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This article introduces distance-based paper analytical devices (dPADs) integrated with molecularly imprinted polymers (MIPs) and carbon dots (CDs) for simultaneous quantification of cytokine biomarkers, namely C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-a), and interleukin-6 (IL-6) in human biological samples for diagnosis of cytokine syndrome. Using fluorescent CDs and MIP technology, the dPAD exhibits high selectivity and sensitivity. Detection is based on fluorescence quenching of CDs achieved through the interaction of the target analytes with the MIP layer on the paper substrate. Quantitative analysis is easily accomplished by measuring the distance length of quenched fluorescence with a traditional ruler and naked eye readout enabling rapid diagnosis of cytokine syndrome and the underlying infection. Our sensor demonstrated linear ranges of 2.50-24.0 pg mL-1 (R2 = 0.9974), 0.25-3.20 pg mL-1 (R2 = 0.9985), and 1.50-16.0 pg mL-1 (R2 = 0.9966) with detection limits (LODs) of 2.50, 0.25, and 1.50 pg mL-1 for CRP, TNF-a, and IL-6, respectively. This sensor also demonstrated remarkable selectivity compared to a sensor employing a non-imprinted polymer (NIP), and precision with the highest relative standard deviation (RSD) of 5.14%. The sensor is more accessible compared to prior methods relying on expensive reagents and instruments and complex fabrication methods. Furthermore, the assay provided notable accuracy for monitoring these biomarkers in various human samples with recovery percentages ranging between 99.22% and 103.58%. By integrating microfluidic systems, nanosensing, and MIPs technology, our developed dPADs hold significant potential as a cost-effective and user-friendly analytical method for point-of-care diagnostics (POC) of cytokine-related disorders. This concept can be further extended to developing diagnostic devices for other biomarkers. [ABSTRACT FROM AUTHOR]

Epidemiological studies have explored the relationship between allergic diseases and cancer risk or prognosis in AllergoOncology. Some studies suggest an inverse association, but uncertainties remain, including in IgE‐mediated diseases and glioma. Allergic disease stems from a Th2‐biased immune response to allergens in predisposed atopic individuals. Allergic disorders vary in phenotype, genotype and endotype, affecting their pathophysiology. Beyond clinical manifestation and commonly used clinical markers, there is ongoing research to identify novel biomarkers for allergy diagnosis, monitoring, severity assessment and treatment. Gliomas, the most common and diverse brain tumours, have in parallel undergone changes in classification over time, with specific molecular biomarkers defining glioma subtypes. Gliomas exhibit a complex tumour‐immune interphase and distinct immune microenvironment features. Immunotherapy and targeted therapy hold promise for primary brain tumour treatment, but require more specific and effective approaches. Animal studies indicate allergic airway inflammation may delay glioma progression. This collaborative European Academy of Allergy and Clinical Immunology (EAACI) and European Association of Neuro‐Oncology (EANO) Position Paper summarizes recent advances and emerging biomarkers for refined allergy and adult‐type diffuse glioma classification to inform future epidemiological and clinical studies. Future research is needed to enhance our understanding of immune–glioma interactions to ultimately improve patient prognosis and survival. [ABSTRACT FROM AUTHOR]

Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies. Patients with IMCAs develop cerebellar symptoms, characterized mainly by gait ataxia, showing an acute or subacute clinical course. We present a novel concept of latent autoimmune cerebellar ataxia (LACA), analogous to latent autoimmune diabetes in adults (LADA). LADA is a slowly progressive form of autoimmune diabetes where patients are often initially diagnosed with type 2 diabetes. The sole biomarker (serum anti-GAD antibody) is not always present or can fluctuate. However, the disease progresses to pancreatic beta-cell failure and insulin dependency within about 5 years. Due to the unclear autoimmune profile, clinicians often struggle to reach an early diagnosis during the period when insulin production is not severely compromised. LACA is also characterized by a slowly progressive course, lack of obvious autoimmune background, and difficulties in reaching a diagnosis in the absence of clear markers for IMCAs. The authors discuss two aspects of LACA: (1) the not manifestly evident autoimmunity and (2) the prodromal stage of IMCA's characterized by a period of partial neuronal dysfunction where non-specific symptoms may occur. In order to achieve an early intervention and prevent cell death in the cerebellum, identification of the time-window before irreversible neuronal loss is critical. LACA occurs during this time-window when possible preservation of neural plasticity exists. Efforts should be devoted to the early identification of biological, neurophysiological, neuropsychological, morphological (brain morphometry), and multimodal biomarkers allowing early diagnosis and therapeutic intervention and to avoid irreversible neuronal loss. [ABSTRACT FROM AUTHOR]

Background: Uterine fibroids are benign monoclonal tumors originating from the smooth muscle cells of the myometrium, constituting the most prevalent pathology within the female genital tract. Uterine sarcomas, although rare, still represent a diagnostic challenge and should be managed in centers with adequate expertise in gynecological oncology. Objectives: This article is aimed to summarize and discuss cutting-edge elements about the diagnosis and management of uterine fibroids and sarcomas. Methods: This paper is a report of the lectures presented in an expert meeting about uterine fibroids and sarcomas held in Palermo in February 2023. Outcome: Overall, the combination of novel molecular pathways may help combine biomarkers and expert ultrasound for the differential diagnosis of uterine fibroids and sarcomas. On the one hand, molecular and cellular maps of uterine fibroids and matched myometrium may enhance our understanding of tumor development compared to histologic analysis and whole tissue transcriptomics, and support the development of minimally invasive treatment strategies; on the other hand, ultrasound imaging allows in most of the cases a proper mapping the fibroids and to differentiate between benign and malignant lesions, which need appropriate management. Conclusions and Outlook: The choice of uterine fibroid management, including pharmacological approaches, surgical treatment, or other strategies, such as high-intensity focused ultrasound (HIFU), should be carefully considered, taking into account the characteristics of the patient and reproductive prognosis. [ABSTRACT FROM AUTHOR]

Background: The Taiwan Oncology Society (TOS) and the Taiwan Society of Pathology (TSP) have collaborated to present a joint position paper on the molecular tumor boards (MTBs) within the medical institutions of Taiwan. Materials and Methods: To raise awareness of MTBs among health-care professionals, policymakers, and the public, a total of 20 experts from TOS and TSP formulated a joint consensus statement through a voting process. Results: The joint statement proposes key recommendations: (1) MTB discussions encompass diverse molecular analyses including next-generation sequencing (NGS), RNA sequencing, whole-exon sequencing, and whole-genomic sequencing addressing relevant genomic changes, tumor mutation burden, microsatellite instability, and specific biomarkers for certain cancers. (2) MTB meetings should involve multidisciplinary participants who receive regular updates on NGS-related clinical trials. (3) Prioritize discussing cases with unique clinical needs, gene alterations lacking treatments, untreatable neoplasms, or oncogenes unresponsive to targeted therapies. (4) Base MTB discussions on comprehensive patient data, including genetics, pathology, timing of specimen collection, and NGS outcomes. (5) MTBs offer treatment recommendations: standard therapies, off-label use, clinical trials, genetic counseling, and multidisciplinary reviews. (6) MTB effectiveness can be gauged by member composition, case reviews, treatment suggestions, and patient outcomes. Encourage government incentives for MTB engagement. Conclusion: The primary aim of this initiative is to promote the advancement of precision oncology in Taiwan. [ABSTRACT FROM AUTHOR]

Based on surface biomolecular imprinting technology, a rotary microfluidic electrochemical paper-based chip (MIP-ePADs) was proposed for sensitive and selective detection of human interleukin 6 (IL-6) and procalcitonin (PCT). Compared with the traditional method, the sample can be added directly on the MIP-ePAD by rotating the working electrode, which avoids the loss of the liquid to be tested and greatly simplifies the process of electropolymerization imprinting and template elution. Our experimental results show that linear concentration ranges of IL-6 and PCT in the electrochemical molecularly imprinted microfluidic paper-based chip ranged from 0.01 to 5 ng mL−1, with their detection limits being 3.5 and 2.1 pg mL−1, respectively. For the detection of actual serum samples, there was no significant difference between the results of MIP-ePADs and the traditional electrochemiluminescence method used in hospitals, indicating that the paper-based chip can be used for stable and accurate analysis and detection. The chip greatly reduces the cost of clinical trials due to its advantages of easy preparation and low cost. The chip can be used for the analysis of non-antibody inflammation markers and can be widely used in home and hospital treatment detection. This method will not only play an important role in rapid detection, but also provide new ideas for the improvement of rapid detection technology. [ABSTRACT FROM AUTHOR]

Simple Summary: Blood clots are formed when blood vessels are injured. They help stop bleeding and heal wounds, but can also cause serious problems if they block blood flow or break off and travel to other organs. This study investigates how blood clots differ in people with cancer compared to healthy or non-cancerous individuals. This study found that cancer patients have higher levels of histones in their blood, which make their clots stiffer and resistant to lysis. Further, clots formed in cancer patients have higher viscoelastic properties, and hence are harder to break down. These findings suggest that cancer patients have abnormal clotting properties that may increase their risk of developing thrombosis, and evaluating these properties can be helpful in detecting cancer. Background: Blood viscoelasticity and plasma protein levels can play an important role in the diagnosis and prognosis of cancer. However, the role of histones and DNA in modulating blood clot properties remains to be investigated. This study investigates the differences in blood viscoelasticity and plasma protein levels among cancer patients, individuals with other diseases, and healthy individuals. Methods: Blood samples were collected from 101 participants, including 45 cancer patients, 22 healthy individuals, and 34 individuals with other diseases. Rheological properties of clots formed in vitro by reconstituted elements of fibrinogen or plasma were analyzed with an Anton Paar Rheometer, USA. Plasma protein levels of D-dimer, TPA, EPCR, fibrinogen, and histone H3 were measured through ELISA. Blood clots were formed with or without DNA and histones (H3) by adding thrombin and calcium to plasma samples, and were evaluated for viscoelasticity, permeability, and degradation. Results: Cancer patients show higher blood viscoelasticity and plasma D-dimer levels compared to healthy individuals and individuals with other diseases. Our in vitro analysis showed that the addition of histone to the plasma results in a significant decrease in viscoelasticity and mean fiber thickness of the clot formed thereafter. In parallel studies, using plasma from patients, DNA and histones were detected in fibrin clots and were associated with less degradation by t-PA. Moreover, our results show that the presence of DNA and histones not only increases clots' permeability, but also makes them more prone to degradation. Conclusions: Plasma histones and DNA affect the structure of the clot formed and induce defective fibrinolysis. Moreover, the increased viscoelastic properties of plasma from cancer patients can be used as potential biomarkers in cancer prognosis. [ABSTRACT FROM AUTHOR]

Background: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. Objective: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. Methods: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. Results: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. Conclusion: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges. [ABSTRACT FROM AUTHOR]

Rapid, simple, and sensitive analysis of relevant proteins is crucial in many research areas, such as clinical diagnosis and biomarker detection. In particular, clinical data on cancer biomarkers show great promise in forming reliable predictions for early cancer diagnostics, although the current analytical systems are difficult to implement in regions of limited recourses. Paper-based biosensors, in particular, have recently received great interest because they meet the criteria for point-of-care (PoC) devices; the main drawbacks with these devices are the low sensitivity and efficiency in performing quantitative measurements. In this work, we design a low-cost paper-based nanosensor through plasmonic calligraphy by directly drawing individual plasmonic lines on filter paper using a ballpoint pen filled with gold nanorods (AuNR) as the colloidal ink. The plasmonic arrays were further successively coated with negatively and positively charged polyelectrolyte layers employed as dielectric spacers to promote the enhancement of the emission of carboxyl-functionalized quantum dots (QD)—previously conjugated with specific antibodies—for indirect detection of the carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). The efficiency, sensitivity, as well as the specificity of our portable nanosensor were validated by recording the luminescence of the QD@Ab complex when different concentrations of CEACAM5 were added dropwise onto the calligraphed plasmonic arrays. [ABSTRACT FROM AUTHOR]

Human sweat can be collected non-invasively with low infectivity; however, its application as a determination method has been challenged due to the presence of trace amounts of chiral metabolites. Moreover, its application as a biological fluid for disease diagnosis has not been previously reported. In this study, the human dried sweat spot paper (DSSP) method was proposed for the derivatization of a novel mass spectrometric chiral probe, N -[1-Oxo-5-(triphenylphosphonium) pentyl]-(S)-3-aminopyrrolidine (OTPA), determination and resolution of DL-lactic acid (DL-LA) enantiomers in human elbow sweat. The methodological validation revealed the resolution (Rs) as 1.78, the limit of detection (S/N = 3) as 20.83 fmol, good linearity (R2 ≥ 0.9996), and the intra-day and intra-day stability with RSD ranging from 0.53 to 10.85 %, while the average recovery rate of D-LA and L-LA were 104.00 % ± 4.68 % and 107.41 % ± 8.34 %, respectively, with high accuracy. In addition, the method was applied for the determination of DL-LA in the sweat on elbow of 10 healthy volunteers and 30 diabetic patients. The results demonstrated that the D/L ratio and L/D ratio were significantly different (p < 0.0001). In addition, a moderate positive linear correlation between the D/L-LA ratio in human sweat and fasting blood glucose level (r = 0.7744, p < 0.0001) was observed, thereby suggesting that the D/L ratio of lactate in human sweat correlate the glucose level in human fasting blood. The D/L lactate ratio in human sweat could be used as a potential biomarker for diabetes screening. The method can be used to screen for diabetes by providing a dry sweat paper to test equipment and has the potential to be a non-invasive early-warning diagnostic tool for diabetes. [Display omitted] • A dried sweat spot paper method for estimating DL-LA enantiomers in human sweat. • The D/L and L/D ratios of LA in diabetic patient sweat are significantly different. • The D/L-LA ratio in human sweat is positively correlated with fasting blood glucose levels. • DSSP combined with UHPLC-MS/MS accurately quantified D/L-LA ratio is a non-invasive preventive method for screening for diabetes. [ABSTRACT FROM AUTHOR]

In clinical trials, biochemical markers provide useful information on the drug's mode of action, therapeutic response and side effect monitoring and can act as surrogate endpoints. In pharmacological intervention development for sarcopenia management, there is an urgent need to identify biomarkers to measure in clinical trials and that could be used in the future in clinical practice. The objective of the current consensus paper is to provide a clear list of biochemical markers of musculoskeletal health and aging that can be recommended to be measured in Phase II and Phase III clinical trials evaluating new chemical entities for sarcopenia treatment. A working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) proposed classifying biochemical markers into 2 series: biochemical markers evaluating musculoskeletal status and biochemical markers evaluating causal factors. For series 1, the group agreed on 4 biochemical markers that should be assessed in Phase II or Phase III trials (i.e., Myostatin-Follistatin, Brain Derived Neurotrophic Factor, N-terminal Type III Procollagen and Serum Creatinine to Serum Cystatin C Ratio – or the Sarcopenia Index). For series 2, the group agreed on 6 biochemical markers that should be assessed in Phase II trials (i.e., the hormones insulin-like growth factor-1 (IGF-I), dehydroepiandrosterone sulphate, and cortisol, and the inflammatory markers C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-α), and 2 in Phase III trials (i.e., IGF-I and CRP). The group also proposed optional biochemical markers that may provide insights into the mode of action of pharmacological therapies. Further research and development of new methods for biochemical marker assays may lead to the evolution of these recommendations. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to design a paper strip-based non-invasive urine analysis system for the qualitative detection of biomarker aquaporin-1 (AQP1) in renal cancer (RC). RC accounts for 3% of all cancers and 85% of all kidney tumors and mainly originates from the kidney cortex. In recent times, higher urine concentration of AQP1 in patients with RC was confirmed as a specific biomarker of the disease. Hence, the noninvasive, user-friendly and self-diagnostic method is required for the detection of aquaporin biomarkers in RC. Design/methodology/approach: The present research work was focused on the development and characterization of a dye conjugated cyclodextrin-based miniaturized system for impregnation on Whatman filter paper to identify RC using AQP1 biomarker present in urine samples. Findings: It was observed that the test strip dipped into the urine sample, and the yellow color intensity increased with a decrease in AQP1 concentration due to the transformation of the dye system of free basic form into bound acidic form. The Hue-Saturation-Value profiling was used to observe the effect of color change using a smartphone application. The paper strip-based urine analysis system is highly sensitive for the detection of AQP1 in the range of 10 to 1,000 ng. Originality/value: The successful validation indicated that this biosensor is likely to contribute to the development of point-of-care, novel, personalized diagnostics and ensure prolonged survival of RC patients in the near future. [ABSTRACT FROM AUTHOR]

Schematic diagram depicting the synthesis process of the intelligent paper-based biosensor and its colorimetric detection application for biomarkers in urine. (FP: filter paper; CPBA: Carboxyphenylboric acid; HRP: horseradish peroxidase; TMB: 3,3′,5,5′-tetramethylbenzidine; GLU: glusose; UA: uric acid; SAR: sarcosine; GOx: glucose oxidase; UOx: urate oxidase; SOx: urate oxidase.) [Display omitted] • A green, low-cost, portable and visual intelligent paper-based biosensor was created. • This sensor immobilized HRP in horseradish by a borate-modified filter paper. • This sensor can detect many substances simultaneously and improve detection efficiency. • This sensor boasts the advantages of superior sensitivity, stability and selectivity. In the increasing demand for real-time testing, the imperative for a straightforward, rapid, portable, and effective biosensor is evident. In this study, an intelligent paper-based biosensor was developed, employing cost-effective and readily available filter paper as a matrix to prepare boronate affinity paper-based materials. The immobilization of horseradish peroxidase (HRP) from crude horseradish extract onto the material surface was realized. Ultimately, a cold assembly technique was employed to construct this intelligent paper-based biosensor, which combined with a smartphone APP, facilitated the easy, accurate, and simultaneous detection of the content of glucose (GLU), uric acid (UA), and sarcosine (SAR) in urine, significantly enhancing the convenience and practicality of real-time monitoring. Additionally, UV spectroscopy served as an auxiliary method to affirm the reliability of the detection outcomes. For the detection of GLU, UA, and SAR, the biosensor exhibited linear ranges of 2–200, 2–500, and 2–500 µmol L–1, respectively, with detection limits (LODs) of 1 µmol L–1 for all analytes. In practical urine sample analysis, the recovery rates of GLU, UA, and SAR detected by the intelligent paper-based biosensors were within a reasonable range, with relative standard deviations below 3.5 %. This fully demonstrates the high accuracy and reliability of the intelligent paper-based biosensor. The development of this low-cost, portable biosensor provides a new method for the detection of biomarkers related to H 2 O 2. [ABSTRACT FROM AUTHOR]

Despite significant advances in the diagnosis and treatment of cardiovascular diseases, recent calls have emphasized the unmet need to improve precision-based approaches in cardiovascular disease. Although some studies provide preliminary evidence of the diagnostic and prognostic potential of circulating coding and non-coding RNAs, the complex RNA biology and lack of standardization have hampered the translation of these markers into clinical practice. In this position paper of the CardioRNA COST action CA17129, we provide recommendations to standardize the RNA development process in order to catalyse efforts to investigate novel RNAs for clinical use. We list the unmet clinical needs in cardiovascular disease, such as the identification of high-risk patients with ischaemic heart disease or heart failure who require more intensive therapies. The advantages and pitfalls of the different sample types, including RNAs from plasma, extracellular vesicles, and whole blood, are discussed in the sample matrix, together with their respective analytical methods. The effect of patient demographics and highly prevalent comorbidities, such as metabolic disorders, on the expression of the candidate RNA is presented and should be reported in biomarker studies. We discuss the statistical and regulatory aspects to translate a candidate RNA from a research use only assay to an in-vitro diagnostic test for clinical use. Optimal planning of this development track is required, with input from the researcher, statistician, industry, and regulatory partners. [ABSTRACT FROM AUTHOR]

Background: Harmful Alcohol use is frequent among opioid dependents patients undergoing agonist maintenance treatment. The objective assessment of harmful alcohol use can be done using laboratory measures of serum biomarkers. For community-based patients, there is often a requirement of an alternative method due to lack of onsite laboratory services. The aim of the study was to examine filter paper as a matrix to measure serum biomarkers of harmful alcohol use. Methods: The initial phase involved standardization of the filter-paper-based assay. Conditions were optimised for extraction and estimation of alcohol biomarkers (Aspartate Aminotransferase; AST, Alanine Aminotransferase; ALT, Gamma Glutamyl transferase; GGT and Carbohydrate Deficient Transferrin; CDT) from the filter paper. For clinical validation, serum samples were collected from community clinics. Biomarker levels obtained from both the methods were correlated using linear regression analysis. Limits of agreement between the two methods was estimated using the Intraclass Correlation Coefficient (ICC). Results: The extraction of enzymes (AST, ALT and GGT) from filter paper was carried out using the substrate buffer available with the reagent kit (Randox, UK). CDT was readily extracted from filter paper using deionised water. Serum biomarker levels measured from samples collected from community clinics correlated well with filter paper extracted levels (ICC 0.97-0.99). More than 90% of alcohol biomarker levels were recovered from the filter paper matrix using this method. Conclusion: Filter paper has the potential to be used as a matrix to objectively measure alcohol biomarkers among opioid-dependent patients from community settings lacking onsite laboratory facilities. [ABSTRACT FROM AUTHOR]

Plain language summary: Biomarkers may offer unforeseen insights into clinical diagnosis, as well as the likely course and outcome of a condition. In this paper, the focus is on the use of biological molecules found in body fluids or tissues for diagnosis and prediction of outcome in ovarian cancer patients. In cancer care, biomarkers are being used to develop personalised treatment plans for patients based on the unique characteristics of their tumour. This tailoring of care can be used to pursue specific targets identified by biomarkers, or treat the patient according to specific tumour characteristics. Surgery is one of the core treatments for ovarian cancer, whether it is offered in primary surgery or following chemotherapy in delayed surgery. Biomarkers already exist to guide the treatment of tumours with chemotherapy, but very little research has determined the value of biomarkers in tailoring surgical care for ovarian cancer. Such research is required to identify new biomarkers and assess their effectiveness in a clinical setting as well as to help identify specific tumour types to guide surgery. Biomarkers could help to determine the success of removing the disease surgically, or help to identify tumour deposits that persist after chemotherapy. All of these aspects would improve current practice. This Scientific Impact Paper highlights research that may pave the way towards bespoke surgery according to the biological characteristics of a tumour and aid gynaecological oncologists to provide surgical treatment according to individual need, rather than a blanket approach for all. [ABSTRACT FROM AUTHOR]

The modification of an easily available resource like paper to circumvent expensive or intensive sample pretreatment could be the answer to sample analysis in resource-poor regions. Therefore, a novel on-paper device combining sample collection with affinity sample pretreatment is introduced here. Universal smart affinity samplers are produced by a simple KIO4-mediated oxidation of cellulose, which functionalizes the paper. This is followed by immobilization of streptavidin. Streptavidin serves as a universal anchor for biotinylated antibodies, enabling simple preparation of tailor-made affinity samplers. The functionality of the device was tested using a model protein (human chorionic gonadotropin, hCG) and biotinylated anti-hCG antibodies for affinity capture. In a laboratory setting, the performance was demonstrated, and a 14-fold increase of target binding compared to binding without bmAb was achieved. The recovery of hCG captured with bmAb-treated samplers was determined to be 33% and comparable to previously described affinity capture approaches. Application of the smart affinity samplers to human serum containing hCG showed an R2 of 0.98 (200–1000 pg mL−1), precision of ≤ 9.1% RSD, and estimated limit of detection of 65 pg mL−1. Although further optimization and validation are necessary prior to application to real samples in clinical settings, the potential of the device for use in determination of low abundant biomarkers in complex samples has been demonstrated. [ABSTRACT FROM AUTHOR]

Peroxidase‐mimicking nanozymes have been extensively studied, however, their application is limited by the requirement for an acidic pH. Herein, the development of Co‐doped mesoporous cerium oxide (Co‐m‐ceria) is reported, which operates optimally at a near‐neutral pH and exhibits a peroxidase‐like catalytic efficiency that is 600‐times higher than that of pristine m‐ceria. Density functional theory (DFT) calculations for the application of pristine and various metal‐doped m‐ceria in peroxidase‐like reactions under different pH environments are conducted to select Co as the appropriate dopant. The high peroxidase‐like activity of Co‐m‐ceria under neutral conditions and its mesoporous nature enable its application in a one‐pot cascade reaction system, wherein biomarkers of oxidative enzymes can be detected without altering the pH. Five different oxidative enzymes are immobilized in the pores of Co‐m‐ceria at high loadings, followed by incorporation of the enzyme‐containing Co‐m‐ceria in paper microfluidic devices for the convenient and simultaneous detection of multiple biomarkers. The Co‐m‐ceria‐incorporated paper microfluidic device enables the selective and sensitive determination of multiple biomarkers using a smartphone‐acquired image. This study demonstrates the potential of the rational design of nanozymes and their application in paper microfluidic devices, laying the groundwork for future applications of nanozymes in point‐of‐care testing environments. [ABSTRACT FROM AUTHOR]

Few biomarker-based validation studies have examined error in online self-report dietary assessment instruments, and food records (FRs) have been considered less than food frequency questionnaires (FFQs) and 24-hour recalls (24HRs). We investigated measurement error in online and paper-based FFQs, online 24HRs, and paper-based FRs in 3 samples drawn primarily from 3 cohorts, comprising 1,393 women and 1,455 men aged 45–86 years. Data collection occurred from January 2011 to October 2013. Attenuation factors and correlation coefficients between reported and true usual intake for energy, protein, sodium, potassium, and respective densities were estimated using recovery biomarkers. Across studies, average attenuation factors for energy were 0.07, 0.07, and 0.19 for a single FFQ, 24HR, and FR, respectively. Correlation coefficients for energy were 0.24, 0.23, and 0.40, respectively. Excluding energy, the average attenuation factors across nutrients and studies were 0.22 for a single FFQ, 0.22 for a single 24HR, and 0.51 for a single FR. Corresponding correlation coefficients were 0.31, 0.34, and 0.53, respectively. For densities (nutrient expressed relative to energy), the average attenuation factors across studies were 0.37, 0.17, and 0.50, respectively. The findings support prior research suggesting different instruments have unique strengths that should be leveraged in epidemiologic research. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) has become the third leading cause of global death. Insufficiency in early diagnosis and treatment of COPD, especially COPD exacerbations, leads to a tremendous economic burden and medical costs. A cost-effective and timely prevention requires decentralized point-of-care diagnostics at patients' residences at affordable prices. Advances in point-of-care (POC) diagnostics may offer new solutions to reduce medical expenditures by measuring salivary and blood biomarkers. Among them, paper-based analytical devices have been the most promising candidates due to their advantages of being affordable, biocompatible, disposable, scalable, and easy to modify. In this review, we present salivary and blood biomarkers related to COPD endotypes and exacerbations, summarize current technologies to collect human whole saliva and whole blood samples, evaluate state-of-the-art paper-based analytical devices that detect COPD biomarkers in saliva and blood, and discuss existing challenges with outlooks on future paper-based POC systems for COPD diagnosis and management. [ABSTRACT FROM AUTHOR]

Enzyme-linked immunosorbent assay (ELISA) is widely used for the detection of disease biomarkers. However, it utilizes time-consuming procedures and expensive instruments, making it infeasible for point-of-care (POC) analysis especially in resource-limited settings. In this work, a multicolorimetric ELISA biosensor integrated on a paper/polymer hybrid microfluidic device was developed for rapid visual detection of disease biomarkers at point of care, without using costly equipment. This multicolormetric ELISA platform was built on multiple distinct color variants resulted from the catalytic oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) and the etching of gold nanorods (AuNRs). The vivid color changes could be easily distinguished by the naked eye, and their red mean values allowed quantitative biomarker detection, without using any sophisticated instruments. When this multicolorimetric ELISA was integrated on a paper/polymer hybrid analytical device, it not only provided integrated processing and high portability but also enabled fast assays in about 50 min due to the unique advantages of paper/polymer hybrid devices. The limit of detection of 9.1 ng/μL of the hepatitis C virus core antigen, a biomarker for hepatitis C, was achieved using this multicolorimetric ELISA platform. This multicolor ELISA analytical device provides a new versatile, user-friendly, affordable, and portable immunosensing platform with high potential for on-site detections of various viruses, proteins, and biomarkers for low-resource settings such as at home, public venues, rural areas, and developing nations. [ABSTRACT FROM AUTHOR]

Multiplex detection can enhance diagnostic precision and improve diagnostic efficiency, providing important assistance for epidemiological investigation and epidemic prevention. There is a great need for multi-detection sensing platforms to accurately diagnose diseases. Herein, we reported a μPAD-based chemiluminescence (CL) assay for ultrasensitive multiplex detection of AIV biomarkers, based on three DNAzyme/Lum/PEI/CaCO 3. Three time-resolved CL signals were sequentially generated with detection limits of 0.32, 0.34, and 0.29 pM for H1N1, H7N9, and H5N1, respectively, and with excellent selectivity against interfering DNA. The recovery test in human serum displayed satisfactory analysis capabilities for complex biological samples. The μPAD-based CL assay achieved multiplex detection within 70 s, with a high time resolution of 20 s. The proposed strategy has the advantages of low cost, high sensitivity, good selectivity, and wide time resolution, the μPAD-based CL assay has shown great potential in the early and accurate diagnosis of diseases. We reported a μPAD-based CL assay for ultrasensitive multiplex detection of AIV biomarkers, based on three DNAzyme/Lum/PEI/CaCO 3. The platform achieved multiplex detection within 70 s, with a wide time resolution of 20 s, demonstrating great potential in the early and accurate diagnosis of diseases. [Display omitted] • A low-cost, portable μPAD with time-resolved CL signals was fabricated. • The CL assay successfully detected H1N1, H7N9, and H5N1 within 70 s, with a wide time resolution of 20 s. • Dual amplification of the sensor was achieved based on the CHA reaction and DNAzyme catalysis. • The CL assay had a wide linear range (1.0 pM−10 nM) and high detection sensitivity at pM level. • The CL assay was able to visualize trace H1N1, H7N9, and H5N1 down to 10 pM. [ABSTRACT FROM AUTHOR]

As a crucial biomarker for some diseases, the determination of cholesterol in human serum is of great significance for the diagnosis and prevention of these diseases. Hence, a portable cholesterol detection method is necessary for clinical and domestic applications. Here, a portable paper sensor was designed for cholesterol detection by modifying screen-printed electrode (SPE) with nanoporous gold (NPG). To achieve the reliable cholesterol detection, a synergistic strategy was proposed based on the oxidation of cholesterol by cholesterol oxidase (ChOx) and the reduction of oxidation product (H 2 O 2) by NPG. Compared to existing electrochemical sensors, the resulting paper sensor exhibited a wider linear response in a range from 50 μM to 6 mM as well as a higher sensitivity of 32.68 μA mM−1 cm−2 with a lower detection limit of 8.36 μM. Moreover, the portable paper sensor presented strong anti-interference capability and stability in the detection of cholesterol in human serum, and the data detected by the portable paper sensor were consistent with that obtained by an automatic biochemical analyzer. These unique performances confirmed that the proposed paper sensor was a sensitive, reliable, and portable cholesterol detection method, making it a good choice for cholesterol detection. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of death worldwide producing an estimated cost of $161.2 billion in the US in 2017 only. Early detection of cancer can not only reduce cancer mortality rates but also dramatically reduce healthcare costs given that the 17 million new cancer cases in 2018 are estimated to grow 27.5 million new cases by 2040. Analytical devices based upon paper substrates can provide effective, rapid, and extremely low‐cost alternatives for early cancer detection compared to existing testing methods. However, low concentrations of biomarkers in body fluids as well as the possible association of any given biomarker with multiple diseases remains one of the greatest challenges to widespread adoption of these paper‐based devices. Fortunately, recent advances have opened the possibility of detecting multiple biomarkers within the same device, which can be predictive of a patient's condition with unprecedented cost‐effectiveness. Accordingly, this review highlights the recent advancements in paper‐based analytical devices with a multiplexing focus. The primary areas of interest include lateral flow assay and microfluidic paper‐based assay formats, signal amplification approaches to enhance the sensitivity for a specific cancer type, along with current challenges and future outlook for the detection of multiple cancer biomarkers. [ABSTRACT FROM AUTHOR]

Ovarian cancer has a poor cure rate and rates of relapse are high. Current recurrence detection is limited by non-specific methods such as blood testing and ultrasound. Based on reports that human epididymis four (HE4) / creatinine (CRE) ratios found in urine are elevated in ovarian cancers, we have developed a paper-based device that combines lateral flow technology and cell phone analysis to quantitatively measure HE4/CRE. Surrogate samples were used to test the performance over clinically expected HE4/CRE ratios. For HE4/CRE ratios of 2 to 47, the percent error was found to be 16.0% on average whether measured by a flatbed scanner or cell phone. There was not a significant difference between the results from the cell phone or scanner. Based on published studies, error in this method was less than the difference required to detect recurrence. This promising new tool, with further development, could be used at home or in low-resource settings to provide timely detection of ovarian cancer recurrence. [ABSTRACT FROM AUTHOR]

A novel CuS grafted PEDOT:PSS conducting paper-based electrochemical immunosensor has been successfully fabricated for the detection of EpCAM antigen. Electrical conductivity is further improved by doping the CuS@PEDOT:PSS/WP electrode with different organic solvents such as N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide (DMA), ethylene glycol (EG) and dimetyl sulfoxide (DMSO). It is observed that DMSO doped conducting paper shows the highest conductivity (6.1 × 10−2 S/cm) among all these solvents. This low cost, biodegradable electrochemical paper-based immunosensor (BSA/anti-EpCAM/EP) possesses a broad linear range from 0.01 pg/mL to 1000 ng/mL for EpCAM antigen detection. The immunosensor is found to have high sensitivity of 104.31 μA pg−1 mL. This conducting paper based immunosensor is further used to detect EpCAM antigen in human serum samples, thereby confirming a cost effective clinical tool over other costly conventional techniques. • An electrochemical paper-based immunosensor has been designed using CuS and PEDOT:PSS. • This low cost and flexible platform may be a promising candidate over other costly conventional electrodes. • It exhibits high sensitivity of 104.31 μA pg−1 mL in broad range of 0.01 pg/mL to 1000 ng/mL, for EpCAM detection. • The clinical applicability and validity has been checked with human serum sample. [ABSTRACT FROM AUTHOR]

Development of the portable device is significant for sensitive and rapid detection of an anthrax biomarker dipicolinic acid (DPA), existing in the B. anthracis. In this work, a novel HAp:Tb-EDTA paper-based ratiometric fluorescent sensor was obtained by a simple one-pot method for rapid and sensitive DPA detection. With the increased DPA concentration, the luminescence intensity of HAp (hydroxyapatite) remained constant, and thus applied as the stable reference signal, while the luminescence signal of Tb3+-EDTA was significantly enhanced due to the antenna effect. Therefore, the HAp:Tb-EDTA paper-based sensor was endowed with self-calibrated and ratiometric fluorescent detection performance for DPA. The proposed sensor showed excellent detection performance with a detection limit as low as 10.8 nM in the linear range of 0.5–30 μM. After combination with a smartphone, rapid visual and fluorescent detection of DPA was achieved. The proposed sensor was successfully applied to detect DPA from B. subtilis spore real samples, showing the application prospects of the paper-based sensors and opening a new horizon to develop novel paper-based point-of-care testing (POCT) devices. A sensing platform was constructed by a HAp:Tb-EDTA paper-based ratiometric fluorescent probe prepared by a one-pot method and combined with a smartphone. The sensing platform has good stability and can be used for sensitive detection of DPA released from Bacillus subtilis spores. [Display omitted] • A novel HAp:Tb-EDTA paper-based ratiometric fluorescent probe was facilely constructed. • The Tb3+-EDTA recognition unit uniformly distributed on HAp with a paper-like structure, making it superior to that based on commercial test papers. • A portable platform was constructed through combining with smartphones for real samples detection, showing widespread application prospects. • Opening a new horizon to develop novel paper-based point-of-care testing (POCT) devices. [ABSTRACT FROM AUTHOR]

Paper-based analytical devices (PADs), thanks to the versatility, cheapness, availability, biodegradability, and porosity of paper, have emerged as flexible sensing platforms for determining various analytes. However, lack of selectivity can be a problem in complex analysis conditions and samples. To improve the selectivity and specificity of PADs, they can be integrated with molecularly imprinted polymers (MIPs). The high selectivity of the sensor is the essential feature for biomarker analysis because the reliable and accurate determination of biomarkers provides valuable information about various diseases, especially cancer. Therefore, MIP-PAD systems offer a good option for biomarker analysis. This way, it is possible to achieve point-of-care tests, early diagnosis, and affordability. This review points out the significant processes of MIP-PAD fabrication and characterization (paper selection and fabrication, synthesis of MIP). The most recent applications of MIP-PADs for biological samples are explained and discussed in detail. Lastly, the commercialization of MIP-PADs is evaluated. This study is the first in the literature to assess MIP-PADs for biomarkers analysis. • The evaluation of MIP-PADs for biomarker detection. • Comprehensive research for fabrication and characterization of MIP-PADs. • The successful sensor applications of MIP-PADs for biological samples. • The place of MIP-PADs in commercial applications. [ABSTRACT FROM AUTHOR]

We developed a highly efficient and low‐cost organic solvents‐resistant microfluidic paper‐based analytical device (μPAD) coupled with paper spray mass spectrometry (PS‐MS) for quantitative determination of C18‐ceramide as a prognostic biomarker for several diseases. Several models of μPAD patterns have been examined to select the most resistant and efficient microchannel barriers, which can provide continuous spray at ionization zone and prevent "coffee ring" effect. Moreover, the developed μPAD has enabled the analysis of low concentration of C18‐ceramide because of the maximum supply of deposited analyte through microchannel. The MS results confirmed the formation of doubly and singly charged metal ion complexes between ceramide and different metal ions. Notably, the complexation that occurs between lithium ions and C18‐ceramide showed a high relative abundance compared with other formed complexes. Taking into account the relative abundance of complex [Cer + Li]+ at 572.8 m/z, it can be considered as a stable ion and therefore be used for the analysis of C18‐ceramide at low concentrations. Complexation of C18‐ceramide and lithium confirmed with quantum chemical calculations. The proposed method represents good linearity with a regression coefficient of 0.9956 for the analysis of C18‐ceramide and reaches a limit of detection to 0.84 nM. It has been adapted successfully for practical application in human serum samples with high recovery values in range of 92%–105%. The developed μPAD‐MS technique provides clear advantages by reducing the experimental steps and simplifying the operation process and enables to identify subnanomolar concentration of C18‐ceramide in human serum samples. [ABSTRACT FROM AUTHOR]

This review explains in simple terms, accessible to the non-statistician, general principles regarding the correct research methods to develop and then evaluate imaging biomarkers in a clinical setting, including radiomic biomarkers. The distinction between diagnostic and prognostic biomarkers is made and emphasis placed on the need to assess clinical utility within the context of a multivariable model. Such models should not be restricted to imaging biomarkers and must include relevant disease and patient characteristics likely to be clinically useful. Biomarker utility is based on whether its addition to the basic clinical model improves diagnosis or prediction. Approaches to both model development and evaluation are explained and the need for adequate amounts of representative data stressed so as to avoid underpowering and overfitting. Advice is provided regarding how to report the research correctly. Key Points: • Imaging biomarker research is common but methodological errors are encountered frequently that may mean the research is not clinically useful. • The clinical utility of imaging biomarkers is best assessed by their additive effect on multivariable models based on clinical factors known to be important. • The data used to develop such models should be sufficient for the number of variables investigated and the model should be evaluated, preferably using data unrelated to development. [ABSTRACT FROM AUTHOR]

Executive Summary: With an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine. [ABSTRACT FROM AUTHOR]

• IFCC position paper about CDT outlining caveats, key points, and recommendations. • Alcohol intake versus CDT is discussed as well as the cut-off and expected range. • Comparison studies using inadequate study populations will lead to wrong outcome. • Standardisation has led to test accuracy improvements in national EQAS. Carbohydrate deficient transferrin (CDT) is a biomarker for excessive alcohol consumption utilized in clinical and forensic medicine and workplace testing. Previously, many different analytical methods for CDT were used and the measurand varied considerably, making direct comparison of test results difficult. To end this confusion, the IFCC established a working group on CDT standardisation (WG-CDT) which completed its tasks in 2017. This IFCC position paper by the WG-CDT summarizes state of the art information about the measurand and the analytical methods and gives concise recommendations for its utilization. The results achieved by the CDT standardisation process led to accuracy improvements in national external quality assessment schemes over the years. A brief review of ROC based comparison studies with the traditional biomarkers (GGT, MCV, ALT and AST) discusses the bias resulting from inadequate study populations. In large groups of the general population the superior diagnostic performance of CDT is confirmed. The relationship between alcohol intake versus resulting CDT is discussed as well as the cutoff and measurement uncertainty. Concerning the application in practice, potential pitfalls are considered and recommendations handling both analytical and preanalytical caveats are given. Finally, some examples of serious misunderstandings in publications about CDT are addressed. [ABSTRACT FROM AUTHOR]

Urine is commonly used for clinical diagnosis and biomedical research. The discovery of extracellular vesicles (EV) in urine opened a new fast‐growing scientific field. In the last decade urinary extracellular vesicles (uEVs) were shown to mirror molecular processes as well as physiological and pathological conditions in kidney, urothelial and prostate tissue. Therefore, several methods to isolate and characterize uEVs have been developed. However, methodological aspects of EV separation and analysis, including normalization of results, need further optimization and standardization to foster scientific advances in uEV research and a subsequent successful translation into clinical practice. This position paper is written by the Urine Task Force of the Rigor and Standardization Subcommittee of ISEV consisting of nephrologists, urologists, cardiologists and biologists with active experience in uEV research. Our aim is to present the state of the art and identify challenges and gaps in current uEV‐based analyses for clinical applications. Finally, recommendations for improved rigor, reproducibility and interoperability in uEV research are provided in order to facilitate advances in the field. [ABSTRACT FROM AUTHOR]

Ferritin, a blood cell protein containing iron, is a crucial biomarker that is used to estimate the risk assessment of iron deficiency anemia. For point-of-care analysis, a reliable, cost-effective, selective, sensitive, and portable tool is extremely necessary. In this study, a label-free electrochemical immunosensor for detecting ferritin using a paper-based analytical device (ePAD) was created. The device pattern was custom designed onto filter paper to successfully fabricate a deliverable immunosensor. Graphene oxide was first modified onto the working electrode using an inkjet printing technique. An activation step of the electrode surface was then performed using standard 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)/N-hydroxysulfosuccinimide (sulfo-NHS) chemistry. Anti-ferritin antibodies were covalently immobilized onto the amine-reactive ester surface. The amount of ferritin was monitored by observing the electrochemical signal of the selected redox couple by differential pulse voltammetry (DPV). In the presence of ferritin, the sensor showed a considerable decrease in electrochemical response in a concentration-dependent manner. In contrast, there was no observable change in current response detected in the absence of ferritin. The current response provided a good correlation with ferritin concentrations in the range of 1 to 1000 ng mL−1, and the limit of detection (3SD/slope) was found to be 0.19 ng mL−1. This fabricated immunosensor offered good selectivity, reproducibility, and long-term storage stability. In addition, this proposed immunosensor was successfully applied to detect ferritin in human serum with satisfactory results. The promising results suggested that this handmade paper-based immunosensor may be an alternative device for the diagnosis of iron deficiency anemia. [ABSTRACT FROM AUTHOR]

The use of microfluidic paper-based analytical devices (μPADs) for aiding medical diagnosis is a growing trend in the literature mainly due to their low cost, easy use, simple manufacturing, and great potential for application in low-resource settings. Many important biomarkers (proteins, ions, lipids, hormones, DNA, RNA, drugs, whole cells, and more) and biofluids are available for precise detection and diagnosis. We have reviewed the advances μPADs in medical diagnostics have achieved in the last few years, focusing on the most common human biofluids (whole blood/plasma, sweat, urine, tears, and saliva). The challenges of detecting specific biomarkers in each sample are discussed, along with innovative techniques that overcome such limitations. Finally, the difficulties of commercializing μPADs are considered, and future trends are presented, including wearable devices and integrating multiple steps in a single platform. • μPADs can be applied for simple and low-cost diagnosis in low-resource settings. • The challenges of applying μPADs to human biofluids are analyzed. • Recent advancements to overcome specific drawbacks for each fluid are discussed. • Difficulties in commercializing μPADs and future tendencies are presented. [ABSTRACT FROM AUTHOR]

The accurate detection of glucose and cholesterol plays a pivotal role in disease diagnosis and home care. To this end, biochemical analyzers have become extensively utilized tools for measuring disease biomarkers. Nonetheless, their poor portability and high cost have restricted their accessibility, limiting their use to laboratory settings and hindering the adoption of point-of-care testing (POCT). In contrast, the emergence of portable and affordable paper-based testing platform has revolutionized diagnostic testing by providing distance signals, enhancing intuitiveness and visual accessibility. Consequently, these platforms have become increasingly suitable for POCT. We have developed a POCT platform that integrated AuNS@Ag, stimulus-responsive hydrogel and test strips, enabling visual distance reading of glucose. The silver-coated AuNS and enzyme were encapsulated within a temperature-responsive N-isopropylacrylamide-acrylamide (NIPAM-AcAm) hydrogel to act as target recognition and reaction units respectively. Glucose can diffuse freely within the hydrogel porous matrix, thereby instigating enzyme-catalyzed reaction that induce alterations in the photothermal effect of the system. This dynamic process ensures efficient and responsive modulation of the system's photothermal properties. By ingeniously capturing distance signals induced by the photothermal effect-mediated water release the visualization and quantification of target substances are achieved, with a linear range spanning from 0 to 30 mM. The consistency between distance-based POCT platform and commercial blood glucose meter demonstrates that the platform provides a portable, affordable and reliable method for visual reading biomarkers. The proposed strategy enables direct, visual quantitative analysis of the target without the need for additional analytical instruments. Particularly, this method holds significant promise as an efficient platform for cholesterol and other disease markers measurement. [Display omitted] • A POCT platform was constructed for visible distance-readout of disease marker. • AuNS@Ag was employed as target recognition unit for photothermal signal output. • Temperature-responsive hydrogel as carrier and framework for the platform. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has been as unprecedented as unexpected, affecting more than 105 million people worldwide as of 8 February 2020 and causing more than 2.3 million deaths according to the World Health Organization (WHO). Not only affecting the lungs but also provoking acute respiratory distress, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is able to infect multiple cell types including cardiac and vascular cells. Hence a significant proportion of infected patients develop cardiac events, such as arrhythmias and heart failure. Patients with cardiovascular comorbidities are at highest risk of cardiac death. To face the pandemic and limit its burden, health authorities have launched several fast-track calls for research projects aiming to develop rapid strategies to combat the disease, as well as longer-term projects to prepare for the future. Biomarkers have the possibility to aid in clinical decision-making and tailoring healthcare in order to improve patient quality of life. The biomarker potential of circulating RNAs has been recognized in several disease conditions, including cardiovascular disease. RNA biomarkers may be useful in the current COVID-19 situation. The discovery, validation, and marketing of novel biomarkers, including RNA biomarkers, require multi-centre studies by large and interdisciplinary collaborative networks, involving both the academia and the industry. Here, members of the EU-CardioRNA COST Action CA17129 summarize the current knowledge about the strain that COVID-19 places on the cardiovascular system and discuss how RNA biomarkers can aid to limit this burden. They present the benefits and challenges of the discovery of novel RNA biomarkers, the need for networking efforts, and the added value of artificial intelligence to achieve reliable advances. [ABSTRACT FROM AUTHOR]

Lateral flow immunochromatographic assays (LFIAs) are analytical devices used to detect the presence of one or more target analytes in a liquid sample. While LFIAs are one of the simplest and inexpensive types of immunoassays, they consist of multiple components (sample pad, conjugate pad, membrane, absorbent pad, backing card) and materials, requiring time-consuming device assembly. Here, we report a unique lateral flow immunochromatographic assay constructed from a single piece of cellulose paper, which is fabricated via laser cutting. Compared with conventional lateral flow immunochromatographic devices, this single-layer immunoassay enables simpler and faster fabrication, while minimizing material consumption and overall device costs. For proof-of-concept, this device was used to detect Plasmodium falciparum histidine-rich protein 2 (PfHRP2), a biomarker for malaria infection, which could be detected at concentrations as low as 4 ng mL−1 by the naked eye with no cross reactivity with other common Plasmodium protein biomarkers. While offering similar speed and ease-of-use as conventional LFIAs with a higher detection sensitivity than existing LFIAs for PfHRP2 detection, this single-layer lateral flow immunoassay has the potential to improve malaria testing, as well as the detection of other important protein biomarkers for point-of-care testing. [ABSTRACT FROM AUTHOR]

[Display omitted] • PEDOT:PSS and Borophene nanosheets modified conducting paper. • Cost efficient and flexible biosensor for protein biomarker detection. • Environment friendly biosensing platform with smoke free degradation. • Ultralow LOD (0.49 ng ml−1) and wider LDR (1 ng ml−1 - 60 µg ml−1) for swine flu detection. Here, we report results of the studies related to the fabrication of nanomaterial modified paper [Whatman paper modified with poly(3,4-ethylenedioxythiophene):poly(4-styrene sulfonate) (PEDOT:PSS) and Borophene nanosheets] based biosensor for proteinaceous Serum Amyloid A (SAA) biomarker detection. For the fabrication of stable and cost-efficient nanomaterial modified conducting paper, we used simple dip coating method followed by solvent treatment. The incorporation of Borophene nanosheets onto the conducting paper resulted in enhance electrochemical performance, flexibility and signal stability. The flexibility of fabricated electrode is validated via bending and folding studies; it continues to maintain conductivity even after being folded 40 times. Furthermore, this paper sensor may be quickly and properly disposed of by simple burning method without emitting smoke. It was also observed that no any harmful/heavy element was present after disposal of the paper sensor. During fabrication of paper based sensor, anti-SAA was physically immobilized and further bovine serum albumin (BSA) was used to block the non-specific binding sites. To examine structural and morphological features of the synthesized material and the fabricated paper electrodes; X-ray diffraction, transmission electron microscopy, scanning electron microscopy, contact angle, and Fourier-transform infrared spectroscopy were used. The fabricated immunoelectrode (BSA/anti-SAA/Borophene/CP) is highly efficient to detect SAA with ultralow limit of detection of 0.49 ng mL−1, wider linear detection range in between 1 ng mL−1 - 60 µg mL−1 and high durability of 42 days. Finally, SAA protein in spiked serum samples was analyzed using the fabricated immunosensor, and the obtained results show good correlation with the standard SAA protein samples. [ABSTRACT FROM AUTHOR]

Pathogens cause various infectious diseases and high morbidity and mortality which is a global public health threat. The highly sensitive and specific detection is of significant importance for the effective treatment and intervention to minimise the impact. However, conventional detection methods including culture and molecular method gravely depend on expensive equipment and well-trained skilled personnel, limiting in the laboratory. It remains challenging to adapt in resource-limiting areas, e.g., low and middle-income countries (LMICs). To this end, low-cost, rapid, and sensitive detection tools with the capability of field testing e.g., a portable device for identification and quantification of pathogens, has attracted increasing attentions. Recently, paper-based microfluidic analytical devices (μPADs) have shown a promising tool for rapid and on-site diagnosis, providing a cost-effective and sensitive analytical approach for pathogens detection. The fast turn-round data collection may also contribute to better understanding of the risks and insights on mitigation method. In this paper, critical developments of μPADs for in-field detection of pathogens both for clinical diagnostics and environmental surveillance are reviewed. The future development, and challenges of μPADs for rapid and onsite detection of pathogens are discussed, including using the cross-disciplinary development with, emerging techniques such as deep learning and Internet of Things (IoT). [Display omitted] • The state-of-the-art on μPAD is critically reviewed. • μPAD enables onsite detections of biochemical markers from molecules to organisms. • Insights is provided highlighting on multidisciplinary aspects. [ABSTRACT FROM AUTHOR]

Total joint arthroplasty (TJA) has significantly improved the quality of life for millions suffering from end-stage arthritis. However, periprosthetic joint infections (PJI) remain a serious complication, necessitating extensive interventions and prolonged antimicrobial treatments. The aging population is expected to lead to a rise in TJA cases, subsequently increasing the incidence of PJI, particularly in the elderly who face higher mortality rates. Current diagnostic methods for suspected PJI, such as radiographs and biochemical markers like CRP and ESR, exhibit limited sensitivity. Therefore, there is a critical need for a specific synovial fluid biomarker assay to enhance PJI diagnosis using specific SF-based assay. This study introduces a novel microfluidic chip with a paper-based aptamer-sandwich assay for the quantitative detection of HNP 1, a crucial PJI biomarker, in synovial fluid. The assay leverages the advantages of aptamers over antibodies, demonstrating high selectivity and affinity for target molecules. The integration of a nitrocellulose (NC) membrane onto the microfluidic platform represents a significant advancement, reducing background signals and simplifying the assay procedure without intricate procedure and pre-treatment. The NC membrane-based microfluidic device offers rapid, cost-effective, and highly sensitive detection of HNP 1, with a limit of detection of 0.5 mg L−1. The microfluidic device demonstrates exceptional performance, detecting up to four clinical samples in approximately 42 min on a single chip with 100 % accuracy, as confirmed by analysis of 12 clinical samples and comparison with "gold-standard". Moreover, the assay exhibits a wide dynamic range of 0.5–100 mg L-1, underscoring its potential as a powerful tool for PJI diagnosis in clinical settings. This work introduces a paper-based microfluidic system tailored for rapid HNP 1 detection using synovial fluid near joint region (and not serum via blood) for better diagnosis. The innovative paper-based aptamer-sandwich assay yields results within 42-min. Significantly, it boasts a wide dynamic range, detecting levels from an impressive 0.5 mg L-1, crucial in the 2.6 mg L-1 threshold region. This heightened sensitivity and expansive detection capability establish our assay as a leader in PJI diagnostics, promising unmatched precision and efficiency in clinical applications. Schematic representation of the automated paper-based aptamer sandwich assay for periprosthetic joint infection (PJI) detection. The microfluidic chip features a reaction zone utilizing an NC membrane as the paper substrate, along with a dual aptamer assay for efficient aptamer-sandwich formation. Detection is achieved via the PMT module and subsequent analysis using fluorescent microscopy to differentiate PJI-positive and negative synovial fluid (SF) samples. [Display omitted] • We devised a novel paper-based aptamer-sandwich assay integrated into an automated microfluidic platform to detect HNP 1. • 42-minute swift operated assay, streamlined pretreatment steps, no extra quenching methods needed. • Clinical samples assessed on chip; results compared to gold standard ELISA (designed for serum, adjusted for SF). [ABSTRACT FROM AUTHOR]

Elevated serum IgE levels are associated with allergic disorders, parasitosis and specific immunologic abnormalities. In addition, epidemiological and mechanistic evidence indicates an association between IgE-mediated immune surveillance and protection from tumour growth. Intriguingly, recent studies reveal a correlation between IgE deficiency and increased malignancy risk. This is the first review discussing IgE levels and links to pathological conditions, with special focus on the potential clinical significance of ultra-low serum IgE levels and risk of malignancy. In this Position Paper we discuss: (a) the utility of measuring total IgE levels in the management of allergies, parasitosis, and immunodeficiencies, (b) factors that may influence serum IgE levels, (c) IgE as a marker of different disorders, and d) the relationship between ultra-low IgE levels and malignancy susceptibility. While elevated serum IgE is generally associated with allergic/atopic conditions, very low or absent IgE may hamper anti-tumour surveillance, indicating the importance of a balanced IgE-mediated immune function. Ultra-low IgE may prove to be an unexpected biomarker for cancer risk. Nevertheless, given the early stage of investigations conducted mostly in patients with diseases that influence IgE levels, in-depth mechanistic studies and stratification of malignancy risk based on associated demographic, immunological and clinical co-factors are warranted. [ABSTRACT FROM AUTHOR]

Elevated serum IgE levels are associated with allergic disorders, parasitosis and specific immunologic abnormalities. In addition, epidemiological and mechanistic evidence indicates an association between IgE‐mediated immune surveillance and protection from tumour growth. Intriguingly, recent studies reveal a correlation between IgE deficiency and increased malignancy risk. This is the first review discussing IgE levels and links to pathological conditions, with special focus on the potential clinical significance of ultra‐low serum IgE levels and risk of malignancy. In this Position Paper we discuss: (a) the utility of measuring total IgE levels in the management of allergies, parasitosis, and immunodeficiencies, (b) factors that may influence serum IgE levels, (c) IgE as a marker of different disorders, and d) the relationship between ultra‐low IgE levels and malignancy susceptibility. While elevated serum IgE is generally associated with allergic/atopic conditions, very low or absent IgE may hamper anti‐tumour surveillance, indicating the importance of a balanced IgE‐mediated immune function. Ultra‐low IgE may prove to be an unexpected biomarker for cancer risk. Nevertheless, given the early stage of investigations conducted mostly in patients with diseases that influence IgE levels, in‐depth mechanistic studies and stratification of malignancy risk based on associated demographic, immunological and clinical co‐factors are warranted. [ABSTRACT FROM AUTHOR]

Microvesicles and exosomes are promising liquid biopsy biomarkers. However, conventional isolation techniques damage and contaminate the biomarkers. We developed an origami-paper-based device for effective isolation of biomarkers with less damage and in fewer steps. The multi-folded device enables the preconcentration of the microvesicles/exosomes on specific layers (∼5-fold) by the ion concentration polarization technique and they were simply isolated from the rest of the sample by unfolding the device. [ABSTRACT FROM AUTHOR]

The lack of sensitivity is a major problem among microfluidic paper-based analytical devices (μPADs) for early disease detection and diagnosis. Accordingly, the present study presents a method for improving the enrichment factor of low-concentration biomarkers by using shallow paper-based channels realized through a double-sided wax-printing process. In addition, the enrichment factor is further enhanced by exploiting the ion concentration polarization (ICP) effect on the cathodic side of the nanoporous membrane, in which a stationary sample plug is obtained. The occurrence of ICP on the shallow-channel μPAD is confirmed by measuring the current–voltage response as the external voltage is increased from 0 to 210 V (or the field strength from 0 to 1.05 × 104 V m−1) over 600 s. In addition, to the best of our knowledge, the electroosmotic flow (EOF) speed on the μPAD fabricated with a wax-channel is measured for the first time using a current monitoring method. The experimental results show that for a fluorescein sample, the concentration factor is increased from 130-fold in a conventional full-thickness paper channel to 944-fold in the proposed shallow channel. Furthermore, for a fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) sample, the proposed shallow-channel μPAD achieves an 835-fold improvement in the concentration factor. The concentration technique presented here provides a novel strategy for enhancing the detection sensitivity of μPAD applications. [ABSTRACT FROM AUTHOR]

With more than 23 million infections and more than 814,000 deaths worldwide, the coronavirus disease-2019 (COVID-19) pandemic is still far from over. Several classes of drugs including antivirals, antiretrovirals, anti-inflammatory, immunomodulatory, and antibiotics have been tried with varying levels of success. Still, there is lack of any specific therapy to deal with this infection. Although less than 30% of these patients require intensive care unit admission, morbidity and mortality in this subgroup of patients remain high. Hence, it becomes imperative to have general principles to guide intensivists managing these patients. However, as the literature emerges, these recommendations may change and hence, frequent updates may be required. [ABSTRACT FROM AUTHOR]

In a resource-limited country like India, rationing of scarce critical care resources might be required to ensure appropriate delivery of care to the critically ill patients suffering from COVID-19 infection. Most of these patients require critical care support because of respiratory failure or presence of multiorgan dysfunction syndrome. As there is no pharmacological therapy available, respiratory support in the form of supplemental oxygen, noninvasive ventilation, and invasive mechanical ventilation remains mainstay of care in intensive care units. As there is still dearth of direct evidence, most of the data are extrapolated from the experience gained from the management of general critical care patients. [ABSTRACT FROM AUTHOR]

Abstract We present a QR code paper microfluidic colorimetric assay that can exploit the hardware and software on mobile devices, and circumvent sample preparation by directly targeting volatile biomarkers. Our platform is a printable microarray of well-defined reaction regions, which outputs an instant diagnosis by directing the user to a URL containing their test result, while simultaneously storing epidemiological data for remote access and bioinformatics. To assist in the rapid identification of Escherichia coli in bloodstream infections, we employed an existing colorimetric reagent (p -dimethylaminocinnamaldehyde) and adapted its use to detect volatile indole, a biomarker produced by E. coli. Our assay was able to quantitatively detect indole in the headspace of E. coli culture after 12 h of growth (27.0 ± 3.1 ppm), assisting in species-level identification hours earlier than existing methods. Results were confirmed with headspace solid-phase microextraction (HS-SPME) two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-ToFMS), which estimated indole concentration in E. coli culture to average 32.3 ± 5.2 ppm after 12 h of growth. This QR paper microfluidic platform represents a novel development in both telemedicine and diagnostics using volatile biomarkers. We envision that our QR code platform can be extended to other colorimetric assays for real-time diagnostics in low-resource environments. Highlights • Volatile indole can be detected on a paper substrate with a colorimetric reagent. • Colorimetric signal correlates linearly with volatile indole concentration. • Indole can be colorimetrically detected in the headspace of E. coli culture. • Benchmarking with GCxGC-TOFMS showed that paper sensor measurements were accurate. • Digital QR code paper-based microfluidic sensors are feasible diagnostic platforms. [ABSTRACT FROM AUTHOR]

Abstract Citrate is currently considered a preferred biomarker for the early stage detection of prostate cancer. In the present work, based on the highly efficient catalytic properties of gold nanoclusters, a novel system for optical determination of citrate was successfully established under optimized conditions. Cysteine-capped gold nanoclusters (Cys-AuNCs) are shown to have an intrinsic peroxidase-mimetic activity. In the presence of H 2 O 2, Cys-AuNCs nanostructures are able to catalyse the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) with high efficiency to produce a blue dye (with an absorbance maximum at 650 nm). Citrate has carboxylic and hydroxyl groups that can bind with free amino and free carboxyl cysteine groups via hydrogen bonds, thus creating a coating on the surface of the gold nanocluster and inhibiting the cluster oxidation activity. Accordingly, a visual, sensitive and simple colorimetric method using Cys-AuNCs as peroxidase mimetic was developed for detecting citrate. A suitable linear relationship for citrate was obtained for the range of 0.5 to 1000 μM. The limit of detection (LOD) of the proposed method was calculated as 0.1 μM and the relative standard deviation (RSD) was obtained to be less than 4.0%. Moreover, the biosensor was used to perform a paper assay on a Y-shaped microfluidic device and make use of the distinctive features of microchannels such as short response time, very low reagent volume required, low fabrication cost etc. A detection limit of 0.4 μM was achieved through the paper test and a good linear range was observed between 1.0 μM–10 mM. The proposed method was further applied to citrate detection in the human urine sample. Graphical Abstract Unlabelled Image Highlights • The first approach for colorimetric detection of citrate as biomarker was investigated. • The method was used to perform a paper assay on a Y-shaped microfluidic device. • A detection limit of 0.4 µM was achieved through the paper test • The assay was applied to citrate detection in the human urine sample. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer Disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory and other cognitive functions. Protein Kinase Cε (PKCε) is an isoform that most effectively suppresses Amyloid Beta (Aβ) production and synaptic loss. Methods: In this study, spatial learning and memory for treated rats were evaluated by the Morris water maze test. The activity (total PKC), mRNA expression, and protein level of PKCε in the platelet and hippocampal tissue were evaluated using immunosorbent assay, real-time qPCR, and western blotting analysis, respectively. Results: The traveled distance was significantly prolonged, and escape latency significantly increased in Aβ-treated groups. PKC activity assay showed that there was a remarkable difference between the Aβ-treated and sham-operated groups on days 10 and 30 in the hippocampus and also day 30 in platelet after the injection of Aβ. A significant effect in PKC activity was observed between days 0 and 10, days 0 and 30, as well as days 5 and 30. Aβ significantly downregulated the PKCε mRNA expression in the hippocampus of rats on day 30; however, no significant difference was observed in platelet. Western blot analysis demonstrated that Aβ significantly reduced PKCε protein expression in the hippocampus of treated groups on day 30. Conclusion: The expression level of PKCε was downregulated following the injection of Aβ in the hippocampus, but no significant difference was observed between the AD and sham groups in platelet that may be due to the low concentration of PKCε or duration of Aβ exposure in the rat brain. [ABSTRACT FROM AUTHOR]