Duration Of Action Research Articles

Evidence for interacting but decoupled controls of decisions and movements in nonhuman primates.

Many recent studies indicate that control of decisions and actions is integrated during interactive behavior. Among these, several carried out in humans and monkeys conclude that there is a coregulation of choices and movements. Another perspective, based on human data only, proposes a decoupled control of decision duration and movement speed, allowing, for instance, trading decision duration for movement duration when time pressure increases. Crucially, it is not currently known whether this ability to flexibly dissociate decision duration from movement speed is specific to humans, whether it can vary depending on the context in which a task is performed, and whether it is stable over time. These are important questions to address, especially to rely on monkey electrophysiology to infer the neural mechanisms of decision-action coordination in humans. To do so, we trained two macaque monkeys in a perceptual decision-making task and analyzed data collected over multiple behavioral sessions. Our findings reveal a strong and complex relationship between decision duration and movement vigor. Decision duration and action duration can covary but also "compensate" each other. Such integrated but decoupled control of decisions and actions aligns with recent studies in humans, validating the monkey model in electrophysiology as a means of inferring neural mechanisms in humans. Crucially, we demonstrate for the first time that this control can evolve with experience, in an adapted manner. Together, the present findings contribute to deepening our understanding of the integrated control of decisions and actions during interactive behavior.NEW & NOTEWORTHY The mechanism by which the integrated control of decisions and actions occurs, coupled or interactive but decoupled, is debated. In the present study, we show in monkeys that decisions and actions influence each other in a decoupled way. For the first time, we also demonstrate that this control can evolve depending the subject's experience, allowing the trade of movement time for decision time and limiting the temporal discounting of reward value.

Dopamine D4 receptors in the lateral habenula regulate anxiety-related behaviors in a rat model of Parkinson's disease

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopamine (DA) and 5-hydroxytryptamine (5-HT) containing systems, which are implicated in the pathophysiology of anxiety, it is not clear how activation and blockade of LHb D4 receptors affects anxiety-like behaviors, particularly in Parkinson’s disease related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced anxiety-like behaviors, which attribute to hyperactivity of LHb neurons and decrease in the level of DA in the medial prefrontal cortex (mPFC), amygdala and ventral hippocampus (vHip) compared to sham-operated rats. Intra-LHb injection of D4 receptor agonist A412997 induced or increased the expression of anxiety-like behaviors, while injection of D4 receptor antagonist L741742 showed anxiolytic effects in sham-operated and the SNc-lesioned rats. However, the doses producing behavioral effects in the lesioned rats were higher than those of sham-operated rats. Intra-LHb injection of A412997 increased firing rate of LHb neurons, and decreased levels of DA and 5-HT in the mPFC, amygdala and vHip; conversely, L741742 decreased firing rate of LHb neurons, and increased levels of DA and 5-HT in two groups of rats. Compared to sham-operated rats, the duration of A412997 and L741742 action on the firing rate of neurons was markedly shortened in the lesioned rats. Collectively, these findings suggest that D4 receptors in the LHb are involved in the regulation of anxiety-like behaviors, and degeneration of the nigrostriatal pathway down-regulates function and/or expression of these receptors.

Development of the novel formulations of perospirone for the treatment of schizophrenia.

Schizophrenia is a severe mental illness. Its clinical features include positive symptoms (hallucinations, delusions, thought disorders), negative symptoms (avolition, anhedonia, poverty of thought, social withdrawal), and cognitive dysfunction. A large number of antipsychotic drugs with traditional dosage forms are available to mitigate the symptoms of schizophrenia but the duration of action is commonly short, often requiring frequent administration. The perospirone hydrochloride hydrate (PER), as a second-generation antipsychotic drug, shows therapeutic effects on both positive and negative symptoms of schizophrenia, with less impact on cognitive function. However, it suffers from a short half-life, fluctuating blood concentration, instability in the circulating leading to peak-trough fluctuations, and poor patient compliance due to the required frequent administration. Based on the hydrophilic matrix, we developed novel formulations of PER, including the extended-release and the controlled-release tablets of PER. The resulting formulations delayed the drug release and prolonged the persistence of PER, leading to an extended half-life and reduced fluctuations in blood concentration with stable therapeutic levels and an improved absorption with higher bioavailability, thus reducing dosing frequency. These oral extended-release and controlled-release tablets promise to alleviate patients' medication discomfort and provide long-term sustained drug release. They would provide a platform with broad prospects for the clinical treatment of schizophrenia.

COMPARATIVE STUDY ON ANTHROPOMETRIC AND MOTOR DIFFERENCES IN U15 BASKETBALL PLAYERS

Basketball is a predominantly aerobic sport during which high-intensity anaerobic actions are performed. In recent years, this characteristic has evolved in terms of demands on the athlete and intensity of the competition, implying an increase in the number and duration of explosive actions. To meet the demands of this sport, good technical, tactical, physical and mental training is required. The research purpose was to determine the anthropometric and motor differences between two male basketball teams from a private club, both playing in the U15 age category. The study included 32 athletes who were divided into two groups. One group was made up of 16 players representing the club’s elite team, and the other group also consisted of 16 players representing the club’s secondary team for this age category. All players were tested in the same sports hall on two different days, during their training for the U15 National Basketball Championship of Romania. Anthropometric and physical characteristics were measured using a test battery with six variables: Height, Weight, Body mass index, 10 m Sprint, Standing long jump, Vertical jump, and Little Marathon. The methods used were: literature review, observation, mathematical statistics, tabular and graphical methods. Differences in anthropometric and physical values between the basketball players of the two teams were determined using the t-Test for independent small samples (Assuming Equal Variances). Our research hypothesis is confirmed, since there are significant anthropometric and motor differences between the players of the two representative club teams, justifying the presence of the elite team in the U15 National Basketball Championship.

Assessment of use and Awareness of Diclofenac in Syria

Diclofenac, known as diclone in Syria, is the most widely used drug in multiple medical conditions. This research was conducted to assess the use and awareness of diclofenac in Syria through a survey. 601 responses were included in this research.Most participants were female (67.7%), between the ages of 18 and 30 years (82.9%), and did not have a chronic disease (86.3%). More than half of the participants were university students (53.4%). A high proportion of the participants had a university education level (87.7%). The most commonly used dosage form for diclofenac was tablets among participants(70.9%). 43.8% chose 50mg as the dose of diclofenac. Most participants improved after using diclofenac (73.7%). Participants were satisfied after diclofenac treatment (66.56%). Most had no side effects after treatment with diclofenac (79.5%). 81.3% of the participants who experienced side effects suffered from stomach pain. Fortunately, 84.4% of the participants did not use the injection combining diclofenac with cortisone and an antibiotic. 56.38% used this combination to treat respiratory infections. A minority of the participants experienced allergic reactions after taking this medication (4%). More than two-thirds of the participants will continue to use diclofenac for pain management in the future (65.9%).77.9% of the participants used diclofenac without a prescription. Most participants used this medicine after a meal (82%). 36.6% of the participants recorded half an hour as the onset of diclofenac. The participants reported an action duration of 6 hours (24.5%) and 8 hours (31%). This study confirmed the high use of diclofenac among the Syrians. A good level of awareness was observed among the surveyed participants.

A Hybrid Multiobjective Control Strategy Based on Combination of Modulated Model Predictive Control and Phase‐Shifted Modulation for a Unidirectional Five‐Level Rectifier

ABSTRACTThe unidirectional multilevel rectifier has immense potential in high‐power medium‐voltage industrial applications. This paper proposes a multiobjective control method based on the combination of optimal‐vector‐pair modulated model predictive control (OVP‐M2PC) and a phase‐shifted modulation strategy for a unidirectional five‐level rectifier. This strategy takes both of the inductor current tracking and capacitor voltage balancing as the control objectives. First, an optimal vector pair is determined based on the AC‐side current variation rate, and then, through combining the calculated action duration of OVP with carrier phase‐shifted modulation, inductor current tracking is achieved. Second, capacitor voltage balancing control is carried out by compensating for the duty cycles which also decouples the input current tracking and output capacitor voltage balance control. Compared with traditional FCS‐MPC, under the proposed control strategy, complex cost function calculation and weighting factor tuning are not required, which much reduced computational burden. Multiobjective control is achieved with better performance in both steady‐state and dynamic conditions. The superiority of the proposed strategy over traditional FCS‐MPC are validated through simulations and hardware experiments.

Early adoption of triamcinolone acetonide suprachoroidal injection for uveitic macular edema: a physician survey

ObjectiveTo obtain physicians’ “real-world” perspectives on early experiences with triamcinolone acetonide suprachoroidal injection (SCS-TA) for treatment of patients with uveitic macular edema (UME).ResultsTwelve retina/uveitis specialists in the United States were surveyed about SCS-TA injection procedure and patient outcomes. Survey participants administered ≥ 291 SCS-TA injections to 243 patients with UME with various disease characteristics (etiologies, chronicity, and anatomical subtypes). Commonly reported reasons for SCS-TA adoption included potential for lowering the risk of steroid-associated intraocular pressure elevations versus intravitreal injections or implants (100%), potential for longer duration of action versus intravitreal steroid injections or implants (92%), and desire to use a new delivery modality (83%). Nearly all participants (92%) found injection procedure relatively easy post-training, with most (75%) procedurally comfortable after completing 2–5 injections. 58% of participants indicated that their patients gained 2–3 lines of vision by first follow-up visit, and 92% reported having patients who experienced 100–150 μm or greater reduction in central subfield thickness. Overall, 92% of participants were satisfied with SCS-TA treatment outcomes. Findings from this survey of early adopters of SCS-TA indicate that the suprachoroidal injection technique was easy to learn and resulted in favorable patient outcomes consistent with clinical trial data.

Targeting PfCLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment.

Malaria still causes over 600,000 deaths annually, with rising resistance to frontline drugs by Plasmodium falciparum increasing this number each year. New medicines with novel mechanisms of action are, therefore, urgently needed. In this work, we solved the cocrystal structure of the essential malarial kinase PfCLK3 with the reversible inhibitor TCMDC-135051 (1), enabling the design of covalent inhibitors targeting a unique cysteine residue (Cys368) poorly conserved in the human kinome. Chloroacetamide 4 shows nanomolar potency and covalent inhibition in both recombinant protein and P. falciparum assays. Efficacy in parasites persisted after a 6 h washout, indicating an extended duration of action. Additionally, 4 showed improved kinase selectivity and a high selectivity index against HepG2 cells, with a low propensity for resistance (log MIR > 8.1). To our knowledge, compound 4 is the first covalent inhibitor of a malarial kinase, offering promising potential as a lead for a single-dose malaria cure.

The effects of anaesthesia on the cardiovascular, respiratory and nervous systems during inhalational anaesthesia: A case report.

Our understanding of the effects of anaesthesia is incomplete. Anaesthesia works primarily by causing widespread depression of the central nervous system. This article will consider the anaesthesia provided for a patient undergoing a hysteroscopy, endometrial ablation and biopsy for abnormal uterine bleeding. The relationship between physiology and the effects of anaesthesia is discussed. Several effects of anaesthesia are observed during the case. Relating to the respiratory system, preoxygenation increased end tidal oxygen by 39%, delaying desaturation during apnoea. Propofol had a profound effect on the patient's respiratory rate by inhibiting the ventilatory drive, resulting in apnoea. The cardiovascular system was affected by tracheal intubation. Stimulation of the sympathetic nervous system caused a 96% increase in heart rate. Induction of anaesthesia resulted in hypotension, treated with the administration of ephedrine, causing vasoconstriction. Modified rapid sequence induction required an increased dose of rocuronium, resulting in an increased duration of action at the neuromuscular junction. The prolonging muscle paralysis required sugammadex as a reversal agent. This case demonstrated the effects of anaesthesia on the respiratory, cardiovascular and nervous systems.

Ethoxy-erianin phosphate inhibits angiogenesis in colorectal cancer by regulating the TMPO-AS1/miR-126-3p/PIK3R2 axis and inactivating the PI3k/AKT signaling pathway

Colorectal cancer (CRC) is the third most common malignancy, with increasing prevalence and mortality. How the ethoxy-erianin phosphate (EBTP) mediates CRC development remains unclear. Therefore, the current study evaluated the effects of EBTP on the proliferation, migration, and angiogenesis of CRC cells using CCK-8, Wound-healing, Transwell, and Tube formation assays. RNA sequencing and molecular docking techniques helped predict that EBTP could inhibit angiogenesis by regulating PIK3R2 expression while clarifying the mechanism behind EBTP-mediated CRC angiogenesis. Subsequently, several in vitro experiments indicated that PIK3R2 overexpression significantly improved the proliferation, migration, and angiogenesis of CRC cells while knocking down PIK3R2 expression inhibited their proliferation, migration, and angiogenesis. Simultaneously, PIK3R2 expression in CRC cells gradually decreased with increased EBTP concentration and action duration. Moreover, PIK3R2 overexpression in CRC cells could reverse the inhibitory EBTP effect in angiogenesis. Mouse experiments also depicted that EBTP inhibited CRC angiogenesis by down-regulating PIK3R2 expression. In addition, EBTP could inhibit PI3K/AKT pathway activity and indirectly control PIK3R2 expression through the lncRNA TMPO-AS1/miR-126-3p axis. Our findings highlighted that EBTP could inhibit CRC angiogenesis using the TMPO-AS1/miR-126-3p/PIK3R2/PI3k/AKT axis, providing a novel strategy for anti-angiogenic therapy in CRC.

Emerging RNAi Therapies to Treat Hypertension.

Hypertension (HTN), often dubbed the "silent killer," poses a significant global health challenge, affecting over 1.3 billion individuals. Despite advances in treatment, effective long-term blood pressure (BP) control remains elusive, necessitating novel therapeutic approaches. Poor control of BP remains a leading cause of cardiovascular morbidity and mortality worldwide and is becoming an even larger global health problem due to the aging population, rising rates of obesity, poorer dietary patterns and overall cardiometabolic health, and suboptimal rates of patient adherence and optimal BP control. Ribonucleic acid interference (RNAi) technology, which leverages the body's natural gene-silencing mechanism, has emerged as a promising strategy for several diseases and has recently been tested for its antihypertensive effects. We systematically reviewed peer-reviewed articles from databases including PubMed, EMBASE, and Scopus for studies examining RNAi's role in managing HTN, focusing on mechanisms, clinical utility, and safety profile. Key early-phase trials of some RNAi-leading candidate drugs are detailed. Also highlighted are challenges such as target specificity, delivery mechanisms, durability of effect, and immunogenicity. We conclude by summarizing how RNAi has a significant potential role in HTN therapy due to their unique benefits, such as long-term duration of action, infrequent dosing, and lack of major side effects.

Efficacy and safety of a diffusion-based extended-release fluticasone propionate intra-articular injection (EP-104IAR) in knee osteoarthritis (SPRINGBOARD): a 24-week, multicentre, randomised, double-blind, vehicle-controlled, phase 2 trial.

Corticosteroids are among the few effective treatments for knee osteoarthritis, but short duration of action limits their utility. EP-104IAR, a long-acting formulation of fluticasone propionate for intra-articular injection, optimises the action of fluticasone propionate through novel diffusion-based extended-release technology. The SPRINGBOARD trial assessed the efficacy, safety, and pharmacokinetics of EP-104IAR in people with knee osteoarthritis. SPRINGBOARD was a randomised, vehicle-controlled, double-blind, phase 2 trial done at 12 research sites in Denmark, Poland, and Czech Republic. We recruited adults aged 40 years or older with primary knee osteoarthritis (Kellgren-Lawrence grade 2-3) who reported Western Ontario and McMaster Universities Osteoarthritis Arthritis Index (WOMAC) pain scores of at least 4 and no more than 9 out of 10. Participants were randomly assigned (1:1) to receive one intra-articular dose of 25 mg EP-104IAR or vehicle control. Randomisation was done via interactive web-based access to a central predefined computer-generated list with block size of six (allocated by clinical site). Participants and assessors were masked to treatment allocation. Participants were followed up for 24 weeks. The primary outcome was the difference between groups in change in WOMAC pain score from baseline to week 12, analysed in all participants who were randomly assigned and received treatment. Safety, including laboratory analyses, and pharmacokinetics from quantification of fluticasone propionate in peripheral blood were assessed in all participants who received a dose of randomly assigned treatment. A person with lived experience of knee osteoarthritis was involved in study interpretation and writing of the report. This trial is registered with ClinicalTrials.gov, NCT04120402, and the EU Clinical Trials Register, EudraCT 2021-000859-39, and is complete. Between Sept 10, 2021, and Nov 16, 2022, 1294 people were screened for eligibility, and 319 were randomly assigned to EP-104IAR (n=164) or vehicle control (n=155). One participant in the EP-104IAR group was excluded from all analyses because treatment was not administered due to an adverse event. 318 participants (135 [42%] male and 183 [58%] female, 315 [99%] White) received randomly assigned treatment and were included in the primary analysis and safety analysis (EP-104IAR, n=163; vehicle control, n=155). At week 12, least squares mean change in WOMAC pain score from baseline was -2·89 (95% CI -3·22 to -2·56) in the EP-104IAR group and -2·23 (-2·56 to -1·89) in the vehicle control group, with a between-group difference of -0·66 (-1·11 to -0·21; p=0·0044); a significant between-group difference persisted to week 14. 106 (65%) of 163 participants in the EP-104IAR group had one or more treatment-emergent adverse event compared with 89 (57%) of 155 participants in the vehicle control group. Effects on serum glucose and cortisol concentrations were minimal and transient. There were no treatment-emergent deaths or treatment-related serious adverse events. Plasma concentrations of fluticasone propionate showed a blunted initial peak with terminal half-life of approximately 18-20 weeks. These phase 2 results suggest that EP-104IAR has the potential to offer clinically meaningful pain relief in knee osteoarthritis for an extended period of up to 14 weeks, longer than published data for currently marketed corticosteroids. There were minimal effects on glucose and cortisol, and stable fluticasone propionate concentrations in plasma. The safety and efficacy of EP-104IAR will be further evaluated in phase 3 trials, including the possibility of bilateral and repeat dosing with EP-104IAR. Eupraxia Pharmaceuticals. For the Danish translation of the abstract see Supplementary Materials section.

Thermal stresses in bimetallic plate under induction heating by nonstationary electromagnetic field

A thermomechanical problem is formulated for a bimetallic plate subjected to induction heating by a nonstationary electromagnetic field. As the object of the study, a plate with layers made of stainless steel and copper is selected. The stress intensities in the constituent layers of the plate are numerically analyzed on its external surfaces and at the contact interface of the constituent layers. The analysis is conducted based on the amplitude-frequency characteristics and the duration of the nonstationary electromagnetic action. The research is carried out for two cases of electromagnetic carrier wave frequencies including those equal to the first resonance frequency and those extending outside the resonance frequency range of the electromagnetic field.

Current evidence on the use of sugammadex for neuromuscular blockade antagonism during electroconvulsive therapy - a narrative review.

Depression is a common mental health problem that is associated with significant disability and mortality. Electroconvulsive therapy (ECT) has been demonstrated to be effective at resolving expression of suicidal intent in patients with depression. In less acute situations, patients are usually referred for ECT after several medication trials. Neuromuscular blocking agents (NMBAs) are used to block tonic-clonic motor activity and associated physical harm during the delivery of ECT. Succinylcholine (Sch), with its rapid onset of muscle relaxation, short self-terminating duration of action, and rapid subsequent return of spontaneous ventilation, is the NMBA of choice for ECT. However, the use of Sch is problematic or contraindicated is some situations. Although non-depolarizing NMBAs can be used, the variable time to onset of adequate muscle relaxation and prolonged duration of action have limited their widespread acceptance as alternatives to Sch. Recently, however, with the widespread availability of sugammadex, a chemically modified γ- cyclodextrin that rapidly and predictably reverses the effect of non-depolarizing NMBAs, the muscle relaxation achieved by rocuronium can predictably and effectively be reversed. In situations where Sch is contraindicated or otherwise problematic, rocuronium, followed by pharmacological antagonism with sugammadex, can provide a safe and effective muscle relaxation approach comparable to that of Sch in terms of duration of action. This review provides a summary of the current state of evidence for the use of sugammadex during ECT, which should lend support to further acceptance and future studies of sugammadex in the context of ECT.

Safety Profiles Related to Dosing Errors of Rapid-Acting Insulin Analogs: A Comparative Analysis Using the EudraVigilance Database.

Diabetes is a widespread condition that can lead to multiple and severe complications. Rapid-acting insulin analogs (RAIAs) and long-acting insulin analogs are prescribed for the effective management of diabetes. RAIAs are expected to be associated with a higher number of dosing errors because of their rapid onset, short duration of action, and the need for frequent dosing, compared to other insulin analogs. There are three approved RAIAs on the market: insulin lispro (LIS), insulin aspart (ASP), and insulin glulisine (GLU). The aim of this study is to evaluate the real-world evidence on dosing errors reported for RAIAs in EudraVigilance (EV), an established pharmacovigilance database, in comparison to other insulin analogs and human insulins. A descriptive analysis and a disproportionality analysis were conducted. ASP and LIS were associated with high percentages of adverse drug reactions (ADRs) (22% and 17%, respectively), with over 70% of the reports involving serious ADRs. A higher frequency of cardiac and eye disorder ADRs was observed for LIS compared with ASP and GLU. GLU showed a higher frequency of ADRs in the skin and subcutaneous tissue disorders category. LIS dosing errors accounted for 5% of the total number of cases, while dosing errors for ASP and GLU were less than 3%. The most frequently reported dosing errors involved improper dosing (49%). Although there were fewer dosing errors of RAIAs in comparison to other insulins, the severity of the potential outcome highlights the importance of precise dosing and timing. Improved the monitoring and reporting of these dosing errors could enhance diabetes patient care. Additionally, smart medical devices could improve therapeutic outcomes.

Development of synergistic antifungal in situ gel of miconazole nitrate loaded microemulsion as a novel approach to treat vaginal candidiasis

Limited solubility is the main cause of the low local availability of anti-candidiasis drug, miconazole nitrate (MN). The study’s objective was to develop and characterize microemulsion (ME) based temperature-triggered in situ gel of MN for intravaginal administration to enhance local availability and antifungal activity. The solubility of MN was initially studied in different oils, surfactants, and co-surfactants. Then, pseudo-ternary phase diagrams were constructed to select the best ratio of various components. The ME formulations were characterized by thermodynamic study, droplet size, polydispersity index (PDI), viscosity, and in-vitro antifungal mean inhibition zone (MIZ). Selected MEs were incorporated into different in situ gel bases using a combination of two thermosensitive polymers (poloxamer (PLX) 407 and 188), with 0.6% of hydroxypropyl methylcellulose (HPMC K4M) and gellan gum (GG) as mucoadhesive polymer. ME-based gels (MG) were investigated for gelation temperature, gelation time, viscosity, spreadability, mucoadhesive strength, in vitro release profile, and MIZ test. Furthermore, the optimum MG was assessed for in vivo animal irritation test and FESEM investigation. Tea tree oil, lavender oil, tween 80, and propylene glycol (PG) were chosen for ME preparation for the optimal formulation; formulation ME7 and ME10 were chosen. After incorporation of the selected formulation into a mixture of P407 and P188 (18:2% w/w) with 0.6% mucoadhesive polymer, the resultant MG formulation (MG1) revealed optimum gelation temperature (33 ± 0.01℃) and appropriate viscosity with enhanced sustained release (98%) and retention through sheep vaginal mucosa, MG1 exhibited a better MIZ compared to the 2% MN gel formulation and the marketed MN product, and no rabbit vagina irritation. In conclusion, the miconazole nitrate-loaded MG-based formula sustained the duration of action and better antifungal activity than the marketed miconazole nitrate formulation.

8132 Prolonged Refractory Hypoglycemia For Seven Days After Discontinuation Of Neutral Protamine Hagedorn (NPH) Insulin And Injectable Semaglutide

Abstract Disclosure: A. Musleh: None. M.T. Rauf: None. E. Afroze: None. S. Al-Bacha: None. A 75-year-old male with Type 2 Diabetes was brought to the emergency department (ED) by emergency medical services (EMS) due to altered mentation. The patient’s wife found him unresponsive with seizure-like activity. EMS was called to the scene and obtained a capillary blood glucose reading of 31 mg/dL. Despite initial treatment with 50% dextrose the patient’s capillary blood glucose came down to 21 mg/dL in the ED and was confirmed by venous glucose. Workup including Computed Tomography (CT) imaging was inconsistent with a cerebrovascular accident. Given refractory hypoglycemia and delirium, the patient was started on a dextrose 10% infusion at 150 milliliters per hour. He was admitted to the intensive care unit for closer monitoring. His wife states that the patient had a few episodes of mild hypoglycemia overnight for the past several weeks, which improved after eating. His home medications included NPH insulin 46 units twice daily, empagliflozin 25 mg once daily, and injectable semaglutide 2 mg once weekly. The last dose of NPH insulin was the night before the presentation and the last dose of semaglutide was 5 days prior to admission. Serum creatinine levels were stable at 1.3-1.5 mg/dL throughout the hospitalization, which was below his baseline creatinine of 1.7 mg/dL. Laboratory results were as follows: hemoglobin A1c 5.9%, c-peptide level was 0.3 ng/mL (normal range 0.8-3.9 ng/mL) with a glucose of 68 mg/dL (normal range 70-100 mg/dL), insulin 203.8 mcIU/mL (normal range less than 24 mcIU/mL), proinsulin 3.2 pmol/L (normal range less than or equal to 8 pmol/L), beta-hydroxybutyrate 0.06 mmol/L (normal range 0.02-0.27), cortisol 66.6 mcg/dL (normal range 6.7-22.6 mcg/dL), insulin-like growth factor 1 123 ng/mL (normal range 53-222), and hypoglycemic agent panel was negative. On ICU Day 2, his mentation improved, he was allowed to eat but continued to require dextrose infusion to prevent hypoglycemia. Repeat fasting insulin levels even four days from prior showed an incremental decrease to 59.4 mcIU/mL with a glucose of 77 mg/dL. It took 7 days before the patient was able to maintain glucose above 70 mg/dL off of dextrose infusion. After which he had hyperglycemia requiring gradual reintroduction of his diabetes medicines other than insulin. It is rare to see such prolonged refractory hypoglycemia from an exogenous source of insulin as exhibited in this case. Notably, the patient was on semaglutide and had stable chronic kidney disease without acute kidney injury. Although multiple mechanisms explain the prolonged insulin duration of action in kidney disease, the effects of semaglutide on insulin action are unknown. Presentation: 6/3/2024

Enhancing the Efficacy of Active Pharmaceutical Ingredients in Medicinal Plants through Nanoformulations: A Promising Field.

This article explores the emerging field of nanomedicine as a drug delivery system, aimed at enhancing the therapeutic efficacy of active pharmaceutical ingredients in medicinal plants. The traditional methods of applying medicinal plants present several limitations, such as low bioavailability, poor solubility, challenges in accurately controlling drug dosage, and inadequate targeting. Nanoformulations represent an innovative approach in drug preparation that employs nanotechnology to produce nanoscale particles or carriers, which are designed to overcome these limitations. Nanoformulations offer distinct advantages, significantly enhancing the solubility and bioavailability of drugs, particularly for the poorly soluble components of medicinal plants. These formulations effectively enhance solubility, thereby facilitating better absorption and utilization by the human body, which in turn improves drug efficacy. Furthermore, nanomedicine enables targeted drug delivery, ensuring precise administration to the lesion site and minimizing side effects on healthy tissues. Additionally, nanoformulations can regulate drug release rates, extend the duration of therapeutic action, and enhance the stability of treatment effects. However, nanoformulations present certain limitations and potential risks; their stability and safety require further investigation, particularly regarding the potential toxicity with long-term use. Nevertheless, nanomaterials demonstrate substantial potential in augmenting the efficacy of active pharmaceutical ingredients in medicinal plants, offering novel approaches and methodologies for their development and application.

The delapril-indapamide combination in treatment of arterial hypertension: practical implications in light of the new guidelines.

The recent guidelines issued by the European Society of Hypertension reaffirmed that the degree of control of hypertension remains suboptimal worldwide. In order to increase the proportion of well-controlled patients, in addition to nonpharmacological measures, it is necessary to improve the implementation of drug therapy in the clinical practice as much as possible. Initial therapy should almost always be based on the combination, free or fixed, between ACE inhibitor drugs, or direct angiotensin II inhibitors ('sartans') and diuretics (thiazide or thiazide-like) or calcium channel blockers at the maximum recommended and well-tolerated dose. The combination of the thiazide-like diuretic indapamide with the ACE inhibitor delapril has shown, based on numerous clinical trials and meta-analyses, very good results in terms of antihypertensive efficacy, tolerability, and prevention or regression of organ damage. Indapamide is a thiazide-like diuretic also endowed with direct vasodilator effect and long duration of action. A meta-analysis of 19 randomized clinical trials demonstrated a greater reduction in the incidence of cardiac events, stroke and heart failure with thiazide-like diuretics than with thiazide diuretics. Delapril is a non-sulfhydryl ACE-inhibitor with high affinity for converting enzyme at the cardiac, pulmonary, and peripheral vascular levels. Being strongly lipophilic, delapril inhibits the ACE enzyme at the tissue level more potently than other ACE inhibitors. A peculiar feature of delapril is its weak bradykinin-enhancing effect due to its higher affinity for the C site than the N site of ACE, resulting in a lower incidence of cough and angioneurotic edema compared with other ACE inhibitors. In some meta-analyses, the pressor reduction was statistically, greater with the delapril-indapamide combination than with combinations between hydrochlorothiazide and ACE inhibitors. The combination consists of divisible tablets containing 30 mg delapril and 2.5 mg indapamide, and its pharmacological and clinical properties are not affected by simultaneous food intake. The antihypertensive efficacy of the combination, as well as its components, persists for the entire 24 hours. The recent alarming reports on the incidence of skin cancer during treatment with hydrochlorothiazide should also be a guide in clinical practice toward the preferential choice of a thiazide-like diuretic such as chlorthalidone or indapamide to replace hydrochlorothiazide.

Can long-term institutional owners improve market efficiency in parsing complex legal disputes?

Long-horizon institutional investors can help mitigate information asymmetries around securities class action (SCA) lawsuits. We find that the machine readability of SCA complaint filings can predict the outcome and duration of class actions. Long-term institutional investor ownership leads to a more positive post-SCA announcement price reaction and increases the volatility ratio of prices as a measure of price informativeness. Furthermore, there is a significant interaction effect between long-term institutional ownership and SCA complexity on price informativeness consistent with a superior information processing ability about complex corporate events affecting portfolio firms.