Target Level Research Articles

Predictors of the development of abnormal patterns of circadian blood pressure rhythm in patients with hypertension after a new coronavirus infection

Objective. To determine the predictors of the development of abnormal patterns of circadian blood pressure (BP) rhythm in patients with arterial hypertension (AH) after a new coronavirus infection (NСVI). Materials and methods. The study is a comparative clinical research of the same patients with hypertension before and after NCVI with retrospective evaluation of the data. Within 2 years from 842 patients with cardiovascular risk factors, according to the inclusion and non-inclusion criteria 70 patients with target levels of office BP, home monitoring and 24-hour blood pressure monitoring (ABPM) on the background of a continuous antihypertensive therapy were included in the study. Abnormal patterns of circadian BP were recorded after NCVI during ABPM in all of them. All patients with hypertension underwent a complete examination before and after NCVI. Results. After NCVI in patients with AH who had achieved the target ranges of office BP before its development, at home measurement and ABPM against the background of continuous antihypertensive therapy with high adherence to treatment, in more than 50 % of patients BP readings were not in the target values, in more than 50 % of the examined patients, BP variability was higher than the permissible values, in 73 % of patients the average daily BP was above 53 mm Hg. Abnormal patterns of circadian BP rhythm in patients with hypertension after NCVI were detected in 61.5 %: "Non-dipper" in 28.6 %; "Night-dipper" – in 21.9 %, masked nocturnal hypertension – in 17.1 %. Conclusion. The indicative significance of the development of abnormal patterns of circadian BP rhythm in patients with hypertension after NCVI was demonstrated by 3 qualitative indicators: glomerular filtration rate with cystatin C 60 ml/min/1.73 m2, cardio-ankle vascular index (CAVI) ≥ 9, and a high frequency of AGT gene polymorphism – T/T genotype (in 54.3 % of patients).

B-302 Therapeutic Drug Monitoring (TDM) of Hydroxychloroquine in Whole Blood: Analysis of Over 10,000 Patient Results

Abstract Background Hydroxychloroquine (HCQ), a mainstay of systemic lupus erythematosus (SLE) therapy, improves survival and reduces flares. Therapeutic drug monitoring (TDM) may be useful in 1) identifying and improving adherence issues, 2) titrating daily dose to achieve therapeutic benefits while 3) minimizing retinopathy due to longterm cumulative exposure. Whole blood (WB) is the correct specimen for HCQ TDM because WB HCQ levels are higher than serum or plasma levels, more stable and reflective of the last month of HCQ ingestion, and are better correlated to efficacy and retinopathy risk. Here, we report WB HCQ concentrations in 10,463 clinical patient samples and their distribution. Methods HCQ concentrations in whole blood are measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) and reported in nanograms per milliliters whole blood. Recommended sample collection is ∼ 3 - 6 months into regular stable dosing to reach pharmacokinetic steady state and correlate with clinical efficacy. Results Here, we report the analysis of 10,463 patient samples for whole blood hydroxychloroquine (WB HCQ) concentrations. More than one-third (3752, 35.9%) were within the target range of > 1000 and < 2000 ng/mL. About one-quarter (2568, 24.5%) were within a tighter therapeutic target window, 1000 to 1500 ng/mL. The vast majority (9852, 94.2%,) of all WB HCQ were < 2000 ng/mL with a small percentage >2000 ng/mL (611, 5.8% between 2000 - 9502 ng/mL). About one-third (31.3%) were higher than 1177 ng/mL which corresponds to higher retinopathy risk. Adherence issues were evident in 10.5% (1102) with undetectable (483, 4.6%) and very low (<200 ng/mL) drug (619, 5.9%) (yellow). Depending upon the target threshold, levels < 500 ng/mL or <1000 ng/mL may be considered subtherapeutic as seen in 2498 (23.9%) and 4263 (40.7%) samples, respectively. Conclusions Due to wide pharmacokinetic variability and adherence issues, a given prescribed dose of HCQ does not correspond to WB HCQ, e.g. following 4, 5 or 6 mg/kg/day, levels are known to vary widely from subtherapeutic <500 to >2000 ng/mL. Here, our clinical database reiterates this wide range in WB HCQ levels from undetectable (<25) to 9502 ng/mL in 10,463 patient samples. One-quarter or one-third were within the therapeutic target range of 1000-1500 or 1000-200 ng/mL where >1000 has been associated with better disease control and survival. At the same time, levels less than 1177 avoid higher retinopathy risk. A small percentage of samples, 5.8%, were higher than 2000 ng/mL, suggesting the usefulness in TDM to fine-tune daily dose. In 10%, there was evidence of poor adherence, with very low or no detectable drug, and one quarter to 40% were subtherapeutic (<500 or <1000). The potential benefits of HCQ are many and include reduced flares and improved lupus nephritis, thrombosis risk, and long-term survival. At the same time, prescribed dose does not predict therapeutic levels. TDM-based counseling and dose adjustment may be instrumental in optimizing HCQ benefits while minimizing retinopathy risk. In conclusion, our analysis demonstrates the growing use of whole blood HCQ TDM to facilitate dose titration to safe and most effective target levels.

B-222 Receptor-donor CYP3A5 and CYP3A4 genotype testing in liver transplant patients and its influence in tacrolimus blood levels: a retrospective study

Abstract Background Optimal immunosupression is crucial for transplant success. In orthohepatic transplants, blood target levels of tacrolimus, when coadministred with corticoids and mycophenolic acid, are between 6 and 10 ng/mL during the first three months post-transplant. Notwithstanding, achieving tacrolimus concentrations into this range may be tough because of factors such as liver function status, age, sex, drug-drug interactions, etc. In this way, pharmacogenetic testing of CYP3A5 and CYP3A4 genes have demonstrated to be useful in tacrolimus dosing optimization. Nonetheless, there is no evidence enough for pharmacogenetic based adjusting in liver transplant, specially if receptor and graft’s genotypes differ in these loci. The aim of the present study is to find out how the receptor and donor genotypes in CYP3A5 and CYP3A4 genes affect tacrolimus pharmacokinetics. Methods Genotypic profiling of 108 receptor-donor's pairs biopsies gathered from patients who were underwent hepatic transplant from 2012 to 2019 were carried out using Taqman® OpenArray™ PGx Express 120 panel (ThermoFisher™). We focused on CYP3A5*3, *6 and *7; and CYP3A4*1B, *3 and *22 alleles. Next to pharmacogenetic testing, each patient was classified as very poor, poor, intermediate, rapid or ultrarapid metabolizer according to their own genotype, graft’s genotype or both of them. Patient’s initial dose, at seven days after treatment start and after discharge of tacrolimus and their trough concentrations (C0) were collected from their electronic health records. Tacrolimus levels were measured by affinity chrome-mediated immunoassay. C0 was normalized by weight-adjusted dosage (C/D ratio); then, median C/D ratios between different metabolic profiles were compared through Kruskal-Wallis test. Results When patients were classified based on donor’s genotype isolated or combined with receptor’s genotype, lower C/D ratios were found as metabolizer ability increases (p=0.045 for donors and p=0.027 for combined genotypes, respectively). No statistically differences were found for C/D ratios at seven days and discharge, though that differences were almost significant for donor’s genotypes (p=0.06 in both cases). Conclusions These results show that previous information about both patient’s and specially donor’s CYP genes genotype may improve initial immunosupression and avoid tacrolimus induced toxicity. Pharmacogenetics has been currently proposed as a guide for tacrolimus treatment of some solid organ transplants as kidney transplanted patients. Better understanding of how receptor and donor’s CYP genotype affects its pharmacokinetics, along with liver’s damage markers and other genetic polymorphisms will allow clinicians, in the era of personalized medicine, to improve immunosupressive management.

Reverse design for mixture proportions of recycled brick aggregate concrete using machine learning-based meta-heuristic algorithm: A multi-objective driven study

Construction and Demolition Wastes (CDW) have a significant impact on global waste streams. Brick waste stands out as a prominent type of CDW, and numerous studies have explored its recycling for the creation of environmentally-friendly concrete. Reverse design of recycled brick aggregate concrete (RBAC) mixture proportion is presented in this paper with a focus on four key objectives, that is: compressive strength, cost, and environmental elements (i.e., energy consumption and carbon emission). Based on compiled experimental datasets of 374 samples, the back propagation neural network (BP), random forest (RF), and four meta-heuristic algorithm optimization models were constructed to achieve the desired compressive strength objective. In all machine learning (ML) methods, the compressive strength of RBAC can be predicted with high accuracy, with the SSA-BP (optimized back propagation neural network model using the sparrow search algorithm) model achieving superior results (i.e., NSE=0.91, RPD=3.2). The SSA-BP is therefore used as the objective function for compressive strength. The economic objective is primarily influenced by material costs, and the objective functions of energy consumption and carbon emission are determined by various aspects of production, transportation, and their mixing processes. In order to obtain the optimal RBAC design, the Non-Dominated Sorting Genetic Algorithm (NSGA-III) was implemented considering imperative constraints. Results indicate that cement amount and recycled brick aggregate (RBA)-to-natural aggregate proportion have a positive impact on the compressive strength. The suggested design framework allows for the creation of RBAC composite designs with varying levels of RBA substitution rates and strength targets, providing valuable guidance for tackling the CDW challenge and optimizing RBA usage.

Development and validation of intelligent load control for VRF air-conditioning system with deep learning based load forecasting

Variable refrigerant flow (VRF) air-conditioning systems have seen significant growth in Asia and its application is expanding globally. Despite the expanded application, most previous studies have focused on developing fault detection and diagnostics to achieve energy-efficient operations than on predicting power consumption. It's very difficult to predict the electrical consumption owing to its complex system configuration and various control strategies. A new control strategy is described for optimal adjustment of the desired target level based on time series forecasting using the optimized sequence to sequence model for VRF systems. Sequence to sequence (seq2seq) model with attention mechanism and Bayesian optimization is developed to predict accurate hourly and daily forecasts and rapid feedback control for fluctuating power consumption for VRF systems. The optimized seq2seq model is integrated into the intelligent load control (ILC). ILC can be used to manage VRF systems by dynamically prioritizing indoor units for curtailment using both quantitative inputs and qualitative rules. Overall, the results demonstrate that the deep learning based control allows coordination of the controllable loads of VRF systems in three commercial buildings. ILC with deep learning manages the power consumption within a desired target level, as well as indoor temperature reflecting the status of controlled indoor units, as objective functions of the control algorithm.

Efficacy of continuous glucose monitoring for finding unusual causes of hyperglycemia: a clinical case

Diabetes is a chronic condition that requires constant blood glucose self-monitoring. The carbohydrate metabolism compensation is usually assessed by the level of glycated hemoglobin. But it does not always help reveal the true cause of poor glycemic control. The devices for continuous glucose monitoring allows to assess blood glucose level in real time and find unusual causes of hyper- and hypoglycemia. Achieving target glycemic levels is influen­ced by many factors: age of patients, duration of diabetes, eating habits and eating disorders, level of education, patient’s understan­ding of the diabetes course. One of the reasons for not reaching the target levels of glycemia can be hyperphagic eating disorders, such as night eating syndrome. According to the American Psychiatric Association classification, night eating syndrome belongs to the category of “Other specified eating disorders”. Diagnostic criteria in this syndrome include consumption of > 25 % of food from the daily diet after dinner or at least 2 cases per week of food consumption at night; awareness of these episodes; and at least 3 of the following: morning anorexia, uncontrollable desire to eat between dinner and sleep or at night, conviction that eating will help you fall asleep or return to sleep, insomnia and/or bad mood in the morning. The prevalence of night eating syndrome in the general population is 1.1 %, and in those who refer to metabolic surgery specialists, it is 2–20 %. The presence of night eating syndrome in diabetes adversely affects metabolic control and complicates the management of these patients, in particular, they have higher levels of HbA1c, blood pressure and body mass index compared to individuals without such eating disorder. In this case report, we describe a patient with poor glycemic control who used continuous glucose monitor and was diagnosed with night eating syndrome that helped change management and achieve normoglycemia in the evening and nighttime.

Optimal Trough Concentration of Tacrolimus in Pediatric Patients With Primary Nephrotic Syndrome.

The trough concentration (C0) of tacrolimus in children with nephrotic syndrome (NS) has rarely been explored, so its target level was based on transplant research. This study aimed to determine the optimal tacrolimus C0 in NS children. Data from primary NS children treated with tacrolimus at Wuhan Children's Hospital in the last 10 years were retrospectively collected. According to the cutoff C0 analyzed by receiver-operator characteristics (ROC) analysis, patients were divided into very low- (< 4 ng/mL), low- (4-5 ng/mL), medium- (5-7 ng/mL), and high-concentration (7-10 ng/mL) groups. A total of 196 patients were enrolled for primary outcome analysis. Compared to medium-concentration group, only the very low-concentration group obtained significant inferior primary outcomes, including overall remission rate, relapse-free survival rate, and relapse rate at 6 months. For secondary outcomes, the very low-concentration group experienced more frequent treatment failure in 12 months, whereas the high-concentration group suffered a higher risk of adverse events than the medium-concentration group. For steroid-resistant NS, very low- and low-concentration groups required longer time to achieve remission compared to medium-concentration group. For steroid-sensitive NS, the very low-concentration group suffered a higher relapse frequency than medium-concentration group. Lastly, the dose of tacrolimus required for children with different CYP3A5 genotypes with or without Wuzhi capsules was analyzed. In conclusion, tacrolimus may be targeted to C0 of 4-7 ng/mL during the first 6 months in children with NS. For steroid-resistant NS, C0 of 5-7 ng/mL can achieve a rapid remission.

Antitumor Potential of Guttiferone E Combined With Carboplatin Against Osimertinib-resistant H1975 Lung Cancer Through Apoptosis.

Low selectivity and high frequency of side-effects are the major problems of currently used chemotherapeutics. Among natural compounds, the polyprenylated acylphloroglucinol, guttiferone E, isolated from Brazilian red propolis, has attracted attention due to its marked anticancer properties and was evaluated here for its role against osimertinib-resistant H1975 cells (with double mutations of epidermal growth factor receptor: EGFR L858R/T790M). Guttiferone E was obtained from red propolis using established extraction procedures. Guttiferone E was tested using the H1975 cell line in in vitro (2D and 3D) cell cultures and in vivo in BALB/c athymic nude mice. Live/dead assay was also performed to support the results. Tumor tissues obtained from in vivo studies were used for western blotting. Guttiferone E reduced H1975 cell viability in a concentration-dependent manner. The IC50 values in 2D and 3D cell lines were 2.56±0.12 μM and 11.25±0.34 μM. Furthermore, at 10 mg/kg intraperitoneally, guttiferone E significantly reduced the tumor volume in tumor xenografts when used alone and in combination with carboplatin. Guttiferone E and carboplatin displayed synergistic inhibition of H1975 cells and animal tumors. Co-treatment of guttiferone E with carboplatin induced more prominent apoptosis than treatment with either drug alone. Guttiferone E treatment induced cleavage of poly-ADP ribose polymerase and induced apoptosis by significantly reducing levels of mammalian target of rapamycin, sirtuin 1, sirtuin 7, superoxide dismutase, programmed death-ligand 1, and programmed cell death 1 in tumor tissues. Our results show guttiferone E to be a promising, novel and potent antitumor drug candidate for osimertinib-resistant lung cancer with EGFR L858R/T790M mutations.

Role of Adherence to Treatment in the Correction of the Risk of Cardiovascular Complications in Patients with Arterial Hypertension with Accompanying Diabetes Mellitus

Introduction. The presence of diabetes mellitus (DM), its duration, and the severity of the course significantly affect the degree of damage to target organs and the risk of cardiovascular complications (CVD) in patients with arterial hypertension (AH). It is also known that the effectiveness of the correction of the risks of CVD is influenced not only by the optimization of disease therapy but also by the adherence of patients to treatment, which created the prerequisites for this study. The aim of the study. To investigate the role of adherence to treatment in the correction of the risk of cardiovascular complications in patients with arterial hypertension with accompanying diabetes mellitus. Materials and methods. The study included 120 patients with a stable course of stage II hypertension of 1st-2nd degrees with concomitant type 2 diabetes with the disease duration of more than 1 year. Results. After 3 months of observation, in most patients with good adherence to treatment the target level of BP (in 78.3 ± 5.3 %) and the target level of HvA1c (in 56.7 ± 6.4 %) and a decrease in the 10-year risk of cardiovascular disease according to the SCORE2 diabetes scale (from 34.1 ± 3.7 points to 27.3 ± 3.8 points, p &lt; 0.05) were achieved. The Pearson correlation coefficient between the SCORE2 diabetes risk indicator and the adherence to treatment indicator was: r = -0.916, p &lt; 0.05, which indicates a close feedback relationship. Conclusions. High adherence to treatment in the majority of patients with hypertension with accompanying diabetes allows them to achieve the target levels of blood pressure and glycemia, significantly reduce the risk index of cardiovascular complications, which has a close inverse correlation with the adherence of patients to treatment.

An Audit of Best Medical Therapy Adherence Among Patients with Carotid Artery Stenosis Attending a Tertiary Stroke Centre

Abstract Background Carotid artery stenosis (CAS) is estimated to cause 11-28% of ischaemic strokes annually. The primary objective of this audit was to assess current adherence to best medical therapy (BMT) to patients with CAS in a tertiary stroke centre. Our secondary aim was to assess stability, regression or progression of CAS whilst on BMT. Methods A retrospective chart review was conducted in a tertiary stroke centre over a six-week period. Patients were included if they were aged over 18 years, presenting to an outpatient stroke clinic, and had a known diagnosis of either symptomatic or asymptomatic CAS. The European Stroke Organisation Guidelines were used to define BMT. Results A total of 56 charts were reviewed at three weekly outpatient clinics. Of the 27 patients meeting our inclusion criteria 66% (n=18) were male, median degree of CAS was 50-70% and 78% (n=20) had symptomatic CAS. 89% were on BMT but only 56% achieved a low-density lipoprotein cholesterol (LDL-C) target of &amp;lt;1.8 (median 1.6 (range: 0.7-4.2) and only 66% (n=18) had a documented smoking status. 81% of patients with symptomatic CAS on BMT had stable stenosis, 5% had regression and 14% had progression of stenosis. 50% of asymptomatic patients had progression of the degree of their stenosis. Conclusion Overall adherence to BMT was good at 89% but there is room for improvement particularly in terms of lipid target level and documentation of risk factor status. BMT resulted in stable stenosis and low progression rates particularly in patients with symptomatic CAS. BMT and early detection are essential for management to control progression of CAS, but we have highlighted the opportunity to improve LDL-C targets. Further research is needed to evaluate if the results of this study are translatable to the stroke population in general.

COVID-19 exposure, financial flexibility, and corporate leverage adjustment

This study examines how firm-level exposure to the COVID-19 pandemic affects the speed of leverage adjustment among 3260 US-listed firms from 2019q1 to 2022q1. Using a novel measure of COVID-19 exposure, we find that higher exposure significantly reduces the speed at which firms adjust their leverage towards target levels. This effect is more pronounced for financially constrained firms and those operating in competitive markets. We further show that COVID-19 exposure adversely impacts corporate liquidity, default risk, and financial flexibility. Our findings highlight the role of exogenous shocks in shaping corporate financing decisions.

Enhancement of cognitive function in mice with Alzheimer's disease through hyperbaric oxygen-induced activation of cellular autophagy.

In this study, we examined the effectiveness of hyperbaric oxygen (HBO) therapy in ameliorating cognitive deficits in mice with Alzheimer's disease (AD), while also assessing its impact on the autophagic pathway within the context of AD. 20 double-transgenic mice expressing the amyloid precursor protein and presenilin 1 (APP/PS1) were purposefully selected and randomly assigned to groups A and B. Concurrently, 20 C57BL/6 mice were chosen and randomly categorized into groups C and D, each consisting of 10 mice. Mice in groups B and D received HBO treatment. The Morris water maze assay was used to assess changes in mouse behavior. Immunohistochemistry techniques were used to quantify the expression levels of amyloid-beta 42 (Aβ42) and microtubule-associated protein 1A/1B-light chain 3 (LC3) in hippocampal tissues, while western blot analysis was used to investigate the levels of LC3-II, p62, phosphoinositide 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) proteins within hippocampal tissues. Mice allocated to group B exhibited reduced escape latency and prolonged dwell time in the target quadrant compared to other groups. Histological examination revealed conspicuous plaque-like deposits of Aβ42 in the hippocampal tissues of mice in groups A and B. Group B displayed diminished Aβ42-positive reactants and augmented microtubule-associated protein 1A/1B-LC3-positive reactants compared to group A. LC3-positive reactants were also detected in the hippocampal tissues of mice in groups C and D, surpassing the levels observed in groups A and B. Furthermore, group B demonstrated significantly lower expression of mTOR protein and markedly higher expression of LC3-II protein in mouse hippocampal tissues when compared to group A (P < 0.05). Conversely, there were no significant disparities noted in PI3K and p62 protein expression between groups B and A. Notably, no discernible discrepancies were observed in the expression levels of mTOR, PI3K, LC3-II, and p62 proteins between groups C and D within mouse hippocampal tissues. HBO treatment demonstrates efficacy in enhancing cognitive function in mice with AD and holds promise as a potential therapeutic intervention for AD by facilitating the activation of the mTOR pathway-mediated autophagy.

Direct loss‐based seismic design of low‐rise base‐isolated reinforced concrete buildings

AbstractThis paper proposes a procedure to design low‐rise base‐isolated structures achieving a specific target level of earthquake‐induced loss (e.g., dollars, downtime) while complying with a predefined minimum level of structural reliability. The procedure is “direct” since the target loss is specified at the first step of the process, and virtually no design iterations are required. Direct loss‐based design (DLBD) is enabled by a simplified loss assessment module involving: (1) surrogate probabilistic seismic demand models representing the probability distribution of peak horizontal displacements and accelerations on top of the isolation layer conditional on different ground‐motion intensity levels; (2) approximations of the superstructure response; (3) simplified consequence models for isolation system and superstructure based on damage‐to‐loss ratios (economic loss or repair time); (4) simplified consequence models for acceleration‐ and drift‐sensitive non‐structural components, based on storey loss functions of a potential inventory of components. Given some basic geometrical parameters of the superstructure, DLBD provides the isolation system's force‐displacement curve and the required superstructure's strength complying with a selected loss target. The members' structural detailing follows the principles of direct displacement‐based design, sectional analysis, and the general theory of base isolation. The procedure is illustrated by designing six reinforced concrete wall buildings (two‐, three‐, and four‐storeys) base isolated with lead rubber bearings, to achieve predefined targets of expected repair time. Repair time is benchmarked against a more refined method adopting a cloud‐based non‐linear time history analysis, finding a maximum underestimation of 17%, thus confirming the dependability of DLBD. Such error is almost entirely attributable to the simplified estimation of peak floor accelerations, and it could be potentially eliminated by refining such estimation.

Optimizing tacrolimus dosing in Hispanic renal transplant patients: insights from real-world data.

Tacrolimus, an immunosuppressant used to prevent organ rejection in renal transplant patients, exhibits high inter-patient variability, necessitating therapeutic drug monitoring. Early post-transplant tacrolimus exposure in Hispanics is understudied. Although genotypic information is linked to pharmacokinetic differences, its clinical application remains limited. This study aimed to use a real-world data-driven, pharmacokinetic model-based approach for tacrolimus in Hispanics to determine a suitable initial dose and design an optimal dose titration strategy by simulations to achieve plasma trough concentration target levels of 10-12ng/mL at the earliest. Sparse concentration-time data of tacrolimus were obtained from electronic medical records for self-identified Hispanic subjects following renal transplant. Rich pharmacokinetic literature data was leveraged to estimate structural pharmacokinetic model parameters, which were then fixed in the current analysis. Only apparent clearance was estimated with the sparse tacrolimus data and potential covariates were identified. Simulations of various starting doses and different dose titration strategies were then evaluated. The analysis included 121 renal transplant patients with 2,215 trough tacrolimus concentrations. A two-compartment transit absorption model with allometrically scaled body weight and time-varying hematocrit on apparent clearance adequately described the data. The estimated apparent clearance was 13.7L/h for a typical patient weighing 70kg and at 30% hematocrit, demonstrating a 40% decrease in clearance compared to other patient populations. Model based simulations indicated the best initial dose for the Hispanic population is 0.1mg/kg/day. The proposed titration strategy, with three dose adjustments based on trough levels of tacrolimus, increased the proportion of patients within the target range (10-12ng/mL) more than 2.5-fold and decreased the proportion of patients outside the therapeutic window by 50% after the first week of treatment. Hispanic renal transplant population showed an estimated 40% decrease of apparent clearance in the typical patient compared to other populations with similar characteristics. The proposed dose adjustment attained the target range rapidly and safely. This study advocates for tailored tacrolimus dosing regimens based on population pharmacokinetics to optimize therapy in Hispanic renal transplant recipients.

Hemodynamic management of acute kidney injury.

To discuss the role of hemodynamic management in critically ill patients with acute kidney injury. Acute kidney injury (AKI) may be associated with persistent alterations in renal perfusion, even when cardiac output and blood pressure are preserved. The effects of interventions aiming at increasing renal perfusion are best evaluated by renal Doppler or contrast enhance ultrasound. However, limited data have been acquired with these techniques and the essential of the literature is based on surrogates of renal function such as incidence of use of renal replacement therapy. Fluids may increase renal perfusion but their effects are quite unpredictable and can be dissociated from their impact on cardiac output and arterial pressure. Inotropes can also be used in selected conditions. At the de-escalation phase, fluid withdrawal should be considered. Safe fluid withdrawal may be achieved when applied in selected patients with preserved tissue perfusion presenting signs of fluid intolerance. When applied, stopping rules should be set. Dobutamine, milrinone and levosimendan increase renal perfusion in AKI associated with cardiac failure or after cardiac surgery. However, the impact of these agents in sepsis is not well defined. Regarding vasopressors, norepinephrine is the first-line vasopressor agent, but vasopressin derivative may limit the requirement of renal replacement therapy. Angiotensin has promising effects in a limited size post-Hoc analysis of a RCT, but these data need to be confirmed. While correction of severe hypotension is associated with improved renal perfusion and function, the optimal mean arterial pressure (MAP) target level remains undefined, Systematic increase in MAP results in variable changes in renal perfusion. It sounds reasonable to individualize MAP target, paying attention to central venous and intraabdominal pressures, as well as to the response to an increase in MAP. Recent studies have refined the impact of the various hemodynamic interventions on renal perfusion and function in critically ill patients with AKI. Though several of these interventions improve renal perfusion, their impact on renal function is more variable.

Black raspberry extract stimulates glucose uptake via adenosine monophosphate‐activated protein kinase and phosphatidylinositol‐3 kinase pathways in skeletal muscle cells

AbstractBlack raspberry (Rubus occidentalis) shows beneficial health effects, such as antioxidant, anti‐inflammatory, chemopreventive, antiproliferative, and antihyperglycemic activities. The present study investigated the antihyperglycemic activity of black raspberry extract (BRE) and potential mechanisms in skeletal muscle cells. Differentiated C2C12 myotubes were treated with the BRE (1–1000 μg/mL) or metformin (1 mM). The protein levels of various insulin signaling targets were measured by western blot analysis. BRE significantly increased glucose uptake by upregulated insulin receptor and phosphatidylinositol‐3 kinase (PI3K) in C2C12 cells, leading to enhanced translocation of glucose transporter 4 (GLUT4) to the plasma membrane. The expression of phosphorylated (p)‐adenosine monophosphate‐activated protein kinase (AMPK) was also enhanced by treatment with BRE, this resulting in stimulation of GLUT4 translocation to the plasma membrane and hence glucose uptake in skeletal muscles. These results suggest that BRE has an antihyperglycemic effect by stimulating GLUT4 translocation to the plasma membrane via activating the PI3K and AMPK pathways in skeletal muscle cells, thereby upregulating glucose uptake. Black raspberry is a potential functional food and has important implications for preventing and treating type‐2 diabetes. In addition, our study found that the flavonoids fraction is the main contributor fraction to promote glucose uptake in C2C12 cells.

Bank Branches Expansion and Corporate Cash Holdings: Evidence from the Distribution of Bank Branches in China

ABSTRACT Using the geographical distribution data of banks’ physical branches at micro-firm level, this paper investigates the impact of bank branches expansion on corporate cash holdings. We find that the more the number of bank branches around firms, the less corporate cash holdings, implying that bank branches expansion helps reduce the level of corporate cash holdings. And the negative effect is more prominent in small-sized firms and non-SOEs. Further mechanism tests show that bank branches expansion reduces cash holdings mainly through intensified bank competition and shortening the geographical distance between bank and firm. We also find that bank branches expansion speeds up the dynamic adjustment to the target level of corporate cash holdings and mitigates agency problems. Our study highlights the crucial role played by the geographical distribution of bank branches in shaping corporate financial decisions and provides important policy implications for banking sector reform.

Recent advancements in targeting the immune system to treat hypertension

Hypertension is the key leading risk factor for death globally, affecting ∼1.3 billion adults, particularly in low- and middle-income countries. Most people living with hypertension have uncontrolled high blood pressure, increasing their likelihood of cardiovascular events. Significant issues preventing blood pressure control include lack of diagnosis, treatment, and response to existing therapy. For example, monotherapy and combination therapy are often unable to lower blood pressure to target levels. New therapies are urgently required to tackle this issue, particularly those that target the mechanisms behind hypertension instead of treating its symptoms. Acting via an increase in systemic and tissue-specific inflammation, the immune system is a critical contributor to blood pressure regulation and is considered an early mechanism leading to hypertension development. Here, we review the immune system's role in hypertension, evaluate clinical trials that target inflammation, and discuss knowledge gaps in pre-clinical and clinical data. We examine the effects of anti-inflammatory drugs colchicine and methotrexate on hypertension and evaluate the blockade of pro-inflammatory cytokines IL-1β and TNF-α on blood pressure in clinical trials. Lastly, we highlight how we can move forward to target specific components of the immune system to lower blood pressure. This includes targeting isolevuglandins, which accumulate in dendritic cells to promote T cell activation and cytokine production in salt-induced hypertension. We discuss the potential of the dietary fibre-derived metabolites short-chain fatty acids, which have anti-inflammatory and blood pressure-lowering effects via the gut microbiome. This would limit adverse events, leading to improved medication adherence and better blood pressure control.

Navigating sustainability: key factors in prioritising Sustainable Development Goals

Prioritising sustainable development goals (SDGs) is one of the fundamental approaches to achieving global sustainability objectives, as it helps efficient resource allocation, addresses urgent needs, enhances policy coherence, and measures impact. Despite existing efforts, there remains an unclear understanding of the key factors needed for effective SDG prioritisation, presenting challenges for strategic planning and decision-making. This study provides an evidence-based analysis of these critical factors by examining relevant literature, conducting surveys, and employing Analytical Hierarchy Process (AHP)-based Multi-Criteria Decision Analysis (MCDA). The study identifies four primary factors for SDG prioritisation: SDG interrelations, performance, scope, and alignment. The findings confirm that national prioritisation have more priority compared to global, regional, and sub-national systems, and that prioritisation is more valuable at the indicator level rather than at the goal or target levels. Additionally, prioritisation should initially focus on off-track SDGs. Notably, academia ranks SDG prioritisation based on relationships and performance highly, while government officials emphasise alignment and relevance. Moreover, the results indicate that academia prefers target-level prioritisation, while government officials lean towards indicator level. However, both groups favour national scale over global and regional scales.

Efficient diagnostic classification of diverse pathologies through contextual eye movement data analysis with a novel hybrid architecture

The analysis of eye movements has proven valuable for understanding brain function and the neuropathology of various disorders. This research aims to utilize eye movement data analysis as a screening tool for differentiation between eight different groups of pathologies, including scholar, neurologic, and postural disorders. Leveraging a dataset from 20 clinical centers, all employing AIDEAL and REMOBI eye movement technologies this study extends prior research by considering a multi-annotation setting, incorporating information from recordings from saccade and vergence eye movement tests, and using contextual information (e.g. target signals and latency of the eye movement relative to the target and confidence level of the quality of eye movement recording) to improve accuracy while reducing noise interference. Additionally, we introduce a novel hybrid architecture that combines the weight-sharing feature of convolution layers with the long-range capabilities of the transformer architecture to improve model efficiency and reduce the computation cost by a factor of 3.36, while still being competitive in terms of macro F1 score. Evaluated on two diverse datasets, our method demonstrates promising results, the most powerful discrimination being Attention & Neurologic; with a macro F1 score of up to 78.8%; disorder. The results indicate the effectiveness of our approach in classifying eye movement data from different pathologies and different clinical centers accurately, thus enabling the creation of an assistant tool in the future.