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Bioengineering (Basel, Switzerland) Mar 2024Chest X-ray (CXR) examination serves as a widely employed clinical test in medical diagnostics. Many studied have tried to apply artificial intelligence (AI) programs to...
Chest X-ray (CXR) examination serves as a widely employed clinical test in medical diagnostics. Many studied have tried to apply artificial intelligence (AI) programs to analyze CXR images. Despite numerous positive outcomes, assessing the applicability of AI models for comprehensive diagnostic support remains a formidable challenge. We observed that, even when AI models exhibit high accuracy on one dataset, their performance may deteriorate when tested on another. To address this issue, we propose incorporating a variational information bottleneck (VIB) at the patch level to enhance the generalizability of diagnostic support models. The VIB introduces a probabilistic model aimed at approximating the posterior distribution of latent variables given input data, thereby enhancing the model's generalization capabilities on unseen data. Unlike the conventional VIB approaches that flatten features and use a re-parameterization trick to sample a new latent feature, our method applies the trick to 2D feature maps. This design allows only important pixels to respond, and the model will select important patches in an image. Moreover, the proposed patch-level VIB seamlessly integrates with various convolutional neural networks, offering a versatile solution to improve performance. Experimental results illustrate enhanced accuracy in standard experiment settings. In addition, the method shows robust improvement when training and testing on different datasets.
PubMed: 38671737
DOI: 10.3390/bioengineering11040316 -
ELife Apr 2024Primates can recognize objects despite 3D geometric variations such as in-depth rotations. The computational mechanisms that give rise to such invariances are yet to be...
Primates can recognize objects despite 3D geometric variations such as in-depth rotations. The computational mechanisms that give rise to such invariances are yet to be fully understood. A curious case of partial invariance occurs in the macaque face-patch AL and in fully connected layers of deep convolutional networks in which neurons respond similarly to mirror-symmetric views (e.g. left and right profiles). Why does this tuning develop? Here, we propose a simple learning-driven explanation for mirror-symmetric viewpoint tuning. We show that mirror-symmetric viewpoint tuning for faces emerges in the fully connected layers of convolutional deep neural networks trained on object recognition tasks, even when the training dataset does not include faces. First, using 3D objects rendered from multiple views as test stimuli, we demonstrate that mirror-symmetric viewpoint tuning in convolutional neural network models is not unique to faces: it emerges for multiple object categories with bilateral symmetry. Second, we show why this invariance emerges in the models. Learning to discriminate among bilaterally symmetric object categories induces reflection-equivariant intermediate representations. AL-like mirror-symmetric tuning is achieved when such equivariant responses are spatially pooled by downstream units with sufficiently large receptive fields. These results explain how mirror-symmetric viewpoint tuning can emerge in neural networks, providing a theory of how they might emerge in the primate brain. Our theory predicts that mirror-symmetric viewpoint tuning can emerge as a consequence of exposure to bilaterally symmetric objects beyond the category of faces, and that it can generalize beyond previously experienced object categories.
Topics: Animals; Neural Networks, Computer; Brain; Neurons; Macaca; Models, Neurological; Macaca mulatta
PubMed: 38661128
DOI: 10.7554/eLife.90256 -
Italian Journal of Dermatology and... Apr 2024Allergic contact dermatitis (ACD) is a common inflammatory skin disease caused by delayed hypersensitivity to chemical and biotic contact allergens. ACD significantly...
Allergic contact dermatitis (ACD) is a common inflammatory skin disease caused by delayed hypersensitivity to chemical and biotic contact allergens. ACD significantly affects the patients' quality of life negatively impacting both occupational and non-occupational settings. Patch testing is the gold standard diagnostic in vivo test to precise the ACD etiology and to correctly perform prevention. According to the Italian Medicines Agency (AIFA) legislative decree no. 178 of 29 May 1991, allergens are defined as medicines and therefore they are subject to strict regulation. In 2017, AIFA (decree no. 2130/2017) started a procedure to regulate contact allergens on the Italian market and actually the contact allergens temporarily authorized are reported in AIFA decree no. 98/2022, valid until November 2023. The availability on the market of contact allergens to diagnose ACD and continuous updating on the basis of new epidemiological trends are mandatory, jointly with the continuous update of the baseline and integrative series for patch testing. For this reason, the scientific community represented in Italy by the Skin Allergies Study Group of SIDeMaST (Italian Society of Dermatology and Venereology) and SIDAPA (Italian Society of Allergological, Occupational and Environmental Dermatology) are constantly working, in close relationship with the European scientific communities with large expertise in this important sector of the modern Dermatology. Herein, we report the setting up of regulatory legislation by AIFA and the new Italian Adult Baseline Series for patch testing.
Topics: Italy; Patch Tests; Humans; Dermatitis, Allergic Contact; Allergens
PubMed: 38650492
DOI: 10.23736/S2784-8671.24.07733-8 -
Chemosphere Jun 2024Alkylated polycyclic aromatic hydrocarbons are abundant in crude oil and are enriched during petroleum refinement but knowledge of their cardiotoxicity remains limited....
Alkylated polycyclic aromatic hydrocarbons are abundant in crude oil and are enriched during petroleum refinement but knowledge of their cardiotoxicity remains limited. Polycyclic aromatic hydrocarbons (PAHs) are considered the main hazardous components in crude oil and the tricyclic PAH phenanthrene has been singled out for its direct effects on cardiac tissue in mammals and fish. Here we test the impact of the monomethylated phenanthrene, 3-methylphenanthrene (3-MP), on the contractile and electrical function of the atrium and ventricle of a polar fish, the navaga cod (Eleginus nawaga). Using patch-clamp electrophysiology in atrial and ventricular cardiomyocytes we show that 3-MP is a potent inhibitor of the delayed rectifier current I (IC50 = 0.25 μM) and prolongs ventricular action potential duration. Unlike the parent compound phenanthrene, 3-MP did not reduce the amplitude of the L-type Ca current (I) but it accelerated current inactivation thus reducing charge transfer across the myocyte membrane and compromising pressure development of the whole heart. 3-MP was a potent inhibitor (IC50 = 4.7 μM) of the sodium current (I), slowing the upstroke of the action potential in isolated cells, slowing conduction velocity across the atrium measured with optical mapping, and increasing atrio-ventricular delay in a working whole heart preparation. Together, these findings reveal the strong cardiotoxic potential of this phenanthrene derivative on the fish heart. As 3-MP and other alkylated phenanthrenes comprise a large fraction of the PAHs in crude oil mixtures, these findings are worrisome for Arctic species facing increasing incidence of spills and leaks from the petroleum industry. 3-MP is also a major component of polluted air but is not routinely measured. This is also of concern if the hearts of humans and other terrestrial animals respond to this PAH in a similar manner to fish.
Topics: Animals; Phenanthrenes; Myocytes, Cardiac; Heart; Action Potentials; Water Pollutants, Chemical; Polycyclic Aromatic Hydrocarbons; Perciformes
PubMed: 38643846
DOI: 10.1016/j.chemosphere.2024.142089 -
Biological Procedures Online Apr 2024Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response...
BACKGROUND
Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC.
METHODS
This retrospective study analyzed 337 ESCC resection specimens from 2020-2021 at the Pudong-Branch (Cohort 1) and 114 from 2021-2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations.
RESULTS
The approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment.
CONCLUSION
This work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption (Code and data will be available at https://github.com/WinnieLaugh/ESCC_Percentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhance the efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions.
PubMed: 38632527
DOI: 10.1186/s12575-024-00234-5 -
Drug Design, Development and Therapy 2024Intravenous regional anesthesia (IVRA) using lidocaine provides effective localized analgesia but its duration is limited. The mechanism by which dexmedetomidine...
PURPOSE
Intravenous regional anesthesia (IVRA) using lidocaine provides effective localized analgesia but its duration is limited. The mechanism by which dexmedetomidine enhances lidocaine IVRA is unclear but may involve modulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.
MATERIALS AND METHODS
Lidocaine IVRA with varying dexmedetomidine concentrations was performed in the tails of Sprague-Dawley rats. Tail-flick and tail-clamping tests assessed IVRA analgesia and anesthesia efficacy and duration. Contributions of α adrenergic receptors and HCN channels were evaluated by incorporating an α adrenergic receptor antagonist, the HCN channel inhibitor ZD7288, and the HCN channel agonist forskolin. Furthermore, whole-cell patch clamp electrophysiology quantified the effects of dexmedetomidine on HCN channels mediating hyperpolarization-activated cation current (I) in isolated dorsal root ganglion neurons.
RESULTS
Dexmedetomidine dose-dependently extended lidocaine IVRA duration and analgesia, unaffected by α receptor blockade. The HCN channel inhibitor ZD7288 also prolonged lidocaine IVRA effects, while the HCN channel activator forskolin shortened effects. In dorsal root ganglion neurons, dexmedetomidine concentration-dependently inhibited I amplitude and shifted the voltage-dependence of HCN channel activation.
CONCLUSION
Dexmedetomidine prolongs lidocaine IVRA duration by directly inhibiting HCN channel activity, independent of α adrenergic receptor activation. This HCN channel inhibition represents a novel mechanism underlying the anesthetic and analgesic adjuvant effects of dexmedetomidine in IVRA.
Topics: Rats; Animals; Lidocaine; Dexmedetomidine; Rats, Sprague-Dawley; Colforsin; Anesthesia, Conduction; Cations
PubMed: 38618283
DOI: 10.2147/DDDT.S450971 -
CNS Neuroscience & Therapeutics Apr 2024We aimed to evaluate the potential of a novel selective α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator, LT-102, in treating...
Novel α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator LT-102: A promising therapeutic agent for treating cognitive impairment associated with schizophrenia.
AIMS
We aimed to evaluate the potential of a novel selective α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator, LT-102, in treating cognitive impairments associated with schizophrenia (CIAS) and elucidating its mechanism of action.
METHODS
The activity of LT-102 was examined by Ca influx assays and patch-clamp in rat primary hippocampal neurons. The structure of the complex was determined by X-ray crystallography. The selectivity of LT-102 was evaluated by hERG tail current recording and kinase-inhibition assays. The electrophysiological characterization of LT-102 was characterized by patch-clamp recording in mouse hippocampal slices. The expression and phosphorylation levels of proteins were examined by Western blotting. Cognitive function was assessed using the Morris water maze and novel object recognition tests.
RESULTS
LT-102 is a novel and selective AMPAR potentiator with little agonistic effect, which binds to the allosteric site formed by the intradimer interface of AMPAR's GluA2 subunit. Treatment with LT-102 facilitated long-term potentiation in mouse hippocampal slices and reversed cognitive deficits in a phencyclidine-induced mouse model. Additionally, LT-102 treatment increased the protein level of brain-derived neurotrophic factor and the phosphorylation of GluA1 in primary neurons and hippocampal tissues.
CONCLUSION
We conclude that LT-102 ameliorates cognitive impairments in a phencyclidine-induced model of schizophrenia by enhancing synaptic function, which could make it a potential therapeutic candidate for CIAS.
Topics: Animals; Mice; Rats; Phencyclidine; Schizophrenia; Cognitive Dysfunction; Isoxazoles; Propionates
PubMed: 38615362
DOI: 10.1111/cns.14713 -
Nanomaterials (Basel, Switzerland) Mar 2024Tympanic membrane (TM) perforations, primarily induced by middle ear infections, the introduction of foreign objects into the ear, and acoustic trauma, lead to hearing...
Tympanic membrane (TM) perforations, primarily induced by middle ear infections, the introduction of foreign objects into the ear, and acoustic trauma, lead to hearing abnormalities and ear infections. We describe the design and fabrication of a novel composite patch containing photocrosslinkable gelatin methacryloyl (GelMA) and keratin methacryloyl (KerMA) hydrogels. GelMA-KerMA patches containing conical microneedles in their design were developed using the digital light processing (DLP) 3D printing approach. Following this, the patches were biofunctionalized by applying a coaxial coating with PVA nanoparticles loaded with gentamicin (GEN) and fibroblast growth factor (FGF-2) with the Electrohydrodynamic Atomization (EHDA) method. The developed nanoparticle-coated 3D-printed patches were evaluated in terms of their chemical, morphological, mechanical, swelling, and degradation behavior. In addition, the GEN and FGF-2 release profiles, antimicrobial properties, and biocompatibility of the patches were examined in vitro. The morphological assessment verified the successful fabrication and nanoparticle coating of the 3D-printed GelMA-KerMA patches. The outcomes of antibacterial tests demonstrated that GEN@PVA/GelMA-KerMA patches exhibited substantial antibacterial efficacy against , , and . Furthermore, cell culture studies revealed that GelMA-KerMA patches were biocompatible with human adipose-derived mesenchymal stem cells (hADMSC) and supported cell attachment and proliferation without any cytotoxicity. These findings indicated that biofunctional 3D-printed GelMA-KerMA patches have the potential to be a promising therapeutic approach for addressing TM perforations.
PubMed: 38607098
DOI: 10.3390/nano14070563 -
Alzheimer's & Dementia : the Journal of... May 2024Cognitive decline progresses with age, and Nr4a1 has been shown to participate in memory functions. However, the relationship between age-related Nr4a1 reduction and...
INTRODUCTION
Cognitive decline progresses with age, and Nr4a1 has been shown to participate in memory functions. However, the relationship between age-related Nr4a1 reduction and cognitive decline is undefined.
METHODS
Nr4a1 expressions were evaluated by quantitative PCR and immunochemical approaches. The cognition of mice was examined by multiple behavioral tests. Patch-clamp experiments were conducted to investigate the synaptic function.
RESULTS
NR4A1 in peripheral blood mononuclear cells decreased with age in humans. In the mouse brain, age-dependent Nr4a1 reduction occurred in the hippocampal CA1. Deleting Nr4a1 in CA1 pyramidal neurons (PyrNs) led to the impairment of cognition and excitatory synaptic function. Mechanistically, Nr4a1 enhanced TrkB expression via binding to its promoter. Blocking TrkB compromised the cognitive amelioration with Nr4a1-overexpression in CA1 PyrNs.
DISCUSSION
Our results elucidate the mechanism of Nr4a1-dependent TrkB regulation in cognition and synaptic function, indicating that Nr4a1 is a target for the treatment of cognitive decline.
HIGHLIGHTS
Nr4a1 is reduced in PBMCs and CA1 PyrNs with aging. Nr4a1 ablation in CA1 PyrNs impaired cognition and excitatory synaptic function. Nr4a1 overexpression in CA1 PyrNs ameliorated cognitive impairment of aged mice. Nr4a1 bound to TrkB promoter to enhance transcription. Blocking TrkB function compromised Nr4a1-induced cognitive improvement.
Topics: Animals; Cognitive Dysfunction; Nuclear Receptor Subfamily 4, Group A, Member 1; Mice; Humans; Aging; Male; CA1 Region, Hippocampal; Pyramidal Cells; Receptor, trkB; Leukocytes, Mononuclear; Aged; Female; Mice, Inbred C57BL
PubMed: 38605605
DOI: 10.1002/alz.13819 -
The World Allergy Organization Journal Apr 2024There are limited data regarding the characteristics and management of drug hypersensitivity reactions (DHR) in hospitalized children. This study aims to determine the...
INTRODUCTION
There are limited data regarding the characteristics and management of drug hypersensitivity reactions (DHR) in hospitalized children. This study aims to determine the prevalence, clinical features, and management of DHRs in pediatric inpatients.
METHODS
Children who had pediatric allergy consultation for suspected DHR during hospitalization in Ankara Bilkent City Hospital between August 1, 2020, and July 30, 2021, were included. Patient and reaction characteristics, culprit drugs, and management strategies were recorded. When possible, diagnostic tests (skin or provocation tests) were performed after discharge.
RESULTS
Among the 14,090 hospitalized children, 165 (72% male, median age: 106 months) underwent consultation for 192 suspected DHRs with 246 drugs. Cutaneous eruptions were the most common (94.3%). There was anaphylaxis in 40 patients and severe cutaneous adverse drug reaction in 4 patients (drug rash with eosinophilia and systemic symptoms in 3, acute generalized exanthematous pustulosis in 1). Antimicrobials were the leading cause (78.4%, n = 193/246). In 48 reactions, 60 (24%) culprit drugs could be readministered with close follow-up or desensitization (n = 12). In total, 186 suspected drugs were discontinued, and 115 were replaced with alternative drugs. After discharge, 38 provocation tests (2 positives) and 36 skin tests (1 positive prick test, 1 positive intradermal test, and 1 positive patch test) were performed.
DISCUSSION/CONCLUSIONS
The incidence of suspected DHR among pediatric inpatients was approximately 1.1%. Skin symptoms were the most common manifestation. Twenty-four percent of suspected drugs could be continued during hospitalization. Patients with DHR during hospitalization should be evaluated with a drug allergy work-up unless there are contraindications to testing.
PubMed: 38601275
DOI: 10.1016/j.waojou.2024.100893