Loss of pulsatility with continuous-flow left ventricular assist devices and the significance of the arterial endothelium in von-Willebrand factor production and degradation.

BACKGROUND: Patients on continuous flow ventricular assist devices (CF-VADs) are at high risk for the development of Acquired von-Willebrand Syndrome (AVWS) and non-surgical bleeding. von Willebrand Factor (vWF) plays an essential role in maintaining hemostasis via platelet binding to the damaged endothelium to facilitate coagulation. In CF-VAD patients, degradation of vWF into low MW multimers that are inefficient in facilitating coagulation occurs and has been primarily attributed to the supraphysiological shear stress associated with the CF-VAD impeller. METHODS: In this review, we evaluate information from the literature regarding the unraveling behavior of surface-immobilized vWF under pulsatile and continuous flow pertaining to: (A) the process of arterial endothelial vWF production and release into circulation, (B) the critical shear stress required to unravel surface bound versus soluble vWF which leads to degradation, and (C) the role of pulsatility in on the production and degradation of vWF. RESULTS AND CONCLUSION: Taken together, these data suggests that the loss of pulsatility and its impact on arterial endothelial cells plays an important role in the production, release, unraveling, and proteolytic degradation of vWF into low MW multimers, contributing to the development of AVWS. Restoration of pulsatility can potentially mitigate this issue by preventing AVWS and minimizing the risk of non-surgical bleeding.

Acute Response of Human Aortic Endothelial Cells to Loss of Pulsatility as Seen during Cardiopulmonary Bypass.

Cardiopulmonary bypass (CPB) results in short-term (3-5 h) exposure to flow with diminished pulsatility often referred to as "continuous flow". It is unclear if short-term exposure to continuous flow influences endothelial function, particularly, changes in levels of pro-inflammatory and pro-angiogenic cytokines. In this study, we used the endothelial cell culture model (ECCM) to evaluate if short-term (≤5 h) reduction in pulsatility alters levels of pro-inflammatory/pro-angiogenic cytokine levels. Human aortic endothelial cells (HAECs) cultured within the ECCM provide a simple model to evaluate endothelial cell function in the absence of confounding factors. HAECs were maintained under normal pulsatile flow for 24 h and then subjected to continuous flow (diminished pulsatile pressure and flow) as observed during CPB for 5 h. The ECCM replicated pulsatility and flow morphologies associated with normal hemodynamic status and CPB as seen with clinically used roller pumps. Levels of angiopoietin-2 (ANG-2), vascular endothelial growth factor-A (VEGF-A), and hepatocyte growth factor were lower in the continuous flow group in comparison to the pulsatile flow group whereas the levels of endothelin-1 (ET-1), granulocyte colony stimulating factor, interleukin-8 (IL-8) and placental growth factor were higher in the continuous flow group in comparison to the pulsatile flow group. Immunolabelling of HAECs subjected to continuous flow showed a decrease in expression of ANG-2 and VEGF-A surface receptors, tyrosine protein kinase-2 and Fms-related receptor tyrosine kinase-1, respectively. Given that the 5 h exposure to continuous flow is insufficient for transcriptional regulation, it is likely that pro-inflammatory/pro-angiogenic signaling observed was due to signaling molecules stored in Weible-Palade bodies (ET-1, IL-8, ANG-2) and via HAEC binding/uptake of soluble factors in media. These results suggest that even short-term exposure to continuous flow can potentially activate pro-inflammatory/pro-angiogenic signaling in cultured HAECs and pulsatile flow may be a successful strategy in reducing the undesirable sequalae following continuous flow CPB.

Effects of music intervention on anxiety, depression, and quality of life of cancer patients receiving chemotherapy: a systematic review and meta-analysis.

BACKGROUND: Music may be a safe and effective coping strategy for psychological management. The objectives of this review were to identify the effects of music interventions on anxiety, depression, and quality of life (QoL) among cancer patients receiving chemotherapy. METHODS: Fourteen databases were searched from the inception date to December 2020 to identify eligible randomized controlled trials (RCTs). Gray literature was also examined. The protocol of this systematic review was registered with PROSPERO (registration number: CRD42021223845). Two reviewers independently assessed eligibility, extracted data, and evaluated methodological quality. Meta-analysis was done. Subgroup analysis was conducted for intervention types, the person selecting music, music delivery method, timing, and session duration. RESULTS: Nine RCTs were identified, among which six were eligible for the meta-analysis. All studies were at a high risk of bias, and the overall quality of evidence was low to very low. The pooled results reveal that music intervention could reduce anxiety (SMD: - 0.29, 95% CI - 0.50 to - 0.08) and improve QoL (SMD: 0.42, 95% CI 0.02 to 0.82). However, it fails to affect depression (p = 0.79). The findings demonstrate no significant difference between patient-selected music and researcher-selected music, recorded music, and live music, while a length of 15-20 min/session and offering immediately before chemotherapy are more effective on anxiety than that of 30-45 min and delivering during chemotherapy. CONCLUSIONS: Music intervention may be a beneficial tool for anxiety reduction and QoL among cancer patients receiving chemotherapy. More high-quality RCTs are needed to ascertain the true impact of those outcomes.

Effect of pulsatility on shear-induced extensional behavior of Von Willebrand factor.

BACKGROUND: Patients with continuous flow ventricular assist devices (CF-VADs) are at high risk for non-surgical bleeding, speculated to associate with the loss of pulsatility following CF-VAD placement. It has been hypothesized that continuous shear stress causes elongation and increased enzymatic degradation of von Willebrand Factor (vWF), a key player in thrombus formation at sites of vascular damage. However, the role of loss of pulsatility on the unravelling behavior of vWF has not been widely explored. METHODS: vWF molecules were immobilized on the surface of microfluidic devices and subjected to various pulsatile flow profiles, including continuous flow and pulsatile flow of different magnitudes, dQ/dt (i.e., first derivative of flow rate) of pulsatility and pulse frequencies to mimic in vivo shear flow environments with and without CF-VAD support. VWF elongation was observed using total internal reflection fluorescence (TIRF) microscopy. Besides, the vWF level is measured from the patients' blood sample before and after CF-VAD implantation from a clinical perspective. To our knowledge, this work is the first in providing direct, visual observation of single vWF molecule extension under controlled-pulsatile shear flow. RESULTS: Unravelling of vWF (total sample size n ~ 200 molecules) is significantly reduced under pulsatile flow (p < 0.01) compared to continuous flow. An increase in the magnitude of pulsatility further reduces unravelling lengths, while lower frequency of pulsatility (20 vs. 60 pulses per min) does not have a major effect on the maximum or minimum unravelling lengths. Evaluation of CF-VAD patient blood samples (n = 13) demonstrates that vWF levels decreased by ~40% following CF-VAD placement (p < 0.01), which correlates to single-molecule observations from a clinical point of view. CONCLUSIONS: Pulsatile flow reduces unfolding of vWF compared to continuous flow and a lower pulse frequency of 20 pulses/minute yielded comparable vWF unfolding to 60 pulses/minute. These findings could shed light on non-surgical bleeding associated with the loss of pulsatility following CF-VAD placement.

Comorbidities predict worse prognosis in patients with primary myelofibrosis.

BACKGROUND: Comorbidities have been shown to play an important role in the prognostic assessment of several hematologic conditions; however, the role of comorbidities in primary myelofibrosis has not been studied. The objective of the current study was to evaluate the prevalence and impact of comorbidities in patients with primary myelofibrosis (PMF) using the Adult Comorbidity Evaluation-27 (ACE-27). METHODS: In this retrospective observational cohort study, a total of 349 consecutive patients with a confirmed diagnosis of PMF who presented to the study institution from 2000 to 2008 were evaluated. The authors evaluated the frequency and severity of comorbidities in these patients and assessed their impact on survival in a bivariable model that included the ACE-27 and Dynamic International Prognostic Scoring System scores as covariates. RESULTS: Approximately 64% of patients had at least 1 comorbid condition, and diseases of the cardiovascular system (63%) were most common. Comorbidities had a significant negative impact on survival (P < .001). Patients with severe comorbidities had twice the risk of death as those with no comorbidities. When stratified by demographic and clinical characteristics, comorbidities were found to be significantly associated with worse survival in patients aged < 65 years (P < .001) and those with an ECOG performance status < 1 (P < .001). In a multivariable model that included the ACE-27 and Dynamic International Prognostic Scoring System scores, comorbidities retained a significant association with shorter survival (P ≤ .001). CONCLUSIONS: The assessment of comorbid conditions in patients with PMF, particularly those who are younger and with a good performance status, has important implications for overall prognosis and treatment planning.

Improving Direct Admissions to Internal Medicine Services.

BACKGROUND: Direct admissions from clinic or home to the hospital may improve efficiency and reduce emergency room utilization, but nonoptimized processes may increase the risk of harm during the transition of care. Our multidisciplinary team aimed to understand and improve the process of directly admitting patients to inpatient medicine services at a large academic medical center. METHODS: In this single-institution quality improvement initiative, we identified key communication gaps within the direct admission process and implemented a handoff tool in the form of a templated note and order set to bridge those communication gaps. The primary outcome measure was the monthly utilization rate of the handoff note as a surrogate for handoffs and uptake of the intervention. RESULTS: We launched our intervention in April 2022. We achieved sustained use of the SmartText and a peak of 24% of direct admissions utilizing the SmartText in January 2023. Based on feedback during Plan-Do-Study-Act cycles, we added direct admission instructions for outpatient teams to follow in the order set and reduced text in the handoff note. CONCLUSIONS: This study demonstrates the design and implementation of a quality improvement initiative to identify and address communication gaps for direct admissions of adult medicine patients.

Multi-Institution Survey of Accepting Physicians' Perception of Appropriate Reasons for Interhospital Transfer: A Mixed-Methods Evaluation.

OBJECTIVES: There is a lack of evidence-based guidelines to direct best practices in interhospital transfers (IHTs). We aimed to identify frontline physicians' current and ideal reasons for accepting IHT patients to inform future IHT research and guidelines. METHODS: We conducted a cross-sectional survey of hospitalist physicians across 11 geographically diverse hospitals. The survey asked respondents how frequently they currently consider and should consider various factors when triaging IHT requests. Responses were dichotomized into "highly considered" and "less considered" factors. Frequencies of the "highly considered" factors (current and ideal) were analyzed. Write-in responses were coded into themes within a priori domains in a qualitative analysis. RESULTS: Of the 666 hospitalists surveyed, 238 (36%) responded. Respondents most frequently identified the need for specialty procedural and nonprocedural care and bed capacity as factors that should be considered when triaging IHT patients in current and ideal practice, whereas the least frequently considered factors were COVID-related care, insurance/financial considerations, and patient/family preference. More experienced respondents considered patient/family preference more frequently in current and ideal practice compared with less experienced respondents (33% versus 11% [ P = 0.0001] and 26% versus 9% [ P = 0.01], respectively). Qualitative analysis identified several themes in the domains of Criteria for Acceptance, Threshold for Acceptance, and Indications for Physician-to-Physician Communication. CONCLUSIONS: This geographically diverse sample of hospitalist physicians responsible for accepting IHT patients showed general agreement between primary factors that are currently and that should be considered for IHT acceptance, with greatest weight placed on patients' need for specialty care.

A qualitative study on stress, coping strategies and feasibility of music intervention among women with cancer receiving chemotherapy during COVID-19 pandemic in Vietnam.

Breast and gynaecological cancer (BGC) patients receiving chemotherapy may experience high levels of stress during the COVID-19 pandemic. Music interventions may be effective in lowering their stress levels. This study explored stressors, coping strategies, and the feasibility of music interventions among BGC patients in Vietnam. An exploratory qualitative study with individual face-to-face semi-structured interviews was conducted. A convenience sample of BGC patients receiving chemotherapy was recruited from the oncology centre of a public hospital in Vietnam. Twenty patients were interviewed with open-ended questions developed based on the transactional model of stress and coping to explore stress-causing factors and coping strategies and based on guidelines for music therapy practice to explore their music preferences and perceptions. Field notes and interview transcripts were analysed following the qualitative content analysis approach. Two stressor themes were identified: undesirable experiences during treatment and patients' inability to fulfil their own roles and responsibilities. Our findings revealed a new coping strategy-self-realisation of responsibilities towards the family-that is not listed in the transactional model of stress and coping. Future psychological interventions for stress management among BGC patients should focus on raising the patients' awareness of their values and responsibilities towards their families. Three categories of preferred music genres for stress reduction were identified: religious, softly melodic, and revolutionary music. The patients were aware of the positive effects of music and had different musical preferences. This study also explored the acceptance of music interventions and facilitators and barriers to implementing them among BGC patients in Vietnam. The findings suggest that before implementing music interventions, the musical preferences, religions, and beliefs of each individual should be considered to achieve desirable results. Music interventions for BGC patients receiving chemotherapy in Vietnam are feasible. Further intervention studies are needed to evaluate their effectiveness.

Effectiveness of Community Health Worker-Led Interventions in Enhancing Colorectal Cancer Screening Uptake in Racial and Ethnic Minority Populations: A Systematic Review and Meta-analysis.

BACKGROUND: The colorectal cancer (CRC) screening uptake rate is substantially lower in ethnic minority populations than in the general population. Racial and ethnic minority individuals experience more barriers in obtaining a screening test for CRC when compared with the non-Hispanic White population. OBJECTIVE: To examine the effectiveness of community health worker-led interventions in improving the CRC screening uptake rate in racial and ethnic minority populations. METHODS: Five databases, EMBASE, CINAHL, MEDLINE, Scopus, and PubMed, were systematically searched, and reference lists of the identified articles were manually searched for relevant articles in May 2022. Only randomized controlled trials were included. RESULTS: A total of 10 randomized controlled trials conducted in the United States were included in this review. The findings of the meta-analysis showed that CRC screening uptake was enhanced in participants receiving community health worker-led interventions compared with those receiving no intervention (odds ratio, 2.25; 95% confidence interval, 1.48-3.44; P < .001). The subgroup analysis by diverse racial and ethnic groups and number of components (single vs multiple) of the community health worker-led interventions showed that multicomponent interventions were more effective in increasing the CRC uptake rate among all racial and ethnic groups regardless of their background. CONCLUSIONS: Multicomponent community health worker-led interventions can improve CRC screening uptake in racial and ethnic minority populations. IMPLICATIONS FOR PRACTICE: The findings of the present review show that multicomponent community health worker-led interventions are shown to be effective to improve the CRC screening uptake targeting other racial and ethnic minority groups in other countries.

von Willebrand Factor and Angiopoietin-2 are Sensitive Biomarkers of Pulsatility in Continuous-Flow Ventricular Assist Device Patients.

Nonsurgical bleeding occurs in a significant proportion of patients implanted with continuous-flow ventricular assist devices (CF-VADs) and is associated with nonphysiologic flow with diminished pulsatility. An in vitro vascular pulse perfusion model seeded with adult human aortic endothelial cells (HAECs) was used to identify biomarkers sensitive to changes in pulsatility. Diminished pulsatility resulted in an ~45% decrease in von Willebrand factor (vWF) levels from 9.80 to 5.32 ng/ml (n = 5, p < 0.05) and a threefold increase in angiopoietin-2 (ANGPT-2) levels from 775.29 to 2471.93 pg/ml (n = 5, p < 0.05) in cultured HAECs. These changes are in agreement with evaluation of patient blood samples obtained pre-CF-VAD implant and 30-day postimplant: a decrease in plasma vWF level by 50% from ~45.59 to ~22.49 µg/ml (n = 15, p < 0.01) and a 64% increase in plasma ANGPT-2 level from 7,073 to 11,615 pg/ml (n = 8, p < 0.05). This study identified vWF and ANGPT-2 as highly sensitive to changes in pulsatility, in addition to interleukin-6 (IL-6), IL-8, and tumor necrosis-α (TNF-α). These biomarkers may help determine the optimal level of pulsatility and help identify patients at high risk of nonsurgical bleeding.

Surface Engineering Methods for Powder Bed Printed Tablets to Optimize External Smoothness and Facilitate the Application of Different Coatings.

In a previous attempt to achieve ileo-colonic targeting of bovine intestinal alkaline phosphatase (BIAP), we applied a pH-dependent coating, the ColoPulse coating, directly on powder bed printed (PBP) tablets. However, the high surface roughness necessitated an additional sub-coating layer [Nguyen, K. T. T., Pharmaceutics 2022]. In this study, we aimed to find a production method for PBP tablets containing BIAP that allows the direct application of coating systems. Alterations of the printing parameters, binder content, and printing layer height, when combined, were demonstrated to create visually less rough PBP tablets. The addition of ethanol vapor treatment further improved the surface's smoothness significantly. These changes enabled the direct application of the ColoPulse, or enteric coating, without a sub-coating. In vitro release testing showed the desired ileo-colonic release or upper-intestinal release for ColoPulse or enteric-coated tablets, respectively. Tablets containing BIAP, encapsulated within an inulin glass, maintained a high enzymatic activity (over 95%) even after 2 months of storage at 2-8 °C. Importantly, the coating process did not affect the activity of BIAP. In this study, we demonstrate, for the first time, the successful production of PBP tablets with surfaces that are directly coatable with the ColoPulse coating while preserving the stability of the encapsulated biopharmaceutical, BIAP.

Morphological and functional changes in innervation of a fast forelimb muscle in SOD1-G85R mice.

Muscle endplates become denervated in mice that express mutations of human superoxide dismutase 1 (hSOD1), models of familial amyotrophic lateral sclerosis. This denervation is especially marked in fast limb muscles, and precedes death of motor neuron somata. This study used mice that expressed yellow fluorescent protein (YFP) in neurons to investigate changes in the morphology and function of axons and motor terminals innervating a fast forelimb muscle (epitrochleoanconeus, ETA) in presymptomatic and symptomatic hSOD1-G85R mice, compared to those in mice that express wild-type (wt) hSOD1. The percentage of endplates (identified using fluorescently-labeled α-bungarotoxin) innervated by motor terminals remained high in presymptomatic SOD1-G85R mice, but fell to ~50% in symptomatic mice. The number of large diameter (≥4 µm) axons in the ETA nerve also decreased as mice became symptomatic, and endplate innervation correlated best with the number of large diameter axons. Motor terminal function was assessed using changes in terminal YFP fluorescence evoked by trains of action potentials; different components of the pH-dependent YFP signals reflect stimulation-induced Ca2+ entry and vesicular exo/endocytosis. Most visible motor terminals (>90%) remained capable of responding to nerve stimulation in both pre- and symptomatic hSOD1-G85R mice, but with functional alterations. Responses in presymptomatic terminals suggested reduced acidification and increased vesicular release, whereas symptomatic terminals exhibited increased acidification and reduced vesicular release. The fact that most remaining terminals were able to respond to nerve stimulation suggests that motor terminal-protective therapies might contribute to preserving neuromuscular function in fALS mice.

The Psi(m) depolarization that accompanies mitochondrial Ca2+ uptake is greater in mutant SOD1 than in wild-type mouse motor terminals.

The electrical gradient across the mitochondrial inner membrane (Psi(m)) is established by electron transport chain (ETC) activity and permits mitochondrial Ca(2+) sequestration. Using rhodamine-123, we determined how repetitive nerve stimulation (100 Hz) affects Psi(m) in motor terminals innervating mouse levator auris muscles. Stimulation-induced Psi(m) depolarizations in wild-type (WT) terminals were small (<5 mV at 30 degrees C) and reversible. These depolarizations depended on Ca(2+) influx into motor terminals, as they were inhibited when P/Q-type Ca(2+) channels were blocked with omega-agatoxin. Stimulation-induced Psi(m) depolarization and elevation of cytosolic [Ca(2+)] both increased when complex I of the ETC was partially inhibited by low concentrations of rotenone (25-50 nmol/l). This finding is consistent with the hypothesis that acceleration of ETC proton extrusion normally limits the magnitude of Psi(m) depolarization during mitochondrial Ca(2+) uptake, thereby permitting continued Ca(2+) uptake. Compared with WT, stimulation-induced increases in rhodamine-123 fluorescence were approximately 5 times larger in motor terminals from presymptomatic mice expressing mutations of human superoxide dismutase I (SOD1) that cause familial amyotrophic lateral sclerosis (SOD1-G85R, which lacks dismutase activity; SOD1-G93A, which retains dismutase activity). Psi(m) depolarizations were not significantly altered by expression of WT human SOD1 or knockout of SOD1 or by inhibiting opening of the mitochondrial permeability transition pore with cyclosporin A. We suggest that an early functional consequence of the association of SOD1-G85R or SOD1-G93A with motoneuronal mitochondria is reduced capacity of the ETC to limit Ca(2+)-induced Psi(m) depolarization, and that this impairment contributes to disease progression in mutant SOD1 motor terminals.

A new obligate CXCL4-CXCL12 heterodimer for studying chemokine heterodimer activities and mechanisms.

Chemokines form a family of proteins with critical roles in many biological processes in health and disease conditions, including cardiovascular, autoimmune diseases, infections, and cancer. Many chemokines engage in heterophilic interactions to form heterodimers, leading to synergistic activity enhancement or reduction dependent on the nature of heterodimer-forming chemokines. In mixtures, different chemokine species with diverse activities coexist in dynamic equilibrium, leading to the observation of their combined response in biological assays. To overcome this problem, we produced a non-dissociating CXCL4-CXCL12 chemokine heterodimer OHD4-12 as a new tool for studying the biological activities and mechanisms of chemokine heterodimers in biological environments. Using the OHD4-12, we show that the CXCL4-CXCL12 chemokine heterodimer inhibits the CXCL12-driven migration of triple-negative MDA-MB-231 breast cancer cells. We also show that the CXCL4-CXCL12 chemokine heterodimer binds and activates the CXCR4 receptor.

Formulation of a 3D Printed Biopharmaceutical: The Development of an Alkaline Phosphatase Containing Tablet with Ileo-Colonic Release Profile to Treat Ulcerative Colitis.

Powder bed printing is a 3D-printing process that creates freeform geometries from powders, with increasing traction for personalized medicine potential. Little is known about its applications for biopharmaceuticals. In this study, the production of tablets containing alkaline phosphatase using powder bed printing for the potential treatment of ulcerative colitis (UC) was investigated, as was the coating of these tablets to obtain ileo-colonic targeting. The printing process was studied, revealing line spacing as a critical factor affecting tablet physical properties when using hydroxypropyl cellulose as the binder. Increasing line spacing yielded tablets with higher porosity. The enzymatic activity of alkaline phosphatase (formulated in inulin glass) remained over 95% after 2 weeks of storage at 45 °C. The subsequent application of a colonic targeting coating required a PEG 1500 sub-coating. In vitro release experiments, using a gastrointestinal simulated system, indicated that the desired ileo-colonic release was achieved. Less than 8% of the methylene blue, a release marker, was released in the terminal ileum phase, followed by a fast release in the colon phase. No significant impact from the coating process on the enzymatic activity was found. These tablets are the first to achieve both biopharmaceutical incorporation in powder bed printed tablets and ileo-colonic targeting, thus might be suitable for on-demand patient-centric treatment of UC.

Repetitive nerve stimulation transiently opens the mitochondrial permeability transition pore in motor nerve terminals of symptomatic mutant SOD1 mice.

Mitochondria in motor nerve terminals temporarily sequester large Ca(2+) loads during repetitive stimulation. In wild-type mice this Ca(2+) uptake produces a small (<5 mV), transient depolarization of the mitochondrial membrane potential (Ψ(m), motor nerve stimulated at 100 Hz for 5s). We demonstrate that this stimulation-induced Ψ(m) depolarization attains much higher amplitudes in motor terminals of symptomatic mice expressing the G93A or G85R mutation of human superoxide dismutase 1 (SOD1), models of familial amyotrophic lateral sclerosis (fALS). These large Ψ(m) depolarizations decayed slowly and incremented with successive stimulus trains. Additional Ψ(m) depolarizations occurred that were not synchronized with stimulation. These large Ψ(m) depolarizations were reduced (a) by cyclosporin A (CsA, 1-2 µM), which inhibits opening of the mitochondrial permeability transition pore (mPTP), or (b) by replacing bath Ca(2+) with Sr(2+), which enters motor terminals and mitochondria but does not support mPTP opening. These results are consistent with the hypothesis that the large Ψ(m) depolarizations evoked by repetitive stimulation in motor terminals of symptomatic fALS mice result from mitochondrial dysfunction that increases the likelihood of transient mPTP opening during Ca(2+) influx. Such mPTP openings, a sign of mitochondrial stress, would disrupt motor terminal handling of Ca(2+) loads and might thereby contribute to motor terminal degeneration in fALS mice. Ψ(m) depolarizations resembling those in symptomatic fALS mice could be elicited in wild-type mice following a 0.5-1h exposure to diamide (200 µM), which produces an oxidative stress, but these depolarizations were not reduced by CsA.

An automated health indicator construction methodology for prognostics based on multi-criteria optimization.

In recent years, the development of autonomous health management systems received increasing attention from worldwide companies to improve their performances and avoid downtime losses. This can be done, in the first step, by constructing powerful health indicators (HI) from intelligent sensors for system monitoring and for making maintenance decisions. In this context, this paper aims to develop a new methodology that allows automatically choosing the pertinent measurements among various sources and also handling raw data from high-frequency sensors to extract the useful low-level features. Then, it combines these features to create the most appropriate HI following the previously defined multiple evaluation criteria. Thanks to the flexibility of the genetic programming, the proposed methodology does not require any expertise knowledge about system degradation trends but allows easily integrating this information if available. Its performance is then verified on two real application case studies. In addition, an insightful overview on HI evaluation criteria is also discussed in this paper.

Online joint estimation and prediction for system-level prognostics under component interactions and mission profile effects.

Failure prognostics has become a central element in predictive maintenance. In this domain, the accurate determination of the remaining useful life (RUL) allows making effective maintenance and operation decisions about the assets. However, prognostics is often approached from a component point of view, and system-level prognostics, taking into account component interactions and mission profile effects, is still an underexplored area. To address this issue, we propose an online joint estimation and prediction methodology using a modeling framework based on the inoperability input-output model (IIM). This model can consider the interactions between components and also the mission profile effects on a system's degradation. To estimate the system's parameters in real-time, with a minimum of prior knowledge, an online estimation process based on the gradient descend algorithm is recursively performed when acquiring new measurements. After each update, the estimated model is used to predict the system RUL. The performance of the proposed approach is highlighted through different numerical examples. In addition, these developments are applied to a real industrial application, the Tennessee Eastman Process, in order to show their effectiveness.

Tissue Chips and Microphysiological Systems for Disease Modeling and Drug Testing.

Tissue chips (TCs) and microphysiological systems (MPSs) that incorporate human cells are novel platforms to model disease and screen drugs and provide an alternative to traditional animal studies. This review highlights the basic definitions of TCs and MPSs, examines four major organs/tissues, identifies critical parameters for organization and function (tissue organization, blood flow, and physical stresses), reviews current microfluidic approaches to recreate tissues, and discusses current shortcomings and future directions for the development and application of these technologies. The organs emphasized are those involved in the metabolism or excretion of drugs (hepatic and renal systems) and organs sensitive to drug toxicity (cardiovascular system). This article examines the microfluidic/microfabrication approaches for each organ individually and identifies specific examples of TCs. This review will provide an excellent starting point for understanding, designing, and constructing novel TCs for possible integration within MPS.

Hydrophobic and Hydrophilic Film-Forming Gels for the Controlled Delivery of Drugs with Different Levels of Hydrophobicity.

BACKGROUND: This study aimed to evaluate the effects of hydrophobic and hydrophilic Film-Forming Gels (FFGs) on the controlled delivery of drugs with different levels of hydrophobicity. METHODS: This evaluation was carried out by employing zein and polyvinylpyrrolidone as hydrophobic and hydrophilic film-forming agents, respectively, in combination with hydroxypropyl methylcellulose functionalized as a hydrogel basement at a ratio that had been optimized to achieve the fastest drying time. Free curcumin or terbinafine hydrochloride was subsequently dispersed into blank FFGs to produce the final FFG formulations. RESULTS: Although the extreme hydrophobicity of curcumin strongly limited its topical permeability compared to that of terbinafine hydrochloride, zein FFGs clearly resulted in a favourable sustained release system for highly hydrophobic drugs, such as curcumin. Moreover, polyvinylpyrrolidone would be highly effective for the sustained release of a less hydrophobic drug, such as terbinafine hydrochloride. Analyses of the wettability, surface morphology, chemical interactions and crystallinity of FFGs also helped to elucidate the mechanisms of their drug release profiles. CONCLUSION: This fundamental finding is beneficial for further design studies on FFGs as sustained drug delivery systems for topical drugs with a wide range of hydrophobicities.