Toward the Rapid Diagnosis of Sepsis: Detecting Interleukin-6 in Blood Plasma Using Functionalized Screen-Printed Electrodes with a Thermal Detection Methodology.

This paper reports the detection of the inflammatory and sepsis-related biomarker, interleukin-6 (IL-6), in human blood plasma using functionalized screen-printed electrodes (SPEs) in conjunction with a thermal detection methodology, termed heat-transfer method (HTM). SPEs are functionalized with antibodies specific for IL-6 through electrodeposition of a diazonium linking group and N'-ethylcarbodiimide hydrochloride (EDC) coupling, which was tracked through the use of cyclic voltammetry and Raman spectroscopy. The functionalized SPEs are mounted inside an additively manufactured flow cell and connected to the HTM device. We demonstrate the ability to detect IL-6 at clinically relevant concentrations in PBS buffer (pH = 7.4) with no significant interference from the similarly sized sepsis-related biomarker procalcitonin (PCT). The limit of detection (3σ) of the system is calculated to correspond to 3.4 ± 0.2 pg mL-1 with a working range spanning the physiologically relevant concentration levels in both healthy individuals and patients with sepsis, indicating the sensitivity of the sensor is suitable for the application. Further experiments helped provide a proof-of-application through the detection of IL-6 in blood plasma with no significant interference observed from PCT or the constituents of the medium. Due to the selectivity, sensitivity, straightforward operation, and low cost of production, this sensor platform has the potential for use as a traffic light sensor for the multidetection of inflammatory biomarkers for the diagnosis of sepsis and other conditions in which the rapid testing of blood biomarkers has vital clinical application.

Immature platelet indices alongside procalcitonin for sensitive and specific identification of bacteremia in the intensive care unit.

Hematological markers that can be rapidly analyzed and regularly monitored during a patient's stay on ICU, and that can identify bacterial causes of sepsis are being extensively sought. The significance of platelets in early immunological responses provides justification for assessing their usefulness in the identification of bacteremia amongst sepsis patients. In this preliminary study, the full blood count, including the platelet count by impedance (PLT-I), Immature Platelet Fraction (IPF%) and absolute immature platelet count (AIPC), were analyzed in eighty-two sepsis patients daily over the first 5 days stay on ICU. C-Reactive Protein (CRP), procalcitonin (PCT), and lactate were also analyzed daily. Blood cultures confirmed or excluded the presence of bacteremia. PCT provided the earliest indicator of bacteremia, with significant differences between the two cohorts on day 1. The change in IPF% and AIPC from day 1 to day 2 (Δ IPF% and Δ AIPC) provided the most accurate indication; A combination of Δ IPF% and day 2 PCT, provided a positive predictive value and negative predictive value of 100% and 96.10%, respectively. These data provide strong justification for larger multi-center validation studies to confirm the usefulness of these platelet indices during the assessment of sepsis on the ICU.

Evaluating the Possibility of Translating Technological Advances in Non-Invasive Continuous Lactate Monitoring into Critical Care.

Lactate is widely measured in critically ill patients as a robust indicator of patient deterioration and response to treatment. Plasma concentrations represent a balance between lactate production and clearance. Analysis has typically been performed with the aim of detecting tissue hypoxia. However, there is a diverse range of processes unrelated to increased anaerobic metabolism that result in the accumulation of lactate, complicating clinical interpretation. Further, lactate levels can change rapidly over short spaces of time, and even subtle changes can reflect a profound change in the patient's condition. Hence, there is a significant need for frequent lactate monitoring in critical care. Lactate monitoring is commonplace in sports performance monitoring, given the elevation of lactate during anaerobic exercise. The desire to continuously monitor lactate in athletes has led to the development of various technological approaches for non-invasive, continuous lactate measurements. This review aims firstly to reflect on the potential benefits of non-invasive continuous monitoring technology within the critical care setting. Secondly, we review the current devices used to measure lactate non-invasively outside of this setting and consider the challenges that must be overcome to allow for the translation of this technology into intensive care medicine. This review will be of interest to those developing continuous monitoring sensors, opening up a new field of research.

Modular Synthesis and Biological Investigation of 5-Hydroxymethyl Dibenzyl Butyrolactones and Related Lignans.

Dibenzyl butyrolactone lignans are well known for their excellent biological properties, particularly for their notable anti-proliferative activities. Herein we report a novel, efficient, convergent synthesis of dibenzyl butyrolactone lignans utilizing the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate. The reported synthetic route enables the modification of these lignans to give rise to 5-hydroxymethyl derivatives of these lignans. The biological activities of these analogues were assessed, with derivatives showing an excellent cytotoxic profile which resulted in programmed cell death of Jurkat T-leukemia cells with less than 2% of the incubated cells entering a necrotic cell death pathway.

Low-cost, facile droplet modification of screen-printed arrays for internally validated electrochemical detection of serum procalcitonin.

This manuscript presents the design and facile production of screen-printed arrays (SPAs) for the internally validated determination of raised levels of serum procalcitonin (PCT). The screen-printing methodology produced SPAs with six individual working electrodes that exhibit an inter-array reproducibility of 3.64% and 5.51% for the electrochemically active surface area and heterogenous electrochemical rate constant respectively. The SPAs were modified with antibodies specific for the detection of PCT through a facile methodology, where each stage simply uses droplets incubated on the surface, allowing for their mass-production. This platform was used for the detection of PCT, achieving a linear dynamic range between 1 and 10 ng mL-1 with a sensor sensitivity of 1.35 × 10-10 NIC%/ng mL-1. The SPA produced an intra- and inter-day %RSD of 4.00 and 5.05%, with a material cost of £1.14. Internally validated human serum results (3 sample measurements, 3 control) for raised levels of PCT (>2 ng mL-1) were obtained, with no interference effects seen from CRP and IL-6. This SPA platform has the potential to offer clinicians vital information to rapidly begin treatment for "query sepsis" patients while awaiting results from more lengthy remote laboratory testing methods. Analytical ranges tested make this an ideal approach for rapid testing in specific patient populations (such as neonates or critically ill patients) in which PCT ranges are inherently wider. Due to the facile modification methods, we predict this could be used for various analytes on a single array, or the array increased further to maintain the internal validation of the system.

Immature platelet fraction as a useful marker in the etiological determination of thrombocytopenia.

The etiology of thrombocytopenia is important in treatment and management of the condition. Most platelet parameters that are routinely analyzed in the diagnostic laboratory have not proven useful in identifying the etiology, while specialized assays suffer from poor standardization and lack of agreement between laboratories. The immature platelet fraction (IPF), which indirectly provides a measure of bone marrow function, is showing promise as a valuable marker of thrombopoietic responses. This study set out determine whether the IPF could effectively identify specific underlying etiologies of thrombocytopenia in a large thrombocytopenic cohort, to allow for quicker, more effective management of the condition. The IPF was analyzed in a large cohort of 637 thrombocytopenic patients and 171 healthy control patients on the Sysmex XN 10 hematology analyzer using the specialized fluorescence optical analysis. The thrombocytopenic patients were divided into six cohorts based on etiology. The IPF% was significantly higher in cases of increased platelet consumption (median = 9.55, min = 1.1, max = 77.9) or pseudothrombocytopenia (median = 13.1, min = 0.4, max = 28.8) compared with control (median = 4.2, min = 1.3, max = 12.8). Furthermore, the IPF% was also able to identify idiopathic thrombocytopenic purpura (ITP) (p < 0.05) (median = 13.4, min = 2.8, max = 77.9) from other causes of increased platelet consumptive disorders (infection: median = 6.4, min = 1.1, max = 21.6; hemorrhage: median = 8.9, min = 1.2, max = 20.2). By use of this large thrombocytopenic cohort, the IPF% has been found to be of significant diagnostic value, providing a useful rapid test in the etiological investigation of platelet disorders.

Thieno[2,3-b]pyridine derivatives are potent anti-platelet drugs, inhibiting platelet activation, aggregation and showing synergy with aspirin.

Drugs which inhibit platelet function are commonly used to prevent blood clot formation in patients with Acute Coronary Syndromes (ACS) or those at risk of stroke. The thieno[3,2-c]pyridine class of therapeutic agents, of which clopidogrel is the most commonly used, target the P2Y12 receptor, and are often used in combination with acetylsalicylic acid (ASA). Six thieno[2,3-b]pyridine were assessed for in vitro anti-platelet activity; all derivatives showed effects on both platelet activation and aggregation, and showed synergy with ASA. Some compounds demonstrated greater activity when compared to clopidogrel. These compounds, therefore, represent potential novel P2Y12 inhibitors for improved treatment for patients.