Estimation of the Likelihood Ratio of Different Symptoms for Six Homeopathic Medicines: Prognostic Factor Research.

BACKGROUND: Arsenicum album, Causticum, Nux vomica, Pulsatilla nigricans, Rhus toxicodendron and Sulphur are frequently prescribed homeopathic medicines; however, their symptoms, as mentioned in different homeopathic literature works, have rarely been investigated systematically. Likelihood ratio (LR), based on Bayesian statistics, may reflect a better estimation of the strengths of symptoms than the existing entries in the homeopathic literature. METHODS: A prospective, longitudinal, analytical patient outcome study was conducted in the outpatient departments of D. N. De Homeopathic Medical College and Hospital, Kolkata, on 1,954 patients over 21 months. The outcomes were recorded at each follow-up using the Outcome Related to Impact on Daily Living (ORIDL) +4 to -4 scale. The average period of treatment for each participant was 3 months. The LRs of four symptoms for each of the six selected medicines were calculated. RESULTS: One hundred and two different remedies were prescribed. The prevalence, LR + , and LR - , with respective 95% confidence intervals, of different symptoms were reported. The study found that the following symptoms had particularly high LR+ scores: "intense sympathy for the suffering of others" (Causticum, LR+ = 12.0); "dyspepsia from business anxiety" (Nux vomica, LR+ = 27.4); "burning pain relieved by heat" (Arsenicum album, LR+ = 29.6); "envy" (Pulsatilla nigricans, LR+ = 13.2); "desire for milk" (Rhus toxicodendron, LR+ = 7.5); "very selfish, no regard for others" (Sulphur, LR+ = 20.6). The findings corroborated well with the presentation of the symptoms in different homeopathic materia medica and repertories. ORIDL scores of +2 or greater were identified most prominently for Pulsatilla nigricans (n = 138) and Sulphur (n = 119). CONCLUSION: There was adequate evidence to attribute all the assessed symptoms to the medicines investigated. Further studies with a larger population are warranted to tackle the possible confirmation bias.

Harvesting and manipulating sweat and interstitial fluid in microfluidic devices.

Microfluidic devices began to be used to facilitate sweat and interstitial fluid (ISF) sensing in the mid-2010s. Since then, numerous prototypes involving microfluidics have been developed in different form factors for sensing biomarkers found in these fluids under in vitro, ex vivo, and in vivo (on-body) settings. These devices transport and manipulate biofluids using microfluidic channels composed of silicone, polymer, paper, or fiber. Fluid flow transport and sample management can be achieved by controlling the flow rate, surface morphology of the channel, and rate of fluid evaporation. Although many devices have been developed for estimating sweat rate, electrolyte, and metabolite levels, only a handful have been able to proceed beyond laboratory testing and reach the stage of clinical trials and commercialization. To further this technology, this review reports on the utilization of microfluidics towards sweat and ISF management and transport. The review is distinguished from other recent reviews by focusing on microfluidic principles of sweat and ISF generation, transport, extraction, and management. Challenges and prospects are highlighted, with a discussion on how to transition such prototypes towards personalized healthcare monitoring systems.

Insulin detection in diabetes mellitus: challenges and new prospects.

Tremendous progress has been made towards achieving tight glycaemic control in individuals with diabetes mellitus through the use of frequent or continuous glucose measurements. However, in patients who require insulin, accurate dosing must consider multiple factors that affect insulin sensitivity and modulate insulin bolus needs. Accordingly, an urgent need exists for frequent and real-time insulin measurements to closely track the dynamic blood concentration of insulin during insulin therapy and guide optimal insulin dosing. Nevertheless, traditional centralized insulin testing cannot offer timely measurements, which are essential to achieving this goal. This Perspective discusses the advances and challenges in moving insulin assays from traditional laboratory-based assays to frequent and continuous measurements in decentralized (point-of-care and home) settings. Technologies that hold promise for insulin testing using disposable test strips, mobile systems and wearable real-time insulin-sensing devices are discussed. We also consider future prospects for continuous insulin monitoring and for fully integrated multisensor-guided closed-loop artificial pancreas systems.

Wearable Electrochemical Glucose Sensors in Diabetes Management: A Comprehensive Review.

With the rising diabetic population, the demand for glucose sensing devices has also been on an increasing trend. Accordingly, the field of glucose biosensors for diabetes management has witnessed tremendous scientific and technological advancements since the introduction of the first enzymatic glucose biosensor in the 1960s. Among these, electrochemical biosensors hold considerable potential for tracking dynamic glucose profiles in real time. The recent evolution of wearable devices has opened opportunities to use alternative body fluids in a pain-free, noninvasive or minimally invasive manner. This review aims to present a comprehensive report about the status and promise of wearable electrochemical sensors for on-body glucose monitoring. We start by highlighting the importance of diabetes management and how sensors can contribute toward its effective monitoring. We then discuss the electrochemical glucose sensing mechanisms, evolution of such glucose sensors over time, different versions of wearable glucose biosensors targeting various biofluids, and multiplexed wearable sensors toward optimal diabetes management. Finally, we focus on the commercial aspects of wearable glucose biosensors, starting with existing continuous glucose monitors, followed by other emerging sensing technologies, and concluding with highlighting the key prospects toward personalized diabetes management in connection to an autonomous closed-loop artificial pancreas.

Non-invasive in-vivo glucose-based stress monitoring in plants.

Plant stress responses involve a suite of genetically encoded mechanisms triggered by real-time interactions with their surrounding environment. Although sophisticated regulatory networks maintain proper homeostasis to prevent damage, the tolerance thresholds to these stresses vary significantly among organisms. Current plant phenotyping techniques and observables must be better suited to characterize the real-time metabolic response to stresses. This impedes practical agronomic intervention to avoid irreversible damage and limits our ability to breed improved plant organisms. Here, we introduce a sensitive, wearable electrochemical glucose-selective sensing platform that addresses these problems. Glucose is a primary plant metabolite, a source of energy produced during photosynthesis, and a critical molecular modulator of various cellular processes ranging from germination to senescence. The wearable-like technology integrates a reverse iontophoresis glucose extraction capability with an enzymatic glucose biosensor that offers a sensitivity of 22.7 nA/(µM·cm2), a limit of detection (LOD) of 9.4 µM, and a limit of quantification (LOQ) of 28.5 µM. The system's performance was validated by subjecting three different plant models (sweet pepper, gerbera, and romaine lettuce) to low-light and low-high temperature stresses and demonstrating critical differential physiological responses associated with their glucose metabolism. This technology enables non-invasive, non-destructive, real-time, in-situ, and in-vivo identification of early stress response in plants and provides a unique tool for timely agronomic management of crops and improving breeding strategies based on the dynamics of genome-metabolome-phenome relationships.

Non-invasive monitoring of interstitial fluid lactate through an epidermal iontophoretic device.

The development of a non-invasive sensing technology that allows collection of interstitial fluid (ISF) lactate and its subsequent analysis without exertion requirement, could enable lactate monitoring from rested individuals. Here, we describe a wearable, soft epidermal adhesive patch that integrates a reverse iontophoretic (RI) system, and an amperometric lactate biosensor placed on the anodic electrode with a porous hydrogel reservoir, for simultaneous ISF lactate extraction and quantification via electrochemical sensing, respectively. The iontophoretic system includes agarose hydrogels for preventing skin electrocution, while a porous polyvinyl alcohol-based hydrogel facilitates the effective transport of lactate from skin to the biosensor. The flexible skin-worn device tested on healthy individuals at rest showed rapid lactate collection from the ISF after 10 min of reverse iontophoresis with no evidence of discomfort or irritation to the skin. Detailed characterization of the enzymatic biosensor before and during on-body trials along with relevant control experiments confirmed the efficient extraction and selective detection of ISF lactate. Such an epidermal technology represents the first demonstration of an all-in-one platform that integrates non-invasive collection and subsequent analysis of lactate from iontophoretically extracted ISF toward point-of-care operation.

Disposable screen-printed electrochemical sensing strips for rapid decentralized measurements of salivary ketone bodies: Towards therapeutic and wellness applications.

The interest in ketone bodies (KBs) has intensified recently as they play significant roles in healthcare, nutrition, and wellness applications. We present a disposable electrochemical sensing strip for rapid decentralized detection of ß-hydroxybutyrate (HB), one of the dominant physiological KBs, in saliva. The new salivary enzymatic HB sensor strip relies on a gold-coated screen-printed carbon electrode modified with a reagent layer containing toluidine blue O (TBO mediator), ß-hydroxybutyrate dehydrogenase (HBD enzyme), and the HBD cofactor nicotinamide adenine dinucleotide (NAD+ coenzyme), along with carbon nanotubes (CNTs) and chitosan (Chit) for enhancing the sensor's sensitivity and for encapsulating the enzyme and its cofactor, respectively. The systematic optimization resulted in an attractive analytical performance, with a rapid response time within 60 s, a wide HB dynamic detection range from 0.1 to 3.0 mM along with a low limit of detection (50 µM HB) in an artificial saliva medium. The strip displays high selectivity for HB over acetoacetate (AcAc) and other interferences (i.e., acetaminophen, ascorbic acid, glucose, lactic acid, and uric acid), good reproducibility, and high stability towards temperature or pH effects. The new disposable sensing strip system, coupled with a hand-held electrochemical analyzer, showed rapid HB monitoring in human saliva samples collected from healthy volunteers, with similar temporal profiles to those obtained in parallel capillary blood measurements in response to the intake of keto supplements. This strip enables efficient, reliable, and near real-time salivary HB detection to track non-invasively the dynamics of HB concentrations after intaking commercial supplements towards diverse healthcare and nutrition applications.

Self-Testing of Ketone Bodies, along with Glucose, Using Touch-Based Sweat Analysis.

ß-Hydroxybutyrate (HB) is one of the main physiological ketone bodies that play key roles in human health and wellness. Besides their important role in diabetes ketoacidosis, ketone bodies are currently receiving tremendous attention for personal nutrition in connection to the growing popularity of oral ketone supplements. Accordingly, there are urgent needs for developing a rapid, simple, and low-cost device for frequent onsite measurements of ß-hydroxybutyrate (HB), one of the main physiological ketone bodies. However, real-time profiling of dynamically changing HB concentrations is challenging and still limited to laboratory settings or to painful and invasive measurements (e.g., a commercial blood ketone meter). Herein, we address the critical need for pain-free frequent HB measurements in decentralized settings and report on a reliable noninvasive, simple, and rapid touch-based sweat HB testing and on its ability to track dynamic HB changes in secreted fingertip sweat, following the intake of commercial ketone supplements. The new touch-based HB detection method relies on an instantaneous collection of the fingertip sweat at rest on a porous poly(vinyl alcohol) (PVA) hydrogel that transports the sweat to a biocatalytic layer, composed of the ß-hydroxybutyrate dehydrogenase (HBD) enzyme and its nicotinamide adenine dinucleotide (NAD+) cofactor, covering the modified screen-printed carbon working electrode. As a result, the sweat HB can be measured rapidly by the mediated oxidation reaction of the nicotinamide adenine dinucleotide (NADH) product. A personalized HB dose-response relationship is demonstrated within a group of healthy human subjects taking commercial ketone supplements, along with a correlation between the sweat and capillary blood HB levels. Furthermore, a dual disposable biosensing device, consisting of neighboring ketone and glucose enzyme electrodes on a single-strip substrate, has been developed toward the simultaneous touch-based detection of dynamically changing sweat HB and glucose levels, following the intake of ketone and glucose drinks.

Access and Management of Sweat for Non-Invasive Biomarker Monitoring: A Comprehensive Review.

Sweat is an important biofluid presents in the body since it regulates the internal body temperature, and it is relatively easy to access on the skin unlike other biofluids and contains several biomarkers that are also present in the blood. Although sweat sensing devices have recently displayed tremendous progress, most of the emerging devices primarily focus on the sensor development, integration with electronics, wearability, and data from in vitro studies and short-term on-body trials during exercise. To further the advances in sweat sensing technology, this review aims to present a comprehensive report on the approaches to access and manage sweat from the skin toward improved sweat collection and sensing. It is begun by delineating the sweat secretion mechanism through the skin, and the historical perspective of sweat, followed by a detailed discussion on the mechanisms governing sweat generation and management on the skin. It is concluded by presenting the advanced applications of sweat sensing, supported by a discussion of robust, extended-operation epidermal wearable devices aiming to strengthen personalized healthcare monitoring systems.

Wireless Wearable Electrochemical Sensing Platform with Zero-Power Osmotic Sweat Extraction for Continuous Lactate Monitoring.

Wearable and wireless monitoring of biomarkers such as lactate in sweat can provide a deeper understanding of a subject's metabolic stressors, cardiovascular health, and physiological response to exercise. However, the state-of-the-art wearable and wireless electrochemical systems rely on active sweat released either via high-exertion exercise, electrical stimulation (such as iontophoresis requiring electrical power), or chemical stimulation (such as by delivering pilocarpine or carbachol inside skin), to extract sweat under low-perspiring conditions such as at rest. Here, we present a continuous sweat lactate monitoring platform combining a hydrogel for osmotic sweat extraction, with a paper microfluidic channel for facilitating sweat transport and management, a screen-printed electrochemical lactate sensor, and a custom-built wireless wearable potentiostat system. Osmosis enables zero-electrical power sweat extraction at rest, while continuous evaporation at the end of a paper channel allows long-term sensing from fresh sweat. The positioning of the lactate sensors provides near-instantaneous sensing at low sweat volume, and the custom-designed potentiostat supports continuous monitoring with ultra-low power consumption. For a proof of concept, the prototype system was evaluated for continuous measurement of sweat lactate across a range of physiological activities with changing lactate concentrations and sweat rates: for 2 h at the resting state, 1 h during medium-intensity exercise, and 30 min during high-intensity exercise. Overall, this wearable system holds the potential of providing comprehensive and long-term continuous analysis of sweat lactate trends in the human body during rest and under exercising conditions.

A Wearable Patch for Prolonged Sweat Lactate Harvesting and Sensing.

Operating at low sweat rates, such as those experienced by humans at rest, is still an unmet need for state-of-the-art wearable sweat harvesting and testing devices for lactate. Here, we report the on-skin performance of a non-invasive wearable sweat sampling patch that can harvest sweat at rest, during exercise, and post-exercise. The patch simultaneously uses osmosis and evaporation for long-term (several hours) sampling of sweat. Osmotic sweat withdrawal is achieved by skin-interfacing a hydrogel containing a concentrated solute. The gel interfaces with a paper strip that transports the fluid via wicking and evaporation. Proof of concept results show that the patch was able to sample sweat during resting and post-exercise conditions, where the lactate concentration was successfully quantified. The patch detected the increase in sweat lactate levels during medium level exercise. Blood lactate remained invariant with exercise as expected. We also developed a continuous sensing version of the patch by including enzymatic electrochemical sensors. Such a battery-free, passive, wearable sweat sampling patch can potentially provide useful information about the human metabolic activity.

Osmotically Enabled Wearable Patch for Sweat Harvesting and Lactate Quantification.

Lactate is an essential biomarker for determining the health of the muscles and oxidative stress levels in the human body. However, most of the currently available sweat lactate monitoring devices require external power, cannot measure lactate under low sweat rates (such as in humans at rest), and do not provide adequate information about the relationship between sweat and blood lactate levels. Here, we discuss the on-skin operation of our recently developed wearable sweat sampling patch. The patch combines osmosis (using hydrogel discs) and capillary action (using paper microfluidic channel) for long-term sweat withdrawal and management. When subjects are at rest, the hydrogel disc can withdraw fluid from the skin via osmosis and deliver it to the paper. The lactate amount in the fluid is determined using a colorimetric assay. During active sweating (e.g., exercise), the paper can harvest sweat even in the absence of the hydrogel patch. The captured fluid contains lactate, which we quantify using a colorimetric assay. The measurements show the that the total number of moles of lactate in sweat is correlated to sweat rate. Lactate concentrations in sweat and blood correlate well only during high-intensity exercise. Hence, sweat appears to be a suitable biofluid for lactate quantification. Overall, this wearable patch holds the potential of providing a comprehensive analysis of sweat lactate trends in the human body.

Wearable Osmotic-Capillary Patch for Prolonged Sweat Harvesting and Sensing.

Biomarkers in sweat are a largely untapped source of health information. Most of the currently available sweat harvesting and testing devices are incapable of operating under low-sweat rates such as those experienced by humans at rest. Here we analyze the in vitro and in vivo sampling of sweat through osmosis via the use of a hydrogel interfaced with the skin, without need for active perspiration. The hydrogel also interfaces with paper-based microfluidics to transport the fluid via capillary forces toward a testing zone and then evaporation pad. We show that the hydrogel solute content and area of the evaporation pad regulate the long-term extraction of sweat and its associated biomarkers. The results indicate that the platform can sample biomarkers from a model skin system continuously for approximately 12 h. On-skin testing of the platform on both resting and exercising human subjects confirms that it can sample sweat lactate directly from the surface of skin. The results highlight that lactate in sweat increases with exercise and as a direct result of muscle activity. Implementation of such new principles for sweat fluid harvesting and management via wearable patch devices can contribute toward the advancement of next generation wearables.

Principles of long-term fluids handling in paper-based wearables with capillary-evaporative transport.

We construct and investigate paper-based microfluidic devices, which model long-term fluid harvesting, transport, sensing, and analysis in new wearables for sweat analysis. Such devices can continuously wick fluid mimicking sweat and dispose of it on evaporation pads. We characterize and analyze how the action of capillarity and evaporation can cooperatively be used to transport and process sweat mimics containing dissolved salts and model analytes. The results point out that non-invasive osmotic extraction combined with paper microfluidics and evaporative disposal can enable sweat collection and monitoring for durations longer than 10 days. We model the fluid flow in the new capillary-evaporative devices and identify the parameters enabling their long-term operation. We show that the transport rates are sufficiently large to handle natural sweat rates, while we envision that such handling can be interfaced with osmotic harvesting of sweat, a concept that we demonstrated recently. Finally, we illustrate that the salt film deposited at the evaporation pad would eventually lead to cessation of the process but at the same time will preserve a record of analytes that may be used for long-term biomarker monitoring in sweat. These principles can be implemented in future platforms for wearable skin-interfacing assays or electronic biomarker monitors.