Functional molecular units for guiding biomarker panel design.

<div>AbstractPurpose:<p>To develop and validate a protein-based, multi-marker panel that provides superior pancreatic ductal adenocarcinoma (PDAC) detection abilities with sufficient diagnostic performance.</p>Experimental Design:<p>A total of 959 plasma samples from patients at multiple medical centers were used. To construct an optimal, diagnostic, multi-marker panel, we applied data preprocessing procedure to biomarker candidates. The multi-marker panel was developed using a training set comprised of 261 PDAC cases and 290 controls. Subsequent evaluations were performed in a validation set comprised of 65 PDAC cases and 72 controls. Further validation was performed in an independent set comprised of 75 PDAC cases and 47 controls.</p>Results:<p>A multi-marker panel containing 14 proteins was developed. The multi-marker panel achieved AUCs of 0.977 and 0.953 for the training set and validation set, respectively. In an independent validation set, the multi-marker panel yielded an AUC of 0.928. The diagnostic performance of the multi-marker panel showed significant improvements compared with carbohydrate antigen (CA) 19-9 alone (training set AUC = 0.977 vs. 0.872, <i>P</i> < 0.001; validation set AUC = 0.953 vs. 0.832, <i>P</i> < 0.01; independent validation set AUC = 0.928 vs. 0.771, <i>P</i> < 0.001). When the multi-marker panel and CA 19-9 were combined, the diagnostic performance of the combined panel was improved for all sets.</p>Conclusions:<p>This multi-marker panel and the combined panel showed statistically significant improvements in diagnostic performance compared with CA 19-9 alone and has the potential to complement CA 19-9 as a diagnostic marker in clinical practice.</p></div>

Alzheimer's disease (AD) remains challenging to diagnose, especially early disease. Having serum AD biomarkers would be of significant interest both in the clinical setting and in drug development efforts. We applied a novel serum proteomic approach to interrogate the low-molecular weight proteome for serum AD biomarkers. A discovery study used sera from 58 any-stage AD cases and 55 matched controls analyzed by capillary liquid chromatography-electrospray ionization-tandem mass spectrometry. Candidate biomarkers were statistically modeled and promising biomarkers were retested in a second, blinded confirmatory study (AD cases = 68, controls = 57). Biomarkers that replicated in the second study were modeled for the diagnosis of any-stage and very early stage AD. Further, they were chemically identified by tandem MS. The initial discovery study found 59 novel potential AD biomarkers. Thirteen recurred in more than one multi-marker panel. In a second, blinded, confirmatory study, these same biomarkers were retested in separate specimens. In that study, four markers validated comparing controls to patients with any-stage AD and also with very early AD. The four biomarkers with replicable ability to diagnose AD were then chemically identified. These results suggest novel serum AD diagnostic biomarkers can be found using this approach.

Inducible nitric oxide synthase (iNOS) is a key mediator of inflammation during pathological conditions. We examined, through the use of selective iNOS inhibitors, the role of iNOS in specific pathophysiological processes after spinal cord injury (SCI), including astrogliosis, blood-spinal cord barrier (BSCB) permeability, polymorphonuclear leukocyte infiltration, and neuronal cell death. Administration of iNOS antisense oligonucleotides (ASOs) (intraspinally at 3 h) or the pharmacological inhibitors, N-[3(Aminomethyl) benzyl] acetamidine (1400 W) (i.v./i.p. 3 and 9 h) or aminoguanidine (i.p. at 3 and 9 h) after moderate contusive injury decreased the number of iNOS immunoreactive cells at the injury site by 65.6% (iNOS ASOs), 62.1% (1400 W), or 59% (aminoguanidine) 24 h postinjury. iNOS activity was reduced 81.8% (iNOS ASOs), 56.7% (1400 W), or 67.9% (aminoguanidine) at this time. All iNOS inhibitors reduced the degree of BSCB disruption (plasma leakage of rat immunoglobulins), with iNOS ASO inhibition being more effective (reduced by 58%). Neutrophil accumulation within the injury site was significantly reduced by iNOS ASOs and 1400 W by 78.8% and 20.9%, respectively. Increased astrogliosis was diminished with iNOS ASOs but enhanced following aminoguanidine. Detection of necrotic and apoptotic neuronal cell death by propidium iodide and an FITC-conjugated Annexin V antibody showed that iNOS inhibition could significantly retard neuronal cell death rostral and caudal to the injury site. These novel findings indicate that acute inhibition of iNOS is beneficial in reducing several pathophysiological processes after SCI. Furthermore, we demonstrate that the antisense inhibition of iNOS is more efficacious than currently available pharmacological agents.

Accurate quantification of Young's modulus in biological tissues enhances clinical accuracy in disease diagnosis, therapy, and prevention. Nevertheless, real-time, intraoperative measurement of Young's modulus in organs remains technically challenging. We propose a novel in situ tissue elasticity assessment method based on the principles of the rebound process, where a magnetized probe is used to impact the target tissue, and Young's modulus is calculated based on how quickly the probe rebounds. The proposed method was validated through a theoretical mechanical model and simulation. The measurement accuracy was verified by replicated measurements across different specimens. A portable handheld device was then developed and deployed for clinical feasibility validation in live animal models. Results demonstrate that the proposed method delivers accurate and reliable measurements. The proposed system offers a novel solution for Young's modulus measurement, which can be used for intraoperative conditions such as lesion assessment during hepatectomy and breast-conserving surgery.

Contribution of Red Blood Cell Derived Extracellular Vesicles to Sickle Red Blood Cell Adhesion Discerned Using an Endothelialized Microfluidic Assay

Airway remodeling is a pathophysiologic process at the clinical, cellular, and molecular level relating to chronic obstructive airway diseases such as chronic obstructive pulmonary disease (COPD), asthma and mustard lung. These diseases are associated with the dysregulation of multiple molecular pathways in the airway cells. Little progress has so far been made in discovering the molecular causes of complex disease in a holistic systems manner. Therefore, pathway and network reconstruction is an essential part of a systems biology approach to solve this challenging problem. In this paper, multiple data sources were used to construct the molecular process of airway remodeling pathway in mustard lung as a model of airway disease. We first compiled a master list of genes that change with airway remodeling in the mustard lung disease and then reconstructed the pathway by generating and merging the protein-protein interaction and the gene regulatory networks. Experimental observations and literature mining were used to identify and validate the master list. The outcome of this paper can provide valuable information about closely related chronic obstructive airway diseases which are of great importance for biologists and their future research. Reconstructing the airway remodeling interactome provides a starting point and reference for the future experimental study of mustard lung, and further analysis and development of these maps will be critical to understanding airway diseases in patients.

BackgroundPhelan-McDermid syndrome (PMS) is a rare multisystem disease with global developmental delay and autistic features. Genetically, the disease is based on a heterozygous deletion of chromosome 22q13.3 with involvement of at least part of the SHANK3 gene or heterozygous pathogenic variants in SHANK3. Pathophysiologically, this syndrome has been regarded as a synaptopathy, but current data suggest an additional concept, since axonal functions of neurons are also impaired, thus, the specific pathophysiological processes in this disease are not yet fully understood. Since symptoms of the autism spectrum, regression, and stagnation in development occur, we investigated whether neuroinflammatory and neurodegenerative processes may also play a role. To this end, we analysed biomarkers in cerebrospinal fluid (CSF) and parameters from magnetic resonance imaging with high-resolution structural T1w volumetry and diffusion tensor imaging analysis in 19 Phelan-McDermid syndrome patients.ResultsCSF showed no inflammation but abnormalities in tau protein and amyloid-ß concentrations, however, with no typical biomarker pattern as in Alzheimer’s disease. It could be demonstrated that these CSF changes were correlated with integrity losses of the fibres in the corticospinal tract as well as in the splenium and dorsal part of the cingulum. High CSF levels of tau protein were associated with loss of integrity of fibres in the corticospinal tract; lower levels of amyloid-ß were associated with decreasing integrity of fibre tracts of the splenium and posterior cingulate gyrus. Volumetric investigations showed global atrophy of the white matter, but not the grey matter, and particularly not in temporal or mesiotemporal regions, as is typical in later stages of Alzheimer’s disease.ConclusionsIn summary, alterations of neurodegenerative CSF markers in PMS individuals could be demonstrated which were correlated with structural connectivity losses of the corticospinal tract, the splenium, and the dorsal part of the cingulum, which can also be associated with typical clinical symptoms in these patients. These findings might represent a state of dysfunctional processes with ongoing degenerative and regenerative processes or a kind of accelerated aging. This study should foster further clinical diagnostics like tau- and amyloid-PET imaging as well as novel scientific approaches especially in basic research for further mechanistic proof.

First described in 1853 [1], the Morel-Lavallee lesion is a closed, post-traumatic, soft tissue degloving injury [1–3], characterized by an accumulation of blood, lymph, and other breakdown products between the subcutaneous tissue and underlying fascia [4] (Fig. 1). It is due to shearing stress with disruption of perforating blood vessels and the creation of potential spaces. Morel-Lavallee is most commonly associated with pelvic and acetabular fractures, but it may also occur at various locations [4]; the lesion has been reported occurring over the flank, buttock, lumbar spine, scapula, knee, and elsewhere. Fig. 1 Morel-Lavallee lesion. Morel-Lavallee lesion is a post-traumatic injury characterized by an accumulation of fluid (arrows) between subcutaneous tissue and underlying fascia Clinical presentation of the lesion is pain, swelling, and stiffness at the site of injury. Upon examination, there is an area of tissue swelling that is soft to palpation [4]. Radiological investigations, especially ultrasound imaging and magnetic resonance imaging, are highly valued in the traumatic pathology of soft tissue [5] and so for the diagnosis of this condition [6]. The sonographic appearance is characterized by acute lesions that tend to be heterogeneous and lobular, with irregular margins. The chronic lesions are anechoic with well-defined margins, separating the subcutaneous tissue from the underlying fascia [7, 8]. Additionally, the magnetic resonance imaging appearance depends on the age and amount of blood, fat, and lymph [9]. The differential diagnosis is with muscle and soft tissue hematomas and with bursitis [10], more rarely with neoplasms. There is a lack of consensus regarding the management of these lesions, including non-operative therapies and operative techniques [11–13]. An 18-year-old male presented with left medial knee pain and swelling, 26 days following an injury occurred while playing soccer. Clinical examination showed a fluctuant swelling on the medial aspect of the right knee, without any surrounding cutaneous laceration or edema. Ultrasound of the medial aspect of the right knee, using a linear transducer at 18 MHz (Fig. 1), showed a longitudinal homogenous fluid lesion, located between the subcutaneous tissue and muscle (Morel-Lavallee lesion) (Fig. 2). Magnetic resonance imaging of the lesion (Fig. 3) confirmed, on the medial aspect of the right knee, the presence of a homogenous collection of fluid, between the subcutaneous tissue and the underlying muscle. A conservative approach to treatment was preferred. After 3 months of simple resting of the knee, no significant effusion could be appreciated on sonographic examination. The patient is currently asymptomatic. Fig. 2 Morel-Lavallee lesion. Extended field-of-view sonograms a, b shows a fusiform homogeneous anechoic fluid collection (arrows) with smooth margins, located between subcutaneous tissue and muscle Fig. 3 Morel-Lavallee lesion. Axial and sagittal proton density fat suppressed images confirm the presence of fluid collection (arrows) with smooth margins, located between subcutaneous tissue and muscle Morel-Lavallee lesions [1] are rare but should be suspected in high inertia trauma of the knee, commonly developing secondarily to blunt trauma separation of subcutaneous tissue from the underlying fascia. The diagnosis remains primarily a clinical diagnosis [2], but there is a wide range of differential diagnoses, including hematomas, abscesses, bursitis, fat necrosis, and neoplasms; particularly, the clinical presentation of a post-traumatic hematoma and an acute Morel-Lavallee lesion are similar. Ultrasound and MRI must be used to confirm the diagnosis [2, 4] and for the differential diagnosis. The sonographic and magnetic resonance imaging characteristics of Morel-Lavallee lesions are variable: lesions less than 1 month of age tend to be heterogeneous and irregularly marginated. When they evolve, they became more regularly marginated and homogeneous, but only the anatomic features are typical: a fluid lesion, located between subcutaneous tissue and muscle [6, 8]. The Morel-Lavallee lesion has a specific anatomic location and pathophysiological process that make it more prone to complications and chronicity. No clear best management is known, but the options can be narrowed based on location, age, and size of the lesion [2].

Non-alcoholic fatty liver disease: Not time for an obituary just yet!

Introduction The number of autoptic controls is progressively dropping worldwide during the last decades. Several social, cultural and normative causes may underlie this phenomenon. However, a hidden cause may be represented by the scepticism of physicians about the gain in information given by this practice. There is in fact a general thinking that available diagnostic techniques may be adequate for a correct diagnosis, even in the case of a mortal outcome. Nevertheless, several studies have shown quite relevant discrepancies between premortem and postmortem diagnosis. In this study, the authors evaluate the accuracy of clinical diagnosis in diseases leading the patient to death.Materials and methods Retrospective analysis including all patients died in the Department of Internal Medicine of a General Hospital in Rome during a three year time period (1st January 2007–31 December 2009). Age, sex, period of hospitalization, clinical diagnosis, autoptic diagnosis, cause of death, and level of discrepancy between clinical diagnosis and autoptic control have been collected. Main diagnoses have been classified as follows: (1) discrepancy with a possible influence on survival; (2) discrepancy with no or questionable influence on survival.Results Ninety-two cases (42 males, 50 females; mean age 79.3 years) have been included. Thirty-four main diagnoses (36.9%) have been classified as discrepant (15.2% classified as type 1 discrepancy and 21.7 as type 2).DiscussionA substantial discrepancy between clinical diagnosis and autoptic control is confirmed by the current study, which supports the role of autopsy as a tool for the improvement of medical practice.

Currently there is no single biomarker or panel of markers which is diagnostic of IBD generally, or CD and UC specifically. Diagnosis of IBD still requires radiographic, endoscopic, and microscopic examination. Since GI markers of inflammation are continuously being uncovered, and given that statistical power can be enhanced with multi-marker panels, we are hopeful that the medical laboratory will have the ability, in the near future, to support a non-invasive diagnosis of an inflammatory bowel disease.

The key signaling pathways in cellular processes involve protein-protein interactions (PPIs). A perturbation in the balance of PPIs occurs in various pathophysiological processes. There are a large numbers of experimental methods for detection of PPIs. However, experimental PPI determination is time consuming, expensive, error prone and does not effectively cover transient interactions. Therefore, overlaying and integration of predictive methods with experimental results provides statistical robustness and biological significance to the PPI data. In this chapter, the authors describe PPIs in terms of types, importance, and biological consequences. This chapter also provides a comprehensive description on various computational approaches for PPI prediction. Prediction of PPI can be done through: 1) Genomic information based methods 2) Structure based methods 3) Network topology based methods: 4) Literature and data mining based methods 5) Machine learning methods. For ease of use and convenience, a summary of various databases and software for PPI prediction has been provided.

BACKGROUND Although the implementation process of digital health technologies (DHTs) has been extensively documented in high-income countries, the factors that facilitate and prevent their implementation in lower- and middle-income countries (LMICs) may differ for various reasons. OBJECTIVE To address this gap in research, this scoping review aims to determine the facilitators and barriers to implementing DHTs in LMIC hospital settings following the onset of the COVID-19 pandemic. Additionally, the review outlined the types of DHTs that have been implemented in LMICs’ hospitals during this pandemic and finally developed a classification framework to categorize the landscape of DHTs. METHODS Systematic searches were conducted on PubMed, Scopus, Web of Science, and Google Scholar for studies published from March 2020 to December 2023. We extracted data on authors, publication years, study objectives, study countries, disease conditions, types of DHTs, fields of clinical medicine where the DHTs are applied, study designs, sample sizes, characteristics of the study population, study location, and data collection methods of the included studies. Both quantitative and qualitative data were utilized to conduct a thematic analysis, using a deductive method based on the Practical, Robust Implementation and Sustainability Model (PRISM), to identify facilitators and barriers to DHT implementation. Finally, all accessible DHTs were identified and organized to create a novel classification framework. RESULTS Twelve studies were included from 292 retrieved articles. Telemedicine (n=5) was the most commonly used DHT in LMICs’ hospitals, followed by hospital information systems (n=4), electronic medical records (n=2), and mobile health (n=1). These 4 DHTs, among the other existing DHTs, allowed us to develop a novel classification framework for DHTs. The included studies used qualitative methods (n=4), which included interviews and focus groups, quantitative methods (n=5), or a combination of both (n=2). Among the 64 facilitators of DHT implementation, the availability of continuous on-the-job training (n=3), the ability of DHTs to prevent cross-infection (n=2), and positive previous experiences using DHTs (n=2) were the top 3 reported facilitators. However, of the 44 barriers to DHT implementation, patients with poor digital literacy and skills in DHTs (n=3), inadequate awareness regarding DHTs among health care professionals and stakeholders (n=2), and concerns regarding the accuracy of disease diagnosis and treatment through DHTs (n=2) were commonly reported. CONCLUSIONS In the postpandemic era, telemedicine, along with other DHTs, has seen increased implementation in hospitals within LMICs. All facilitators and barriers can be categorized into 6 themes, namely, (1) Aspects of the Health Care System; (2) Perspectives of Patients; (3) External Environment; (4) Implementation of Sustainable Infrastructure; (5) Characteristics of Health Care Organization; and (6) Characteristics of Patients.

Advanced diagnostic methods in oral and maxillofacial pathology. Part II: immunohistochemical and immunofluorescent methods.

Biomarkers in Lupus Nephritis