bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility and clinical utility of local rapid Nanopore influenza A virus whole genome sequencing for integrated outbreak management, genotypic resistance detection and timely surveillance
Authors: Williams Tom G. S. , Snell Luke B. , Alder Christopher , Charalampous Themoula , Alcolea-Medina Adela , Sehmi Jasveen K. , Al-Yaakoubi Noor , Humayun Gul , Miah Shahjahan , Lackenby Angie , Zambon Maria , Batra Rahul , Douthwaite Sam , Edgeworth Jonathan D. , Nebbia Gaia
Published: August 2023

Rapid respiratory viral whole genome sequencing (WGS) in a clinical setting can inform real-time outbreak and patient treatment decisions, but the feasibility and clinical utility of influenza A virus (IAV) WGS using Nanopore technology has not been demonstrated. A 24 h turnaround Nanopore IAV WGS protocol was performed on 128 reverse transcriptase PCR IAV-positive nasopharyngeal samples taken over seven weeks of the 2022–2023 winter influenza season, including 25 from patients with nosocomial IAV infections and 102 from patients attending the Emergency Department. WGS results were reviewed collectively alongside clinical details for interpretation and reported to clinical teams. All eight segments of the IAV genome were recovered for 97/128 samples (75.8 %) and the haemagglutinin gene for 117/128 samples (91.4 %). Infection prevention and control identified nosocomial IAV infections in 19 patients across five wards. IAV WGS revealed two separate clusters on one ward and excluded transmission across different wards with contemporaneous outbreaks. IAV WGS also identified neuraminidase inhibitor resistance in a persistently infected patient and excluded avian influenza in a sample taken from an immunosuppressed patient with a history of travel to Singapore which had failed PCR subtyping. Accurate IAV genomes can be generated in 24 h using a Nanopore protocol accessible to any laboratory with SARS-CoV-2 Nanopore sequencing capacity. In addition to replicating reference laboratory surveillance results, IAV WGS can identify antiviral resistance and exclude avian influenza. IAV WGS also informs management of nosocomial outbreaks, though molecular and clinical epidemiology were concordant in this study, limiting the impact on decision-making.
Phenotypic and genotypic characterization of Neisseria gonorrhoeae isolates from Yaoundé, Cameroon, 2019 to 2020
Authors: Tayimetha Carolle Yanique , Njunda Longdoh Anna , Akenji Blaise , Founou Raspail Carrel , Feteh Vitalis , Zofou Denis , Chafa Anicet , Oyono Yannick , Etogo Bienvenu , Tseuko Dorine , Fonkoua Marie Christine , Harrison Odile B.
Published: August 2023

This study investigated antimicrobial resistance (AMR) phenotypes and genotypes exhibited by

Neisseria gonorrhoeae

from Yaoundé, Cameroon. AMR to tetracycline, penicillin and ciprofloxacin was observed although none of the isolates had reduced susceptibility to azithromycin, cefixime or ceftriaxone. Whole genome sequence (WGS) data were obtained and, using a threshold of 300 or fewer locus differences in the

N. gonorrhoeae

core gene multilocus sequence typing (cgMLST) scheme, four distinct core genome lineages were identified. Publicly available WGS data from 1355 gonococci belonging to these four lineages were retrieved from the PubMLST database, allowing the Cameroonian isolates to be examined in the context of existing data and compared with related gonococci. Examination of AMR genotypes in this dataset found an association between the core genome and AMR with, for example, isolates belonging to the core genome group, Ng_cgc_300 : 21, possessing GyrA and ParC alleles with amino acid substitutions conferring high-level resistance to ciprofloxacin while lineages Ng_cgc_300 : 41 and Ng_cgc_300 : 243 were predicted to be susceptible to several antimicrobials. A core genome lineage, Ng_cgc_300 : 498, was observed which largely consisted of gonococci originating from Africa. Analyses from this study demonstrate the advantages of using the

N. gonorrhoeae

cgMLST scheme to find related gonococci to carry out genomic analyses that enhance our understanding of the population biology of this important pathogen.
Diagnostic accuracy of CEUS in identifying Solid Pancreatic Lesions:- A meta analysis
Authors: Desai Dev , Patel Shimolee , Shah Hetvi , Shah Abhijay , Verma Anushka , Malafi Maria Eleni
Published: August 2023

Background

Solid pancreatic lesions are crucial to identify because of their high incidence rate and their poor survival rate. Surgical biopsy, ultrasonography, computed tomography, MRI, and PET-CT are examples of diagnostic tools. Although common, endoscopic ultrasonography guided biopsy carries a risk of needle track seeding. A more effective and affordable method for determining the differential diagnosis of solid pancreatic lesions is contrast-enhanced ultrasonography (CEUS). CEUS is a less nephrotoxic method that uses a contrast chemical to distinguish between teratomas, benign tumors, and neuroendocrine tumors. The goal of this meta-analysis is to evaluate how well CEUS can identify solid pancreatic lesions for use in clinical diagnostic procedures.

Methodology

Medical literature comprehensively searched and reviewed without restrictions to particular study designs, or publication dates using PubMed, Cochrane Library and Google Scholar databases for all relevant literature. The extraction of necessary data proceeded after specific inclusion and exclusion criteria were applied. Meta Analysis included 27 RCTs and 3061 patients, and analyzed using the QualSyst yool. The risk of bias was evaluated by using QUADAS-2 analysis.

The statistical software packages MetaDiSc 1.4, RevMan (Review Manager, version 5.3), SPSS (Statistical Package for the Social Sciences, version 20) and Excel in Stata 14 were used to perform the statistical analyses.

Result

According to the findings of four studies, CEUS demonstrates high sensitivity, with values equal to or above 95%, and one study indicates specificity above 95%. True Positive (TP) and True Negative (TN) values are reported as 2080 and 621, respectively, while False Positive (FP) and False Negative (FN) values are noted as 124 and 236. With a 95% confidence interval, CEUS sensitivity is calculated as 0.90 (range: 0.89 to 0.91) and specificity as 0.83 (range: 0.80 to 0.86). The positive predictive value (PPV) of CEUS is estimated at approximately 94.3%. These results highlight CEUS as a promising tool for diagnosing pancreatic lesions.

Conclusion

The study concluded that CEUS (Contrast-Enhanced Ultrasound) is an important diagnostic test for pancreatic lesions. This is due to their high sensitivity and specificity, along with other aspects like enhanced visualization, real-time imaging, and safety benefits. Additionally, CEUS is cost-effective, making it a practical choice in healthcare settings with budget constraints.

Thus, CEUS remains a valuable asset for healthcare professionals in their efforts to accurately diagnose pancreatic lesions.
A Mixed-Effects Model to Predict COVID-19 Hospitalizations Using Wastewater Surveillance
Authors: Daza–Torres Maria L. , Montesinos-López J. Cricelio , Bischel Heather N. , Naughton Colleen C. , Desai Angel N. , Wolfe Marlene K. , Boehm Alexandria B. , Nuño Miriam
Published: August 2023

During the COVID-19 pandemic, many countries and regions investigated the potential use of wastewater-based disease surveillance as an early warning system. Initially, methods were created to detect the presence of SARS-CoV-2 RNA in wastewater. Investigators have since conducted extensive studies to examine the link between viral concentration in wastewater and COVID-19 cases in areas served by sewage treatment plants over time. However, only a few reports have attempted to create predictive models for hospitalizations at county-level based on SARS-CoV-2 RNA concentrations in wastewater. This study implemented a linear mixed-effects model that observes the association between levels of virus in wastewater and county-level hospitalizations. The model was then utilized to predict short-term county-level hospitalization trends in 21 counties in California based on data from March 21, 2022, to May 21, 2023. The modeling framework proposed here permits repeated measurements as well as fixed and random effects. The model that assumed wastewater data as an input variable, instead of cases or test positivity rate, showed strong performance and successfully captured trends in hospitalizations. Additionally, the model allows for the prediction of SARS-CoV-2 hospitalizations two weeks ahead. Forecasts of COVID-19 hospitalizations could provide crucial information for hospitals to better allocate resources and prepare for potential surges in patient numbers.
AI-BASED MRI MONITORING IN MULTIPLE SCLEROSIS: REAL-WORLD CLINICAL VALIDATION
Authors: Barnett Michael , Wang Dongang , Beadnall Heidi , Bischof Antje , Brunacci David , Butzkueven Helmut , Brown J William L , Cabezas Mariano , Das Tilak , Dugal Tej , Guilfoyle Daniel , Klistorner Alexander , Krieger Stephen , Kyle Kain , Ly Linda , Masters Lynette , Shieh Andy , Tang Zihao , van der Walt Anneke , Ward Kayla , Wiendl Heinz , Zhan Geng , Zivadinov Robert , Barnett Yael , Wang Chenyu
Published: August 2023

Modern management of MS targets No Evidence of Disease Activity (NEDA): no clinical relapses, no magnetic resonance imaging (MRI) disease activity and no disability worsening. While MRI is the principal tool available to neurologists for monitoring clinically silent MS disease activity and, where appropriate, escalating treatment, standard radiology reports are qualitative and may be insensitive to the development of new or enlarging lesions. Existing quantitative neuroimaging tools lack adequate clinical validation. In 397 multi-center MRI scan pairs acquired in routine practice, we demonstrate superior case-level sensitivity of a clinically integrated AI-based tool over standard radiology reports (93.3% vs 58.3%), relative to a consensus ground truth, with minimal loss of specificity. We also demonstrate equivalence of the AI-tool with a core clinical trial imaging lab for lesion activity and quantitative brain volumetric measures, including percentage brain volume loss (PBVC), an accepted biomarker of neurodegeneration in MS (mean PBVC -0.32% vs -0.36% respectively), whereas even severe atrophy (>0.8% loss) was not appreciated in radiology reports. Finally, the AI-tool additionally embeds a clinically meaningful, experiential comparator that returns a relevant MS patient centile for lesion burden, revealing, in our cohort, inconsistencies in qualitative descriptors used in radiology reports. AI-based image quantitation enhances the accuracy of, and value-adds to, qualitative radiology reporting. Scaled deployment of these tools will open a path to precision management for patients with MS.
Representation of the hierarchical and functional structure of an ambulatory network of medical consultations through social network analysis, with an emphasis on the role of medical specialties
Authors: Biscione Fernando Martín , da Silva Juliano Domingues
Published: August 2023

Background

Ambulatory Health Care Networks (Amb-HCN) emerge when doctors establish circuits of patient referral and counter-referral in their offices, explicitly or spontaneously. We aimed to characterize the structural and functional topology of an Amb-HCN of a private health insurance provider (PHIP) using objective metrics from graph theory.

Methods

A Social Network Analysis was conducted with administrative claim data of a Brazilian PHIP. Included were beneficiaries of a healthcare plan not restricting the location or physician caring for the patient. A directional and weighted network was constructed, where doctors were vertices and patient referrals between doctors were edges. Vertex-level measures were calculated and grouped into three theoretical constructs: patient follow-up; relationship with authorities; and centrality profiles. To characterize physicians into these profiles, cluster analysis was conducted using the non-hierarchical K-means technique.

Findings

Between 04/01/2021 and 05/15/2022, 666,263 individuals performed 3,863,222 office visits with 4,554 physicians. Non-primary-care medical specialties (e.g., cardiology, endocrinology etc.) were associated with central profile in the graph, while surgical specialties predominated in the periphery, along with pediatrics. Only pediatrics was associated with strong and prevalent patient follow-up. Weak and shared patient follow-up was present for many doctors from internal medicine and family medicine. All profiles exhibited pairwise relationships with each other, and with clinical characteristics and outcomes of the patients they treated. For example, physicians identified as authorities were frequently central and treated patients with more comorbidities. Eleven medical communities were identified with clear territorial and medical specialty segregation.

Conclusions

Viewing the Amb-HCN as a social network provided emerging insights into the most influential actors and specialties, potential gaps in care, and the most prevalent diseases in our patient portfolio. Identifying self-constituted Amb-HCN can form a rational basis for developing more formal networks or monitoring patient care performance without assigning responsibility to single physicians.
Cost-Effectiveness of Prefusion F Protein-Based Vaccines Against Respiratory Syncytial Virus Disease for Older Adults in the United States
Authors: Moghadas Seyed M. , Shoukat Affan , Bawden Carolyn E. , Langley Joanne M. , Singer Burton H , Fitzpatrick Meagan C. , Galvani Alison P.
Published: August 2023

Background

Two prefusion F protein-based vaccines, Arexvy and Abrysvo, have been authorized by the US Food and Drug Administration for protecting older adults against Respiratory Syncytial Virus (RSV)-associated lower respiratory tract illness. We evaluated the health benefits and cost-effectiveness of these vaccines.

Methods

We developed a discrete-event simulation model, parameterized with the burden of RSV disease including outpatient care, hospitalization, and death for adults aged 60 years or older in the US. Taking into account the costs associated with these RSV-related outcomes, we calculated the net monetary benefit using quality-adjusted life-years (QALY) gained as a measure of effectiveness, and determined the range of price-per-dose (PPD) for Arexvy and Abrysvo vaccination programs to be cost-effective from a societal perspective.

Results

Using a willingness-to-pay of $95,000 per QALY gained, we found that vaccination programs could be cost-effective for a PPD under $120 with Arexvy and $111 with Abrysvo over the first RSV season. Achieving an influenza-like vaccination coverage of 66% for the population of older adults in the US, the budget impact of these programs at the maximum PPD ranged from $5.74 to $6.10 billion. If the benefits of vaccination extend to a second RSV season as reported in clinical trials, we estimated a maximum PPD of $250 for Arexvy and $233 for Abrysvo, with two-year budget impacts of $11.59 and $10.89 billion, respectively.

Conclusions

Vaccination of older adults would provide substantial direct health benefits by reducing outcomes associated with RSV-related illness in this population.
Protective effects of sacubitril/valsartan in anthracyclines-induced cardiotoxicity: A Systematic Review and Meta-Analysis
Authors: López Trejo Felipe Israel , Sánchez Barrera Mónica Daniela , Andrade Cuellar Elias Noel , Morales Portano Julieta Danira , Martínez Martínez Laura Aline
Published: August 2023

Background

One of the adverse effects of anthracycline use is cardiotoxicity manifested as heart failure. The benefit of sacubitril/valsartan in patients with heart failure of ischemic origin has been demonstrated, but not due to toxicity. Our objective was to determine if there are protective effects of the use of sacubitril/valsartan in cardiotoxicity induced by anthracyclines.

Methods

A bibliographic search was carried out in PubMed, Cochrane Library, LILACS, Scopus, EBSCO and Google Scholar. A systematic review and meta-analysis was performed to assess mean differences (MD) with 95% confidence intervals following the PRISMA Statement.

Results

558 published articles were found, of which three were submitted to analysis, with a total sample of 69 patients. With the use of sacubitril/valsartan there was an increase in the percentage of left ventricular ejection fraction (LVEF) [MD 6.78% (p < 0.001)], an increase in the percentage of global longitudinal strain of the left ventricle (LV-GLS) [MD 3.37 % (p < 0.001)], and decreased serum levels of NT-proBNP [MD −1003.64 pg/mL (p < 0.001)]; in addition, there was an increase in the distance traveled with the use of sacubitril/valsartan [MD 95.23 meters (p < 0.001)] compared to their baseline values, respectively.

Conclusions

This meta-analysis suggests that there is a benefit from the use of sacubitril/valsartan in patients with heart failure related to the use of anthracyclines on ventricular remodeling and functional capacity. This is the first meta-analysis to our knowledge evaluating this effect. Randomized double-blind placebo-controlled clinical trials are required to confirm these findings.
Intracerebral Hemorrhage etiological classification systems and their correlation with neurological deterioration
Authors: Vázquez-Justes Daniel , Mauri-Capdevila Gerard , Yhovany Gallego , Paul-Arias Miriam , Mitjana Raquel , Purroy Francisco
Published: August 2023

Introduction

Unlike ischemic stroke, the etiological classification of patients with intracerebral hemorrhage (CH) lacks consensus. Our study focuses on two commonly-used classification systems: SMASH-U and H-ATOMIC. The main difference between them lies in the fact that the H-ATOMIC system considers the simultaneous presence of different etiologies in a single patient. The association between the two classifications with relation to neurological deterioration (ND) and clinical outcomes remains so far unexplored.

Methods

We recruited consecutive ICH patients from 2015 to 2022, determining etiology was on discharge. Demographic, radiological and clinical characteristics were recorded. ND during hospitalization in the 7 days after stroke was the main clinical endpoint.

Results

301 patients were recruited. 124 patients (41.2%) experienced ND. The hypertensive subtype was the most frequent etiology with both classifications. In 149 (49.5%) more than one possible etiology for the ICH were recognized. The most frequent combination was hypertension + either probable or possible amyloid angiopathy, in 64 patients (21.3%). Significant differences in ND proportions were observed across groups with both systems. ICH related to anticoagulation was associated with a greater risk of ND: 63.5 % in SMASH-U and 62.5% in patients with a combination of Hypertension and Oral Anticoagulants in H-ATOMIC. Both these etiological groups and that containing combined etiologies were statistically significant according to multivariate analysis. Intraventricular extension, blood pressure control and initial volume were also related to ND.

Conclusion

Etiology of the ICH could be related to the risk of ND during hospitalization. Anticoagulation-related etiologies may present the highest risk, especially when combined with hypertension.
TgF344-AD rat model of Alzheimer’s disease: spatial disorientation and asymmetry in hemispheric neurodegeneration
Authors: Sagalajev Boriss , Lennartz Lina , Vieth Lukas , Gunawan Cecilia Tasya , Neumaier Bernd , Drzezga Alexander , Visser-Vandewalle Veerle , Endepols Heike , Sesia Thibaut
Published: August 2023

BACKGROUND

The TgF344-AD ratline represents a transgenic animal model of Alzheimer’s disease (AD). We previously reported spatial memory impairment in TgF344-AD rats, yet the underlying mechanism remained unknown. We, therefore, set out to determine if spatial memory impairment in TgF344-AD rats is attributed to spatial disorientation. Also, we aimed to investigate whether TgF344-AD rats exhibit signs of asymmetry in hemispheric neurodegeneration, similar to what is reported in spatially disoriented AD patients. Finally, we sought to examine how spatial disorientation correlates with working memory performance.

METHODS

TgF344-AD rats were divided into two groups balanced by sex and genotype. The first group underwent the delayed match-to-sample (DMS) task for the assessment of spatial orientation and working memory, while the second group underwent positron emission tomography (PET) for the assessment of glucose metabolism and microglial activity as in-vivo markers of neurodegeneration. Rats were 13 months old during DMS training and 14-16 months old during DMS testing and PET.

RESULTS

In the DMS task, TgF344-AD rats were more likely than their wild-type littermates to display strong preference for one of the two levers, preventing working memory testing. Rats without lever-preference showed similar working memory, regardless of their genotype. PET revealed hemispherically asymmetric clusters of increased microglial activity and altered glucose metabolism in TgF344-AD rats.

CONCLUSIONS

TgF344-AD rats display spatial disorientation and hemispherically asymmetrical neurodegeneration, suggesting a potential causal relationship consistent with clinical observations. In rats without spatial disorientation, working memory remains intact.
Action planning modulates perceptual confidence through action monitoring processes
Authors: Sanchez Rémi , Davranche Karen , Gajdos Thibaut , Desantis Andrea
Published: August 2023

Dominant models of metacognition suggest that sensory information quality determines perceptual confidence, but recent accounts propose that motor signals also affect confidence judgments. In this study, we investigated the impact of motor planning of perceptual responses on decision confidence, testing two hypotheses. The “fluency hypothesis” suggests that ease of motor response selection and preparation enhances confidence. In contrast, the “monitoring hypothesis” posits that increased action monitoring during response selection boosts confidence, potentially counteracting response fluency. In three pre-registered experiments, participants reported the orientation of a stimulus and indicated their confidence in their response. A cue induced action planning that was either congruent or incongruent with the response side used to report the stimulus orientation. Across experiments, we consistently observed higher confidence when participants prepared spatially incongruent actions compared to congruent ones, regardless of response accuracy. In the third experiment, electroencephalography (EEG) revealed an increased fronto-central P2 amplitude for incongruent actions, suggesting that incongruent action planning heightened early attentional resources needed to resolve response conflict. Incongruent action plans also modulated post-response ERPs at centro-parietal channels (e.g., Pz), typically linked to confidence and error monitoring. These findings align with the “monitoring hypothesis” suggesting that the degree of action monitoring during response selection modulates retrospective decision confidence.

Public Significance Statement

While virtually every decision we make leads to an action, the role of motor processes in decision making has been largely neglected. Our results show that retrospective confidence in a perceptual discrimination task is boosted when the motor execution is spatially incongruent with motor preparation, independently of the correctness of the response. Electroencephalography recordings indicate that this effect could be explained by a larger involvement of early attentional resources related to action monitoring, which has an impact on confidence computations. Taken together, these results suggest that action planning information might trigger monitoring mechanisms susceptible to alter retrospective confidence in our decisions, implying that motor processes are not only the output, but also an input of the decision mechanisms.
Agent-based model demonstrates the impact of nonlinear, complex interactions between cytokines on muscle regeneration
Authors: Haase Megan , Comlekoglu Tien , Petrucciani Alexa , Peirce Shayn M. , Blemker Silvia S.
Published: August 2023

Muscle regeneration is a complex process due to dynamic and multiscale biochemical and cellular interactions, making it difficult to identify microenvironmental conditions that are beneficial to muscle recovery from injury using experimental approaches alone. To understand the degree to which individual cellular behaviors impact endogenous mechanisms of muscle recovery, we developed an agent-based model (ABM) using the Cellular Potts framework to simulate the dynamic microenvironment of a cross-section of murine skeletal muscle tissue. We referenced more than 100 published studies to define over 100 parameters and rules that dictate the behavior of muscle fibers, satellite stem cells (SSC), fibroblasts, neutrophils, macrophages, microvessels, and lymphatic vessels, as well as their interactions with each other and the microenvironment. We utilized parameter density estimation to calibrate the model to temporal biological datasets describing cross-sectional area (CSA) recovery, SSC, and fibroblast cell counts at multiple time points following injury. The calibrated model was validated by comparison of other model outputs (macrophage, neutrophil, and capillaries counts) to experimental observations. Predictions for eight model perturbations that varied cell or cytokine input conditions were compared to published experimental studies to validate model predictive capabilities. We used Latin hypercube sampling and partial rank correlation coefficient to identifyin silicoperturbations of cytokine diffusion coefficients and decay rates to enhance CSA recovery. This analysis suggests that combined alterations of specific cytokine decay and diffusion parameters result in greater fibroblast and SSC proliferation compared to individual perturbations with a 13% increase in CSA recovery compared to unaltered regeneration at 28 days. These results enable guided development of therapeutic strategies that similarly alter muscle physiology (i.e. converting ECM-bound cytokines into freely diffusible forms as studied in cancer therapeutics or delivery of exogenous cytokines) during regeneration to enhance muscle recovery after injury.
Neural geometrodynamics, complexity, and plasticity: a psychedelics perspective
Authors: Ruffini G. , Lopez-Sola E. , Vohryzek J. , Sanchez-Todo R.
Published: August 2023

We explore the intersection of neural dynamics and the effects of psychedelics in light of distinct timescales in a framework integrating concepts from dynamics, complexity, and plasticity. We call this frameworkneural geometrodynamicsfor its parallels with general relativity’s description of the interplay of spacetime and matter. The geometry of trajectories within the dynamical landscape of “fast time” dynamics are shaped by the structure of a differential equation and its connectivity parameters, which themselves evolve over “slow time” driven by state-dependent and state-independent plasticity mechanisms. Finally, the adjustment of plasticity processes (metaplasticity) takes place in an “ultraslow” time scale. Psychedelics flatten the neural landscape, leading to heightened entropy and complexity of neural dynamics, as observed in neuroimaging and modeling studies linking increases in complexity with a disruption of functional integration. We highlight the relationship between criticality, the complexity of fast neural dynamics, and synaptic plasticity. Pathological, rigid, or “canalized” neural dynamics result in an ultrastable confined repertoire, allowing slower plastic changes to consolidate them further. However, under the influence of psychedelics, the destabilizing emergence of complex dynamics leads to a more fluid and adaptable neural state in a process that is amplified by the plasticity-enhancing effects of psychedelics. This shift manifests as an acute systemic increase of disorder and a possibly longer-lasting increase in complexity affecting both short-term dynamics and long-term plastic processes. Our framework offers a holistic perspective of the acute effects of these substances and their potential long-term impacts on neural structure and function.
Population coding of time-varying sounds in the non-lemniscal Inferior Colliculus
Authors: Shi Kaiwen , Quass Gunnar L. , Rogalla Meike M. , Ford Alexander N. , Czarny Jordyn E. , Apostolides Pierre F.
Published: August 2023

The inferior colliculus (IC) of the midbrain is important for complex sound processing, such as discriminating conspecific vocalizations and human speech. The IC’s non-lemniscal, dorsal “shell” region is likely important for this process, as neurons in these layers project to higher-order thalamic nuclei that subsequently funnel acoustic signals to the amygdala and non-primary auditory cortices; forebrain circuits important for vocalization coding in a variety of mammals, including humans. However, the extent to which shell IC neurons transmit acoustic features necessary to discern vocalizations is less clear, owing to the technical difficulty of recording from neurons in the IC’s superficial layers via traditional approaches. Here we use 2-photon Ca2+imaging in mice of either sex to test how shell IC neuron populations encode the rate and depth of amplitude modulation, important sound cues for speech perception. Most shell IC neurons were broadly tuned, with a low neurometric discrimination of amplitude modulation rate; only a subset were highly selective to specific modulation rates. Nevertheless, neural network classifier trained on fluorescence data from shell IC neuron populations accurately classified amplitude modulation rate, and decoding accuracy was only marginally reduced when highly tuned neurons were omitted from training data. Rather, classifier accuracy increased monotonically with the modulation depth of the training data, such that classifiers trained on full-depth modulated sounds had median decoding errors of ∼0.2 octaves. Thus, shell IC neurons may transmit time-varying signals via a population code, with perhaps limited reliance on the discriminative capacity of any individual neuron.

Significance Statement

The IC’s shell layers originate a “non-lemniscal” pathway whose first- and second-order targets are thought important for perceiving conspecific vocalizations and human speech. However, prior studies suggest that individual shell IC neurons are broadly tuned and have high response thresholds, implying a limited reliability of efferent signals. Here we use Ca2+imaging to test how shell IC neurons encode amplitude modulation, a key sound cue for speech perception and stream segregation. We show that the rate and depth of amplitude modulation is accurately represented in the ensemble activity of shell IC neuron populations. Thus, downstream targets can read out a sound’s temporal envelope from a distributed rate code transmitted by populations of broadly tuned neurons.
Air-Liquid Interface Induced Epithelial Delamination
Authors: Liu Chunzi , Fuller Gerald G.
Published: August 2023

Many epithelial tissues reside at air-liquid interfaces, as exemplified by the ocular epithelium, oral mucosa, and alveolar epithelium. The interfacial tension across the epithelial tissues imposes a mechanical challenge to the homeostasis of the tissue. However, the interplay between interfacial properties and homeostasis in biological samples has been overlooked due to a lack of suitable measurement methods and theoretical developments. Here we described a surprising observation in which the surface energy at cell-air interface is sufficient to delaminate a stratified ocular epithelium from its substrate. We demonstrated that the interfacial tension at the epithelium-fluid interfaces can be measured using a modified Schultz method. The measured value is conceptually and numerically distinctive to the tensile modulus measured by deformation-based methods, such as micropippeting and tissue surface tensiometers. Furthermore, a mechanical analysis at the cell-air-liquid triple line during the delamination process revealed a strain hardening behavior of the epithelial layers. Finally, perturbations on different junctional protein complexes revealed that a delicate balance among cortical tension, focal adhesion, and cell-liquid interfacial tension is required for the epithelial tissue mechanical stability.
Pre-diagnosis blood DNA methylation profiling of twin pairs discordant for breast cancer points to the importance of environmental risk
Authors: Bode Hannes Frederik , He Liang , Hjelmborg Jacob V.B. , Kaprio Jaakko , Ollikainen Miina
Published: August 2023

Background

Assessment of breast cancer (BC) risk generally relies on mammography, family history, reproductive history, and genotyping of major mutations. However, assessing the impact of environmental factors, such as lifestyle, health related behavior or external exposures, is still challenging. DNA methylation (DNAm), capturing both genetic and environmental effects, presents a promising opportunity. Previous studies have identified associations and predicted the risk of BC using DNAm in blood, however, these studies did not distinguish between genetic and environmental contributions to these DNAm sites. In this study, associations between DNAm and BC are assessed using paired twin models, which control for shared genetic and environmental effects, allowing testing for associations between DNAm and non-shared environmental exposures and behavior.

Results

Pre-diagnosis blood samples of 32 monozygotic (MZ) and 76 dizygotic (DZ) female twin pairs discordant for BC were collected at the mean age of 56.0 years, with the mean age at diagnosis 66.8 and censoring 75.2 years. We identified 212 CpGs (p<6.4*10−8) and 15 DMRs associated with BC risk across all pairs using paired Cox proportional hazard models. All but one of the BC risk associated CpGs were hypomethylated and 198/212 CpGs had their DNAm associated with BC risk independent of genetic effects. According to previous literature, at least five of the top CpGs were related to estrogen signaling. Following a comprehensive two-sample Mendelian Randomization analysis, we found evidence supporting a dual causal impact of DNAm at cg20145695 (gene body ofNXN, rs480351) with increased risk for estrogen-receptor positive BC and decreased risk for estrogen-receptor negative BC.

Conclusion

While causal effects of DNAm on BC risk are rare, most of the identified CpGs associated with the risk of BC appear to be independent of genetic effects. This suggests that DNAm could serve as a valuable biomarker for environmental risk factors for BC, and may offer potential benefits as a complementary tool to current risk assessment procedures.
Predicting appropriateness of antibiotic treatment among ICU patients with hospital acquired infection
Authors: Rannon Ella , Goldschmidt Ella , Bernstein Daniel , Wasserman Asaf , Coster Dan , Shamir Ron
Published: August 2023

Antimicrobial resistance is a growing threat to global health, leading to ineffective treatment of infection and increasing treatment failure, mortality, and healthcare costs. Inappropriate antibiotic therapy is often administered in the Intensive Care Unit (ICU) due to the urgency of treatment, but can lead to poor patient outcomes. In this study, we developed a machine learning model that predicts the appropriateness of antibiotic treatments for ICU inpatients with ICU-acquired blood infection. We analyzed data from electronic medical records (EMRs), including demographics, administered drugs, previous microbiological cultures, invasive procedures, lab measurements and vital signs. Since EMRs have high rates of missing values and since our cohort is relatively small and imbalanced, we introduced novel computational methods to address these issues. The final model achieved an AUROC of 82.8% and an AUPR of 60.6% on the training set and an AUROC score of 77.3% and an AUPR score of 40.4% on the validation set. Our study shows the potential of machine learning models for inappropriate antibiotic treatment prediction.
Left Atrial Appendage Closure in Patients with Atrial Fibrillation and Acute Ischemic Stroke Despite Anticoagulation
Authors: Abramovitz Fouks Avia , Yaghi Shadi , Selim Magdy , Gökçal Elif , Das Alvin S. , Rotschild Ofer , Silverman Scott B , Singhal Aneesh B. , Kapur Sunil , Greenberg Steven M. , Gurol M. Edip
Published: August 2023

Background

The occurrence of acute ischemic stroke (AIS) while regularly using oral anticoagulants (OAC) is an increasingly recognized problem among nonvalvular atrial fibrillation (NVAF) patients. Due to the high risk of AIS recurrence (reported 5.3-8.9 per 100 patient-years) even when the type of OAC is changed, we aimed to elucidate the potential role of left atrial appendage closure (LAAC) for prevention of recurrent strokes among AIS-despite-OAC patients.

Methods

Through retrospective review of electronic medical records of a single hospital system between January 2015 and October 2021, we collected baseline and follow-up data from consecutive NVAF patients who had AIS despite regular use of OAC per current guidelines and subsequently underwent endovascular LAAC for recurrent stroke prevention. The primary outcome measure was the occurrence of AIS after LAAC, and the safety outcome was symptomatic intracerebral hemorrhage (ICH).

Results

Twenty-nine patients had the endovascular LAAC specifically because of AIS-despite-OAC. The mean age was 73.4 ± 8.7, 13 were female (44.82%). Mean CHA2DS2-VASc score was 5.96 ± 1.32, with an expected AIS risk of 8.44 per 100 patient-years. Fourteen of the patients had two or more past AIS-despite-OAC. After LAAC, 27 patients (93.10%) were discharged on anticoagulant which was discontinued in 17 (58.62%) after transesophageal echocardiogram (TEE) at 6 weeks. Over a mean of 1.75±1.0 years follow-up after LAAC, only one patient had an AIS (incidence rate [IR] 1.97 per 100 patient-years) and one patient had a small ICH (IR 1.97 per 100 patient-years).

Conclusions

LAAC in patients who had AIS-despite-OAC demonstrated a low annual rate of recurrent AIS in our cohort (1.97%) compared both to the expected IR based on their CHA2DS2-VASc scores (8.44%) and to the recent large series of AIS-despite-OAC patients treated with OAC/aspirin only (5.3%-8.9%). These findings support randomized trials of LAAC in patients who have AIS-despite-OAC.
Machine learning model interpretations explain T cell receptor binding
Authors: Carter Brandon , Krog Jonathan , Birnbaum Michael E. , Gifford David K.
Published: August 2023

T cells mediate immune responses against pathogens and cancer through T cell receptors (TCRs) that recognize foreign peptides presented on the cell surface by Major Histocompatibility Complex (MHC) proteins. TCRs carry enormous diversity and differ across individuals, and mechanisms that determine TCR-pMHC binding are poorly understood. The ability to predict TCR-pMHC interactions would accelerate development of cellular therapeutics to design TCRs that specifically bind to a target of interest. We designed a randomized library of 196TCR CDR3βsequences and experimentally evaluated their affinities for the Tax-A02 peptide-MHC target. We trained ML models that predict TCR binding to Tax-A02 from TCR sequence and used model interpretation to identify TCR sequence features associated with binding. We found these features accurately mirror the true sequence features in our experimental data.
Longer mandible or nose? Co-evolution of feeding organs in early elephantiforms
Authors: Li Chunxiao , Deng Tao , Wang Yang , Sun Fajun , Wolff Burt , Jiangzuo Qigao , Ma Jiao , Xing Luda , Fu Jiao , Zhang Ji , Wang Shi-Qi
Published: August 2023

The long-trunked elephantids underwent a significant evolutionary stage characterized by an exceptionally elongated mandible. The initial elongation and subsequent regression of the long mandible, along with its co-evolution with the trunk, present an intriguing issue that remains incompletely understood. Through comparative functional and eco-morphological investigations, as well as feeding preference analysis, we reconstructed the feeding behavior of major groups of longirostrine elephantiforms. In thePlatybelodonclade, the rapid evolutionary changes observed in the narial region, strongly correlated with mandible and tusk characteristics, suggest a crucial evolutionary transition where feeding function shifted from the mandible to the trunk, allowing proboscideans to expand their niches to more open regions. This functional shift further resulted in elephantids relying solely on their trunks for feeding. Our research provides insights into how unique environmental pressures shape the extreme evolution of organs, particularly in large mammals that developed various peculiar adaptations during the late Cenozoic global cooling trends.
Expanding the Drosophila toolkit for dual control of gene expression
Authors: Zirin Jonathan , Jusiak Barbara , Lopes Raphael , Ewen-Campen Ben , Bosch Justin A. , Risbeck Alexandria , Forman Corey , Villalta Christians , Hu Yanhui , Perrimon Norbert
Published: August 2023

The ability to independently control gene expression in two different tissues in the same animal is emerging as a major need, especially in the context of inter-organ communication studies. This type of study is made possible by technologies combining the GAL4/UAS and a second binary expression system such as the LexA-system or QF-system. Here, we describe a resource of reagents that facilitate combined use of the GAL4/UAS and a second binary system in variousDrosophilatissues. Focusing on genes with well-characterizsed GAL4 expression patterns, we generated a set of more than 40 LexA-GAD and QF2 insertions by CRISPR knock-in and verified their tissue-specificity in larvae. We also built constructs that encode QF2 and LexA-GAD transcription factors in a single vector. Following successful integration of this construct into the fly genome, FLP/FRT recombination is used to isolate fly lines that express only QF2 or LexA-GAD. Finally, using new compatible shRNA vectors, we evaluated both LexA and QF systems forin vivogene knockdown and are generating a library of such RNAi fly lines as a community resource. Together, these LexA and QF system vectors and fly lines will provide a new set of tools for researchers who need to activate or repress two different genes in an orthogonal manner in the same animal.
Sex-specific effects of injury and beta-adrenergic activation on metabolic and inflammatory mediators in a murine model of post-traumatic osteoarthritis
Authors: Komaravolu Ravi K. , Mehta-D’souza Padmaja , Conner Taylor , Allen Madeline , Lumry Jessica , Griffin Timothy M.
Published: August 2023

Metabolic processes are intricately linked to the resolution of innate inflammation and tissue repair, two critical steps for treating post-traumatic osteoarthritis (PTOA). Here we used the β-adrenergic receptor (βAR) agonist isoproterenol as a tool to perturb intra-articular metabolism 3.5 weeks after applying a non-invasive single-load compression injury to knees of 12-week-old male and female mice. We examined the acute effects of intra-articular treatment with isoproterenol relative to saline on pain behavior, histology, multiplex gene expression, and synovial fluid metabolomics. Injured knees developed PTOA pathology characterized by heterotopic ossification, loss of tibial and femoral articular cartilage, and infrapatellar fat pad (IFP) atrophy and fibrosis. Isoproterenol modestly increased IFP atrophy and fibrosis, and it also caused sexually dimorphic and injury-dependent effects on IFP and synovium gene expression. In injured joints of female mice, isoproterenol suppressed the upregulation of pro-fibrotic genes and downregulated the expression of adipose tissue genes and pro-inflammatory genes (Adam17,Cd14,Icam1,Csf1r, andCasp1). Injury substantially altered synovial fluid metabolites by increasing amino acids, peptides, sphingolipids, phospholipids, bile acids, and dicarboxylic acids, but these changes were not appreciably altered by isoproterenol. Mechanical allodynia was also not altered by isoproterenol, although isoproterenol downregulated the expression of nociception-associated genes,NgfandTacr1,in injured IFP-synovium of female mice. Overall, these results suggest that βAR activation functions in a sexually dimorphic manner in PTOA joints. The findings support further exploration of therapeutic strategies that target neuro-metabolic signaling pathways for treating PTOA, particularly in women.
The Overexpression of AmpC is Not Required but May Contribute to Imipenem/Relebactam Non-susceptibility
Authors: Freed Shawn , Hanson Nancy D.
Published: August 2023

In the US, carbapenem resistance inPseudomonas aeruginosais strongly linked to the regulation of chromosomal resistance determinants, AmpC and OprD. The β-lactamase AmpC requires overexpression and genetic modifications to be capable of inhibiting imipenem activity. The outer membrane porin OprD can be downregulated or undergo genetic modifications that strongly correlate with imipenem non-susceptibility. Co-administration of imipenem and the β-lactamase inhibitor, relebactam, can lower imipenem MICs and restore susceptibility. However, how this occurs inP. aeruginosaisolates that do not overproduce AmpC or produce a functional OprD for imipenem entry is not understood. Therefore, we investigated whether imipenem could enterP. aeruginosain the absence of OprD and whether any of the chromosomal β-lactamases (AmpC, OXA-51, PIB-1) contributed to imipenem and/or imipenem/relebactam non-susceptibility. This investigation evaluated 17 imipenem non-susceptible clinical isolates and 3 laboratory strains of PAO1, two of which were porin deletion mutants for eitheroprDoropdP. Expression of OXA-50 and PIB-1 RNA was similar to PAO1. However, all 20 isolates exhibited AmpC induction under sub-lethal exposure to imipenem. This occurred in the absence of detectable OprD protein in 18 isolates. Collectively, our data identify that OprD is not the only channel required for imipenem entry and that in many isolates the restored susceptibility to imipenem by imipenem/relebactam was due to the interaction of relebactam on the overexpression of AmpC due to imipenem induction.