in the context of the tissue. Accurate 3D cell segmentation is a critical step in the analysis of this data towards understanding diseases and normal developmentin situ. Current approaches designed to automate 3D segmentation include stitching masks along one dimension, training a 3D neural network architecture from scratch, and reconstructing a 3D volume from 2D segmentations on all dimensions. However, the applicability of existing methods is hampered by inaccurate segmentations along the non-stitching dimensions, the lack of high-quality diverse 3D training data, and inhomogeneity among different dimensions; as a result, they have not been widely used in practice.

Methods

To address these challenges, we formulate the problem of finding cell correspondence across layers with a novel optimal transport (OT) approach. We propose CellStitch, a flexible pipeline that segments cells from 3D images without requiring large amounts of 3D training data. We further extend our method to interpolate internal slices from highly anisotropic cell images to recover isotropic cell morphology.

Results

We evaluated the performance of CellStitch through eight 3D plant microscopic datasets with diverse anisotropic levels and cell shapes. CellStitch substantially outperforms the state-of-the art methods on anisotropic images, and achieves comparable segmentation quality against competing methods in isotropic setting. We benchmarked and reported 3D segmentation results of all the methods with instance-level precision, recall and average precision (AP) metrics.

Conclusion

The proposed OT-based 3D segmentation pipeline outperformed the existing state-of-the-art methods on different datasets with nonzero anisotropy, providing high fidelity recovery of 3D cell morphology from microscopic images.
Constructing neural networks with pre-specified dynamics
Authors: Mininni Camilo J. , Zanutto B. Silvano
Published: June 2023

A main goal in neuroscience is to understand the computations carried out by neural populations that give animals their cognitive skills. Neural network models allow to formulate explicit hypothesis regarding the algorithms instantiated in the dynamic of a neural population, its firing statistics, and the underlying connectivity. Neural networks can be defined by a small set of parameters, carefully chosen to procure specific capabilities, or by a large set of free parameters, fitted with optimization algorithms that minimize a given loss function. In this work we alternatively propose a method to make a detailed adjustment of the network dynamic and firing statistic to better answer questions that link dynamic, structure and function. Our algorithm – termed generalized Firing-to-Parameter (gFTP) – provides a way to construct binary recurrent neural networks whose dynamic strictly follows a user pre-specified transition graph that details the transitions between population firing states triggered by stimulus presentations. Our main contribution is a procedure that detects when a transition graph is not realizable in terms of a neural network, and makes the necessary modifications in order to obtain a new transition graph that is realizable and preserves all the information encoded in the transitions of the original graph. With a realizable transition graph, gFTP assigns values to the network firing states associated with each node in the graph, and finds the synaptic weight matrices by solving a set of linear separation problems. We test gFTP performance by constructing networks with random dynamics, continuous attractor-like dynamics that encode position in 2-dimensional space, and discrete attractor dynamics. We then show how gFTP can be employed as a tool to explore the broad dependencies between structure and function, and the specific dependencies subserving the algorithms instantiated in the network activity.
Genomic and ecological factors shaping specialism and generalism across an entire subphylum
Authors: Opulente Dana A. , LaBella Abigail Leavitt , Harrison Marie-Claire , Wolters John F. , Liu Chao , Li Yonglin , Kominek Jacek , Steenwyk Jacob L. , Stoneman Hayley R. , VanDenAvond Jenna , Miller Caroline R. , Langdon Quinn K. , Silva Margarida , Gonçalves Carla , Ubbelohde Emily J. , Li Yuanning , Buh Kelly V. , Jarzyna Martin , Haase Max A. B. , Rosa Carlos A. , Čadež Neža , Libkind Diego , DeVirgilio Jeremy H. , Hulfachor Amanda Beth , Kurtzman Cletus P. , Sampaio José Paulo , Gonçalves Paula , Zhou Xiaofan , Shen Xing-Xing , Groenewald Marizeth , Rokas Antonis , Hittinger Chris Todd
Published: June 2023

Organisms exhibit extensive variation in ecological niche breadth, from very narrow (specialists) to very broad (generalists). Paradigms proposed to explain this variation either invoke trade-offs between performance efficiency and breadth or underlying intrinsic or extrinsic factors. We assembled genomic (1,154 yeast strains from 1,049 species), metabolic (quantitative measures of growth of 843 species in 24 conditions), and ecological (environmental ontology of 1,088 species) data from nearly all known species of the ancient fungal subphylum Saccharomycotina to examine niche breadth evolution. We found large interspecific differences in carbon breadth stem from intrinsic differences in genes encoding specific metabolic pathways but no evidence of trade-offs and a limited role of extrinsic ecological factors. These comprehensive data argue that intrinsic factors driving microbial niche breadth variation.

One-Sentence Summary

A nearly complete genomic catalog of the yeast subphylum illuminates the evolution of their diverse ecologies and metabolisms.
Testing relationships between multiple regional features and biogeographic processes of speciation, extinction, and dispersal
Authors: Swiston Sarah K. , Landis Michael J.
Published: June 2023

The spatial and environmental features of regions where clades are evolving are expected to impact biogeographic processes such as speciation, extinction, and dispersal. Any number of regional features (such as altitude, distance, area, etc.) may be directly or indirectly related to these processes. For example, it may be that distances or differences in altitude or both may limit dispersal rates. However, it is difficult to disentangle which features are most strongly related to rates of different processes. Here, we present an extensible Multi-feature Feature-Informed GeoSSE (MultiFIG) model that allows for the simultaneous investigation of any number of regional features. MultiFIG provides a conceptual framework for incorporating large numbers of features of different types, including categorical, quantitative, within-region, and between-region features, along with a mathematical framework for translating those features into biogeographic rates for statistical hypothesis testing. Using traditional Bayesian parameter estimation and reversible-jump Markov chain Monte Carlo, MultiFIG allows for the exploration of models with different numbers and combinations of feature-effect parameters, and generates estimates for the strengths of relationships between each regional feature and core process. We validate this model with a simulation study covering a range of scenarios with different numbers of regions, tree sizes, and feature values. We also demonstrate the application of MultiFIG with an empirical case study of the South American lizard genus Liolaemus, investigating sixteen regional features related to area, distance, and altitude. Our results show two important feature-process relationships: a negative distance/dispersal relationship, and a negative area/extinction relationship. Interestingly, although speciation rates were found to be higher in Andean versus non-Andean regions, the model did not assign significance to Andean- or altitude-related parameters. These results highlight the need to consider multiple regional features in biogeographic hypothesis testing.
GATA-regulated transcriptional program dictate cell fate equilibrium to establish the maternal-fetal exchange interface and fetal development
Authors: Ghosh Ananya , Kumar Rajnish , Kumar Ram , Ray Soma , Saha Abhik , Roy Namrata , Dasgupta Purbasa , Marsh Courtney , Paul Soumen
Published: June 2023

The placenta establishes a maternal–fetal exchange interface to transport nutrients and gases between the mother and the fetus. Establishment of this exchange interface relies on the development of multinucleated syncytiotrophoblasts (SynT) from trophoblast progenitors and defect in SynT development often leads to pregnancy failure and impaired embryonic development. Here, we show that mouse embryos with conditional deletion of GATA2 and GATA3 in labyrinth trophoblast progenitors have underdeveloped placenta and die ∼ embryonic day 9.5 (E9.5). Single cell RNA Seq (scRNA-Seq) analysis revealed excessive accumulation of multipotent labyrinth trophoblast progenitors upon conditional deletion of GATA factors. The GATA factor-deleted multipotent progenitors were unable to differentiate to matured SynTs. We also show that the GATA factor-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. Loss of either GATA2 or GATA3 in cytotrophoblast (CTB)-derived human trophoblast stem cells (human TSCs) drastically inhibits SynT differentiation potential. Identification of GATA2 and GATA3 target genes along with comparative bioinformatics analyses revealed that GATA factors directly regulate hundreds of common genes in human TSCs, including genes that are essential for SynT development and implicated in preeclampsia and fetal growth retardation. Thus, our study uncovers a conserved molecular mechanism, in which coordinated function of GATA2 and GATA3 promote trophoblast progenitor-to-SynT commitment ensuring establishment of the maternal–fetal exchange interface.
TRAF6 initiates inflammatory signaling via organizing membraneless cytoplasmic condensates
Authors: Wang Jia , Zhong Xincheng , Yin Hang
Published: June 2023

The tumor necrosis factor receptor-associated factor 6 (TRAF6) is a central molecule in multiple signaling pathways, i.e. the TNF receptor, the Toll-like receptors (TLRs), and interleukin-1 receptor (IL-1R) pathways. Upon pathogen associated molecular patterns (PAMPs) or damage associated molecular patterns (DAMPs) stimulations, TRAF6 activates downstream of NF-κB signaling. However, the precise mechanism of how TRAF6 activates downstream molecules remains unclear.

Here, we demonstrate that TRAF6 acts as a sensor for upstream signals to initiate liquid-liquid phase separation (LLPS) of itself and downstream proteins, forming membraneless condensates. Subsequent recruitment, enrichment and activation of downstream effectors in the condensates lead to robust inflammatory signal transduction. The multivalent interactions mediated by its RING domain, zinc finger domain 1, and coiled-coil domain mediates the LLPS process. Forced phase separation of TRAF6 induced NF-κB activation. Disruption of TRAF6 phase separation abrogates activation of NF-κB signaling. Overall, we uncover the spatial organization of molecules by TRAF6 through phase separation as a subcellular platform to activate inflammatory signaling. Targeting TRAF6 phase separation hold promises for therapeutics aiming autoimmune diseases, inflammation and cancers.
Association between post-infection COVID-19 vaccination and symptom severity of post COVID-19 condition among patients on Bonaire, Caribbean Netherlands: a retrospective cohort study
Authors: Berry D.S.F. , Dalhuisen T. , Marchena G. , Tiemessen I. , Geubbels E. , Jaspers L.
Published: June 2023

Objectives

In this retrospective cohort study, we aimed to investigate symptom severity change following COVID-19 vaccination among post COVID-19 condition (PCC) patients on Bonaire.

Methods

Symptomatic cases who tested positive for SARS-CoV-2 between the start of the pandemic and 1 October 2021, were unrecovered on the interview day and unvaccinated prior to infection were identified from the national case registry. Patients were interviewed by telephone between 15 November and 4 December 2021 about sociodemographic factors, pre-pandemic health, COVID-19 symptoms and vaccination status. We compared symptom severity change between the acute and post-acute disease phase (>4 weeks after disease onset) of 14 symptoms on a five-point Likert scale for 36 PCC patients having received at least one dose of the BNT162 (BioNTech/Pfizer) vaccine and 11 patients who remained unvaccinated, using separate multiple linear regression models.

Results

Most common post-acute symptoms included fatigue (81%), reduced physical endurance (79%), and reduced muscle strength (64%). Post-infection vaccination was significantly associated with reduced severity of heart palpitations, after adjusting for acute phase severity and duration of illness (β 0.60, 95% CI 0.18-1.02). We did not find a statistically significant association with symptom severity change for other, more prevalent symptoms.

Conclusions

Larger prospective studies are needed to confirm our observation in a small study population that post-infection COVID-19 vaccination was associated with reduced severity of heart palpitations among those with this symptom self-attributed to SARS-CoV-2 infection.
Risk screening tools could potentially miss out HIV positive individuals who seek testing services: A secondary program data analysis on the performance characteristics of an adolescent and adult HIV risk screening tool in Uganda
Authors: Lubega Marvin , Guerra Katherine , Ginivan Megan , Kamuntu Yewande , Senyama George , Musoke Andrew , Geoffrey Taasi , Nalubega Sylivia , Khan Shaukat , John Bosco Junior Matovu
Published: June 2023

Introduction

Improving HIV testing efficiency has been documented to save financial and material resources for health. In October 2019, the Ministry of health Uganda deployed an HIV risk screening tool for use in 24 health facilities targeting clients aged 15 years and above in both outpatient and Voluntary Counselling and Testing departments.

Methods

We conducted a retrospective secondary data analysis of routinely collected HIV risk screening program data in Uganda, collected from October to November 2019, to determine the performance characteristics of the adolescent and adult HIV risk screening tool in public health facility settings. Statistical measures for the risk screening tool performance included sensitivity, specificity, positive and negative predictive values, and a cost analysis.

Results

A total of 19,854 clients were screened for HIV testing eligibility; we excluded 150 records with incomplete testing information. The overall positivity rate (cluster weighted prevalence of HIV) among those screened was 4.5% (95% CI: 4.1%-4.8%) versus 3.71% (95% CI: 3.06-4.50) among those not screened. The sensitivity and specificity of the risk screening tool were found to be 90.7% (95% CI: 88.4%, 92.7%) and 75.8%, (75.2-76.4) respectively. With screening, the number needed to test to identify one PLHIV reduced from 27 to 22. Although risk screening would have led to 24.5% (4,825/19,704) reduction in testing volume, 9.3% (68/732) of PLHIV would have been missed as they were misclassified as not eligible for testing. The cost per PLHIV identified fell by 3% from $69 without screening to $66.9 with implementation of the screening tool.

Conclusions

The use of HIV risk screening tool in OPD settings in Uganda demonstrated improved HIV testing efficiency by reducing testing volumes but resulted in screening out of a significant number of people living with HIV. The team recommends that scientifically validated HIV risk screening tools be considered for use by countries.
Correlates of the Post-Stroke cognitive impairment among patients with first-ever stroke admitted at tertiary hospitals in Dodoma, Tanzania: a prospective longitudinal study
Authors: Alphonce Baraka , Meda John , Nyundo Azan
Published: June 2023

Introduction

Stroke patients develop cognitive impairment that, significantly impacting their quality of life, their families, and the community as a whole, but they are not given attention. This study aims to determine the prevalence and predictors of post-stroke cognitive impairment (PSCI) among adult stroke patients admitted to a tertiary hospital in Dodoma, Tanzania.

Methodology

A prospective longitudinal study was conducted at tertiary hospitals in the Dodoma region, central Tanzania. A sample size of 158 participants with the first stroke confirmed by CT/MRI brain aged ≥ 18 years met the criteria. At baseline, social-demographic, cardiovascular risks and stroke characteristics were acquired and then at 30 days, participants were evaluated for depression and apathy.. Descriptive statistics were summarised as continuous data reported as Mean (SD) or Median (IQR), and categorical data were summarised using proportions and frequencies. Univariate and multivariable logistic regression analysis were computed to determine predictors of PSCI

Results

Of 158 participants, the mean age was 58.7 years, 57.6% were female, and 80.4% of participants met the criteria for post-stroke cognitive impairment. After multivariable logistic regression, left hemisphere stroke (AOR: 5.798, CI: 1.030 – 32.623,p= 0.046), a unit cm3increase in infarct volume (AOR: 1.064, 95% CI: 1.018 – 1.113,p= 0.007), and apathy symptoms (AOR: 12.259, CI: 1.112 – 89.173,p= 0.041) had a significant association with PSCI.

Conclusion

The study showed a high prevalence of PSCI; profiling at-risk stroke survivors in a timely intervention may improve their prognosis. Future studies in the area would inform future interventions and policies.
ETIOLOGY OF PRIMARY CEREBELLAR INTRACEREBRAL HEMORRHAGE BASED ON TOPOGRAPHIC LOCALIZATION
Authors: Incontri Diego , Marchina Sarah , Andreev Alexander , Wilson Mitchell , Wang Jia-Yi , Lin David , Heistand Elizabeth C. , Carvalho Filipa , Selim Magdy , Lioutas Vasileios-Arsenios
Published: June 2023

Background

Cerebellar intracerebral hemorrhage (cICH) is often attributed to hypertension or cerebral amyloid angiopathy (CAA). However, deciphering the exact etiology can be challenging. A recent study reported a topographic etiologic relationship with superficial cICH secondary to CAA. We aimed to re-examine this relationship between topography and etiology in a separate cohort of patients and using the most recent Boston criteria version 2.0.

Methods

Retrospective analysis of consecutive patients with primary cICH admitted to a tertiary academic center between 2000-2022. cICH location on brain CT/MRI scan(s) was divided into strictly superficial (cortex, surrounding white matter, vermis), vs deep (cerebellar nuclei, deep white matter) or mixed (both regions). MRIs were rated for markers of cerebral small vessel disease. We assigned possible/probable vs absent CAA using Boston criteria 2.0.

Results

We included 197 patients; 106 (53.8%) females, median age 74 (63-82) years. Fifty-six (28%) patients had superficial cICH and 141 (72%) deep/mixed cICH. MRI was available for 112 (57%) patients [30(26.8%) with superficial and 82(73.2%) with deep/mixed cICH]. Superficial cICH patients were more likely to have possible/probable CAA (48.3% vs 8.6%; OR 11.43, 95%CI 3.26-40.05; p<0.001), strictly lobar cerebral microbleeds (CMBs) (51.7% vs 6.2%; OR 14.18, 95%CI 3.98-50.50; p<0.001), and cortical superficial siderosis (13.8% vs 1.2%; OR 7.70, 95%CI 0.73-80.49; p=0.08). Patients with deep/mixed cICH patients were more likely to have deep/mixed CMBs (59.2% vs 3.4%; OR 41.39, 95% CI 5.01-341.68; p=0.001), lacunes (54.9% vs 17.2%; OR 6.14, 95% CI 1.89-19.91; p=0.002), severe basal ganglia enlarged perivascular spaces (36.6% vs 7.1%; OR 7.63, 95% CI 1.58-36.73; p=0.01), hypertension (84.4% vs 62.5%; OR 3.43, 95% CI 1.61,-7.30; p=0.001), and higher admission systolic blood pressure (172 [146-200] vs 146 [124-158] mmHg, p<0.001).

Conclusions

Our results suggest that superficial cICH is strongly associated with CAA whereas deep/mixed cICH is almost exclusively linked to hypertensive arteriopathy.