Consecutive Days Of Treatment Research Articles

Initial micafungin treatment does not improve outcomes compared to fluconazole treatment in immunocompromised and critically ill patients with candidaemia.

Candidaemia is associated with poor outcomes including high mortality rates. Controversy remains regarding whether fluconazole or an echinocandin is the optimal choice for initial candidaemia treatment, particularly among high-risk patients such as the immunocompromised or critically ill. To understand optimal initial treatment of candidaemia. We conducted a retrospective study of immunocompromised or ICU adult patients with candidaemia from 2010 to 2014. Patients who received ≥3 consecutive days of initial treatment with fluconazole or micafungin were included. The primary outcome was complete response at day 14, defined as clinical improvement and blood culture sterilization. Secondary outcomes included microbiological and clinical success, survival and recurrent candidaemia. A total of 197 patients were included; 76 received fluconazole and 121 received micafungin. There was no difference in complete response between the fluconazole and micafungin groups (ICU: 38% versus 40%, P = 0.87; immunocompromised: 57% versus 59%, P = 0.80). Secondary outcomes including survival were also similar. In multivariable analysis, among ICU patients, Pitt bacteraemia score < 4 (P = 0.002) and time to antifungal (P = 0.037) were associated with meeting the primary outcome; white blood cell count > 11 cells × 103/µL on day 0 (P < 0.001) and Candida isolated from a non-blood site (P = 0.025) were associated with not meeting the primary outcome. Among immunocompromised patients, white blood cells > 11 × 103/µL (P = 0.003) and Candida isolated from a non-blood site (P = 0.026) were associated with not meeting the primary outcome. These data suggest that among ICU or immunocompromised patients, severity of illness rather than initial antifungal choice drove clinical outcomes.

Ionic Liquid Pretreatment Enhances Skin Penetration of 5-Aminolevulinic Acid: A Promising Scheme for Photodynamic Therapy for Acne Vulgaris.

Acne vulgaris is one of the most prevalent skin disorders; it affects up to 85% of adolescents and often persists into adulthood. Topical 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT) provides an alternative treatment for acne; however, its efficacy is greatly undermined by the limited skin permeability of ALA. Herein, biocompatible ionic liquids (ILs) based on aliphatic acid/choline were employed to enhance the dermal delivery of ALA, thereby improving the efficacy of PDT. In addition to the one-step delivery of ALA by utilizing ILs as carriers, a two-step strategy of pretreating the skin with blank ILs, followed by the administration of free ALA, was employed to test the IL-facilitated dermal delivery of ALA in vitro. The cumulative permeation of ALA through the excised rat skin after IL pretreatment was significantly greater than that in the untreated group, the 20% dimethyl sulfoxide (DMSO) penetration enhancer group, and the one-step group. The penetration efficiency was influenced by formulation and treatment factors, including the type of IL, pretreatment duration, water content in the ILs, and concentration of ALA. In rats, IL pretreatment facilitated faster, greater, and deeper ALA-induced protoporphyrin IX (PpIX) accumulation. Moreover, the IL pretreatment regimen significantly improved the efficacy of ALA-based PDT against acne vulgaris in a rat ear model. The model IL choline citrate ([Ch]3[Cit]1) had a moderate effect on the skin barrier. Trans-epidermal water loss could be recovered 1 h after IL treatment, but no irritation to the rat skin was detected after 7 days of consecutive treatment. It was concluded that biocompatible IL pretreatment enhances the penetration of ALA and thus facilitates the transformation of PpIX and improves the efficacy of PDT against acne vulgaris.

Abstract 6637: The Haemophilus influenzae vaccine mitigates pancreatic tumor progression and lowers immunoregulatory cell levels in the tumor microenvironment

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease projected to become the second leading cause of cancer deaths by 2030. First-line chemotherapies gemcitabine and FOLFIRINOX provide little therapeutic benefit and are accompanied by severe adverse toxicities, precluding long-term treatment. In addition, PDAC is notoriously refractory to checkpoint inhibitor immunotherapies, due to poor immunogenicity and a tumor microenvironment dominated by suppressive cell types. Thus, there is an unmet need for innovative, immune-based strategies to combat PDAC. A previous study utilized engineered bacteria to effectively kill PDAC tumor cells by directly delivering immunogenic tetanus toxoid to the tumor. Given the potential toxicity in using live bacteria, our group utilized a less toxic alternative, an FDA-approved Haemophilus influenzae type b vaccine (HibVx) also containing a tetanus toxoid component. To determine the antitumor potential of HibVx, our group used a physiologically relevant murine model, low T cell clone murine PDAC tumor model 641c95 and clinically relevant KPC mice model for PDAC. After tumors were established, animals received three consecutive daily treatments of HibVx via intraperitoneal injection. HibVx-treated animals experienced a dramatic reduction in tumor growth compared to PBS-treated controls (p&amp;lt;0.001). Given that tetanus toxoid is highly immunogenic in nature, changes in intratumoral immune cell populations following HibVx treatments were of great interest. Using flow cytometry analysis, HibVx-treated tumors had a significant increase in natural killer cells compared to control tumors (p&amp;lt;0.05). In addition, HibVx affected myeloid-derived suppressor cell populations (MDSCs), which are heavily implicated in the suppressive nature of PDAC tumors. HibVx also significantly decreased MDSCs within the tumor (p&amp;lt;0.05). In all, these findings position HibVx as an effective immunostimulatory agent that can be used as an alternative to live bacteria-based therapy for the treatment of PDAC. Citation Format: Eileena F. Giurini, Sam G. Pappas, Kajal H. Gupta. The Haemophilus influenzae vaccine mitigates pancreatic tumor progression and lowers immunoregulatory cell levels in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6637.

Pain Assessment in Patients Undergoing Maggot Debridement Therapy in the Process of Local Treatment of Chronic Wounds

(1) Background: Developing and implementing strategies for local wound care focused on improving the quality of life related to health status and reducing treatment costs for this patient group poses a challenge to contemporary healthcare systems. The utilization of Maggot Debridement Therapy (MDT) is one potential form of local therapy for preparing wounds for the healing process. The debridement of the wound bed with medical maggots is highly precise, and the defensins produced by the larvae eliminate bacteria and stimulate tissue regeneration. However, the presence of larvae in the wound may lead to the occurrence of pain symptoms. The aim of the study was to assess the intensity of pain during larval therapy in patients with chronic wounds treated in outpatient settings. (2) Patients and Methods: The study employed a diagnostic survey and estimation; the tool consisted of a research protocol comprising three parts (questionnaires). Inclusion criteria for the study were voluntary consent to participate (completion of the MDT acceptance questionnaire), chronic wounds of vascular etiology or pressure injuries, full-thickness skin or deep tissue damage, and pain intensity not exceeding four on the NRS (Numerical Rating Scale: 0—no pain, 10—the most severe pain) at the time of the study. Patient observation during the 3-day treatment was conducted by a wound care clinic nurse, assessing pain intensity once every 24 h during the larval dressing changes. (3) Results: Out of 348 individuals who qualified for MDT during the study period, 215 individuals participated in the study: 94 women (43.7%) and 121 men (56.3%). The age of the participants ranged from 28 to 97 years (mean 69.87 ± 12.95). Each participant experienced mild pain (2.26 ± 1.60 on the NRS) on the day of qualification for the study. An increase in pain intensity, according to subjective assessments, was reported by 29.3% of participants (n = 63). On the third day of MDT therapy, an increase in pain intensity was observed, reaching a mean value of 4.79 ± 2.12 (p &lt; 0.0001). Participants with pressure injuries showed the lowest pain intensity, which increased in consecutive days for all types of wounds. Additionally, the increase in pain intensity in patients with vascular etiology wounds was greater compared to patients with pressure injuries (p &lt; 0.001). (4) Conclusions: Local wound therapy with Lucilia sericata larvae increases pain intensity in the consecutive days of treatment. The wound area and the time since its occurrence may determine pain symptoms.

Activation of testosterone-androgen receptor mediates cerebrovascular protection by photobiomodulation treatment in photothrombosis-induced stroke rats.

Numerous epidemiological studies have reported a link between low testosterone levels and an increased risk of cerebrovascular disease in men. However, there is ongoing controversy surrounding testosterone replacement therapy due to potential side effects. PBMT has been demonstrated to improve cerebrovascular function and promote testosterone synthesis in peripheral tissues. Despite this, the molecular mechanisms that could connect PBMT with testosterone and vascular function in the brain of photothrombosis (PT)-induced stroke rats remain largely unknown. We measured behavioral performance, cerebral blood flow (CBF), vascular permeability, and the expression of vascular-associated and apoptotic proteins in PT-induced stroke rats treated with flutamide and seven consecutive days of PBM treatment (350 mW, 808 nM, 2 min/day). To gain further insights into the mechanism of PBM on testosterone synthesis, we used testosterone synthesis inhibitors to study their effects on bEND.3 cells. We showed that PT stroke caused a decrease in cerebrovascular testosterone concentration, which was significantly increased by 7-day PBMT (808 nm, 350 mW/cm2 , 42 J/cm2 ). Furthermore, PBMT significantly increased cerebral blood flow (CBF) and the expression of vascular-associated proteins, while inhibiting vascular permeability and reducing endothelial cell apoptosis. This ultimately mitigated behavioral deficits in PT stroke rats. Notably, treatment with the androgen receptor antagonist flutamide reversed the beneficial effects of PBMT. Cellular experiments confirmed that PBMT inhibited cell apoptosis and increased vascular-associated protein expression in brain endothelial cell line (bEnd.3) subjected to oxygen-glucose deprivation (OGD). However, these effects were inhibited by flutamide. Moreover, mechanistic studies revealed that PBMT-induced testosterone synthesis in bEnd.3 cells was partly mediated by 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5). Our study provides evidence that PBMT attenuates cerebrovascular injury and behavioral deficits associated with testosterone/AR following ischemic stroke. Our findings suggest that PBMT may be a promising alternative approach for managing cerebrovascular diseases.

Delayed Administration of an Angiotensin II Type 2 Receptor Agonist Promotes Functional Recovery of the Brain and Heart After Traumatic Brain Injury.

Cardiac injury is a common complication following traumatic brain injury (TBI) that can lead to poor clinical outcomes. Angiotensin II type 2 receptor (AT2R) activation exerts protective roles in the brain and heart, yet its potential impact on TBI or TBI-induced cardiac deficits remains elusive. The goal of this study was to investigate the influence of AT2R activation on recovery after TBI-induced cognitive and cardiac injury using the selective nonpeptide AT2R agonist compound 21 (C21). TBI was induced by cortical impact injury in male adult C57BL/6J mice, and the mice received C21 (0.03 mg/kg, intraperitoneally) starting from 24 h after TBI and continuing once daily. C21 facilitated cognitive function recovery until 1 month after TBI. C21 alleviated blood-brain barrier leakage and brain edema and inhibited the expression of proinflammatory cytokines in the brain after 3 consecutive days of treatment. C21 improved cerebral blood flow after 1 month, although the lesion volume was not affected. C21 also reduced the expression of proinflammatory cytokines in the heart after a 3-day consecutive treatment. Meanwhile, C21 benefited cardiac function, as identified by increased left ventricular ejection fraction 1 month after TBI. In addition, C21 alleviated TBI-induced cardiac hypertrophy and fibrosis; however, blood pressure was not affected. Our results demonstrate that AT2R activation ameliorates TBI-induced neurological and cardiac deficits.

Enoxaparin for VTE thromboprophylaxis during inpatient rehabilitation care: assessment of the standard fixed dosing regimen

BackgroundWe aimed to examine the efficiency of fixed daily dose enoxaparin (40 mg) thromboprophylaxis strategy for patients undergoing inpatient rehabilitation.MethodsThis was an observational, prospective, cohort study that included 63 hospitalized patients undergoing rehabilitative treatment following sub-acute ischemic stroke (SAIS) or spinal cord injury (SCI), with an indication for thromboprophylaxis. Anti-Xa level measured three hours post-drug administration (following three consecutive days of enoxaparin treatment or more) was utilised to assess in vivo enoxaparin activity. An anti-Xa level between 0.2-0.5 U/ml was considered evidence of effective antithrombotic activity.ResultsWe found sub-prophylactic levels of anti-Xa (<0.2 U/ml) in 19% (12/63). Results were within the recommended prophylactic range (0.2-0.5 U/ml) in 73% (46/63) and were supra-prophylactic (>0.5 U/ml) in 7.9% (5/63) of patients. Anti-Xa levels were found to inversely correlate with patients’ weight and renal function as defined by creatinine clearance (CrCl) (p<0.05).ConclusionsOur study confirmed that a one-size-fits-all approach for venous thromboembolism (VTE) prophylaxis may be inadequate for rehabilitation patient populations. The efficacy of fixed-dose enoxaparin prophylaxis is limited and may be influenced by renal function and weight. This study suggests that anti-Xa studies and prophylactic enoxaparin dose adjustments should be considered in certain patients, such as those who are underweight, overweight and or have suboptimal renal function.Trial registrationNo. NCT103593291, registered August 2018.

Therapeutic Plasma Exchange in Children With Acute and Acuteon-Chronic Liver Failure: A Single-Center Experience.

Acute liver failure is a life-threatening condition that may result in death if liver transplant is not performed. The aim of our study was to evaluate patients with acute liver failure or acute-on-chronic liver failure who were followed and treated with therapeutic plasma exchange in a pediatric intensive care unit until they achieved clinical recovery or underwent liver transplant. In this retrospective, singlecenter study, we included patients with acute liver failure or acute-on-chronic liver failure who received therapeutic plasma exchange between April 2020 and December 2021. Clinical findings, laboratory findings, extracorporeal therapies, Pediatric Risk of Mortality III and liver injury unit scores and pretherapy and posttherapy hepatic encephalopathy scores, Model for End-Stage Liver Disease score, and Pediatric End-Stage Liver Disease score were retrospectively analyzed. Nineteen patients were included in the study. One patient was excluded because of positivity for COVID-19. The mean age of children was 62.06 months, ranging from 5 months to 16 years (12 boys, 6 girls). Thirteen patients (72.2%) had acute liver failure, and 5 patients (27.8%) had acute-on-chronic liver failure. No significant difference was shown for mean liver injury unit score (P = .673) and Pediatric Logistic Organ Dysfunction score (P = .168) between patients who died and patients who received treatment at the inpatient clinic and transplant center. However, Pediatric Risk of Mortality score and the mean Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease scores before therapeutic plasma exchange and after therapeutic plasma exchange (after 3 consecutive days of treatment) were statistically significant (P = .001 and P = .004). Therapeutic plasma exchange may assist bridge to liver transplant or assist with spontaneous recovery of liver failure in pediatric patients with acute liver failure or acute-on-chronic liver failure.

The amelioration of ovarian dysfunction by hesperidin in malathion-treated mice through the overexpression of PCNA and FSHR proteins

ObjectiveMalathion (MAL), a pesticide used for decades, is a highly toxic substance. Several studies have documented the negative effects of such agents on reproductive organ physiology, but the precise mechanism of action in the induction of ovarian dysfunction remains unclear. Therefore, the purpose of this research was to examine the effects of the antioxidant hesperidin (HES) on ovarian damage and toxicity caused by malathion. Materials and methodsIn this experiment, forty adult female bulb/c mice weighing 27–30 g were categorized into four groups, namely hesperidin (20 mg/kg, i.p.), malathion (3 mg/kg, i.p.), malathion + hesperidin, and control groups. Following a period of 35 consecutive days of treatment, mice were euthanized, and their ovarian tissues were gathered for the purposes of histopathological analysis by H&E staining, immunohistochemical assessment via proliferating cell nuclear antigen (PCNA) and follicle-stimulating hormone receptor (FSHR) immunostaining, and biochemical evaluation via measuring the levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). In addition, serum samples were collected from the blood of mice to perform hormonal analyses, especially 17β-estradiol (E2), progesterone (P4), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). ResultsThe results demonstrated that MAL exposure resulted in the development of abnormalities in the architecture and structure of ovaries. Also, the treatment of mice with MAL led to declined follicular counts at all three stages, namely, primary, secondary, and tertiary, reduced serum levels of sex hormones, decreased immunoreactivity of FSHR and PCNA, and diminished activity of CAT and SOD enzymes. In contrast, it caused an increase in MDA, IL-1β, and TNF-α, as well as the count of atretic follicles. Nonetheless, it was observed that HES exhibited the ability to ameliorate the deleterious impacts of malathion across all the aforementioned parameters. ConclusionTreatment with HES via upregulating the protein expression of PCNA and FSHR and activating antioxidant defense was able to ameliorate the adverse effects of MAL on ovarian tissues.

Mango (Mangifera indica L.) seed kernel extract suppresses hyperglycemia by modulating pancreatic β cell apoptosis and dysfunction and hepatic glucose metabolism in diabetic rats.

This study investigated the anti-hyperglycemic action of mango seed kernel extract (MKE) and various mechanisms involved in its actions to improve pancreatic β cells and hepatic carbohydrate metabolism in diabetic rats. An intraperitoneal injection of 60mg/kg of streptozotocin (STZ) followed by 30 consecutive days of treatment with MKE (250, 500, and 1000mg/kg body weight) was used to establish a study group of diabetic rats. Using liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS/MS) for identification, 26 chemical compounds were found in MKE and the high-performance liquid chromatography (HPLC) analysis of the MKE also revealed the existence of mangiferin, gallic acid, and quercetin. The results confirmed that in each diabetes-affected rat, MKE mitigated the heightened levels of fasting blood glucose, diabetic symptoms, glucose intolerance, total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C). As demonstrated by a remarkable increment in serum and pancreatic insulin, the diabetic pancreatic β cell function was potentiated by treating with MKE. The effect of MKE on diabetic pancreatic apoptosis clearly reduced the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells, which was related to diminished levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and Bax and an increase in Bcl-xL protein expression. Furthermore, diabetes-induced liver damage was clearly ameliorated along with a notable reduction in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and abnormal liver histology. By enhancing anti-oxidant superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, MKE alleviated diabetes-induced pancreatic and liver oxidative damage, as demonstrated by diminished levels of malondialdehyde. In minimizing the expression levels of glucose 6-phosphatase and phosphoenolpyruvate carboxykinase-1 proteins in the diabetic liver, MKE also enhanced glycogen content and hexokinase activity. Collectively, these findings indicate that by suppressing oxidative and inflammatory processes, MKE exerts a potent anti-hyperglycemic activity in diabetic rats which serve to protect pancreatic β cell apoptosis, enhance their function, and improve hepatic glucose metabolism.

The role of dissociation-related beliefs about memory in trauma-focused treatment

ABSTRACT Objective: Dysfunctional cognitions play a central role in the development of post-traumatic stress disorder (PTSD). However the role of specific dissociation-related beliefs about memory has not been previously investigated. This study aimed to investigate the role of dissociation-related beliefs about memory in trauma-focused treatment. It was hypothesized that patients with the dissociative subtype of PTSD would show higher levels of dissociation-related beliefs, dissociation-related beliefs about memory would decrease after trauma-focused treatment, and higher pre-treatment dissociation-related beliefs would be associated with fewer changes in PTSD symptoms. Method: Post-traumatic symptoms, dissociative symptoms, and dissociation-related beliefs about memory were assessed in a sample of patients diagnosed with PTSD (n = 111) or the dissociative subtype of PTSD (n = 61). They underwent intensive trauma-focused treatment consisting of four or eight consecutive treatment days. On each treatment day, patients received 90 min of individual prolonged exposure (PE) in the morning and 90 min of individual eye movement desensitization and reprocessing (EMDR) therapy in the afternoon. The relationship between dissociation-related beliefs about memory and the effects of trauma-focused treatment was investigated. Results: Dissociation-related beliefs about memory were significantly associated with PTSD and its dissociative symptoms. In addition, consistent with our hypothesis, patients with the dissociative subtype of PTSD scored significantly higher on dissociation-related beliefs about memory pre-treatment than those without the dissociative subtype. Additionally, the severity of these beliefs decreased significantly after trauma-related treatment. Contrary to our hypothesis, elevated dissociation-related beliefs did not negatively influence treatment outcome. Conclusion: The results of the current study suggest that dissociation-related beliefs do not influence the outcome of trauma-focused treatment, and that trauma-focused treatment does not need to be altered specifically for patients experiencing more dissociation-related beliefs about memory because these beliefs decrease in association with treatment.

Alterations in salivary biochemical composition and redox state disruption induced by the anticonvulsant valproic acid in male rat salivary glands

ObjectiveTo investigate the effects of the anticonvulsant valproic acid (VPA) on salivary glands in male rat using biochemical, functional, histomorphometric, and redox state parameters. Materials and methodsTwenty-four male Wistar rats were randomly distributed into three groups (n = 8 per group): Control (0.9% saline solution), VPA100 (100 mg/kg), and VPA400 (400 mg/kg). After 21 consecutive days of treatment with by intragastric gavage. Pilocarpine-induced saliva was collected to determine salivary flow rate, pH, buffering capacity, and biochemical composition. Analyses of histomorphometric parameters and redox balance markers were performed on the parotid and submandibular glands. ResultsSalivary flow rate, pH, buffering capacity, total protein, potassium, sodium, and chloride were similar between groups. However, phosphate and calcium were reduced in VPA400, while amylase was increased in both VPA100 and VPA400. We did not detect significant differences in the areas of acini, ducts, and connective tissue in the salivary glands between the groups. There were no significant changes in the redox status of the submandibular glands. In turn, in the parotid glands we detected reduced total oxidizing capacity and lipid peroxidation, measured as thiobarbituric acid reactive substances (TBARs) and higher uric acid concentration in both the VPA100 and VPA400 groups, and increased superoxide dismutase (SOD) in the VPA400 group. ConclusionChronic treatment with VPA modified the salivary biochemical composition and caused disruption in the redox state of the parotid gland in rats.

The long-term effects of intermittent theta burst stimulation on Alzheimer's disease-type pathologies in APP/PS1 mice

Intermittent theta burst stimulation (iTBS), an emerging and highly efficient paradigm of repetitive transcranial magnetic stimulation (rTMS), has been demonstrated to mitigate cognitive impairment in Alzheimer's disease. Previous clinical studies have shown that the cognitive improvement of iTBS could last several weeks after treatment. Nonetheless, it is largely uncertain how the long-term effects of iTBS treatment are sustained. To investigate whether iTBS has a long-term effect on AD-type pathologies, 6-month-old APP/PS1 mice are administrated with 30 consecutive days of iTBS treatment. After a 2-month interval, morphological alterations in the brain are examined by immunohistochemistry and immunofluorescence staining, while levels of associated proteins are assessed by Western blot at the age of 9 months. We find that iTBS treatment significantly diminishes Aβ burden in the cerebral cortex and hippocampus of APP/PS1 mice. Moreover, we observe that iTBS treatment inhibits the expression of BACE1 and elevates the level of IDE, suggesting that the reduction of Aβ load could be attributed to the inhibition of Aβ production and facilitation of Aβ degradation. Furthermore, iTBS treatment attenuates neuroinflammation, neuronal apoptosis, and synaptic loss in APP/PS1 mice. Collectively, these data indicate that 1 month of iTBS treatment ameliorates pathologies in the brain of AD mice for at least 2 months. We provide the novel evidence that iTBS may exert after-effects on AD-type pathologies via inhibition of Aβ production and facilitation of Aβ degradation.

Efficacy of Saudi propolis and bee pollen in the reduction of oxidative stress induced with CCl4 in a testis mice model

Low testosterone levels are caused by alcoholism, cigarette smoking, and exposure to toxic chemicals. This work focused on investigating the activities of propolis (PE) and bee pollen (BPE) extracts in reducing the oxidative stress of carbon tetrachloride (CCl4) in male mice models. The 48 male Swiss Albino mice weighed 27.5 ± 2.5 g and were divided into: Group1: Control (-) received distilled water only through oral intubation; Group 2: Control (- -) received corn oil by intraperitoneal (i.p.) injection once a day; Group 3: Control (+) received a sublethal dose of CCL4 intraperitoneally the end of the experiment. Group 4: Stander treated with silymarin at a daily dose of 200 mg/kg orally. Group 5: The mice were given 8.4 mg/ kg bw of (PE) orally. Group 6: The mice were given (BPE) extract (140 mg/kg bw) orally. After five consecutive days of treatment, all mice had testis injury in all groups except G1& G2, by a single i.p injection of CCL4 at a dose of 0.5 mL/kg (bw; 20% v/v in corn oil). The result showed a significant increase in luteinizing, follicle-stimulating, and testosterone hormone levels in the serum and semen parameters in the groups treated with PE and BPE. The histological results showed the greatest improvements in testis structures in the BPE group, which was confirmed using (Bcl-2; immunohistochemistry). These results suggest an important role of the antioxidative effects of PE and BPE in the attenuation of CCl4 oxidative stress.

Performance of Urinary Phenyl-γ-Valerolactones as Biomarkers of Dietary Flavan-3-ol Exposure

BackgroundPhenyl-γ-valerolactones (PVLs) have been identified as biomarkers of dietary flavan-3-ol exposure, although their utility requires further characterization. ObjectivesWe investigated the performance of a range of PVLs as biomarkers indicative of flavan-3-ol intake. MethodsWe report the results of 2 companion studies: a 5-way randomized crossover trial (RCT) and an observational cross-sectional study. In the RCT (World Health Organization, Universal Trial Number: U1111-1236-7988), 16 healthy participants consumed flavan-3-ol–rich interventions (of apple, cocoa, black tea, green tea, or water [control]) for 1 d each. First morning void samples and 24-h urine samples were collected with diet standardized throughout. For each participant, 1 intervention period was extended (to 2 d) to monitor PVL kinetics after repeat exposure. In the cross-sectional study, 86 healthy participants collected 24-h urine samples, and concurrent weighed food diaries from which flavan-3-ol consumption was estimated using Phenol-Explorer. A panel of 10 urinary PVLs was quantified using liquid chromatography tandem mass spectrometry. ResultsIn both studies, 2 urinary PVLs [5-(3ʹ-hydroxyphenyl)-γ-valerolactone-4ʹ-sulfate and putatively identified 5-(4ʹ-hydroxyphenyl)-γ-valerolactone-3ʹ-glucuronide] were the principal compounds excreted (>75%). In the RCT, the sum of these PVLs was significantly higher than the water (control) after each intervention; individually, there was a shift from sulfation toward glucuronidation as the total excretion of PVLs increased across the different interventions. In the extended RCT intervention period, no accumulation of these PVLs was observed after consecutive days of treatment, and after withdrawal of treatment on the third day, there was a return toward negligible PVL excretion. All results were consistent, whether compounds were measured in 24-h urine or first morning void samples. In the observational study, the sum of the principal PVLs correlated dose dependently (Rs = 0.37; P = 0.0004) with dietary flavan-3-ol intake, with similar associations for each individually. ConclusionsUrinary 5-(3ʹ-hydroxyphenyl)-γ-valerolactone-4ʹ-sulfate and putatively identified 5-(4ʹ-hydroxyphenyl)-γ-valerolactone-3ʹ-glucuronide are recommended biomarkers for dietary flavan-3-ol exposure.

Healthcare Resource Utilization, Cost and Clinical Outcomes in Patients Diagnosed with COPD Initiating Tiotropium Bromide/Olodaterol versus Fluticasone Furoate/Umeclidinium/Vilanterol Based on Exacerbation History.

ATS and GOLD guidelines recommend treating low-exacerbation risk COPD patients with dual (LAMA/LABA) agents and reserving triple therapy (TT; LAMA/LABA and inhaled corticosteroids [ICS]) for severe cases with higher-exacerbation risk. However, TT often is prescribed across the COPD spectrum. This study compared COPD exacerbations, pneumonia diagnosis, healthcare resource utilization, and costs for patients initiating tiotropium bromide/olodaterol (TIO/OLO) and a TT, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), stratified by exacerbation history. COPD patients who initiated TIO/OLO or FF/UMEC/VI between 06/01/2015-11/30/2019 (index date=first pharmacy fill-date with ≥30 consecutive treatment days) were identified from the Optum Research Database. Patients were ≥40 years old and continuously enrolled for 12 months during the baseline period and ≥30 days during follow-up. Patients were stratified into GOLD A/B (0-1 baseline non-hospitalized exacerbation), No exacerbation (subset of GOLD A/B), and GOLD C/D (≥2 non-hospitalized and/or ≥1 hospitalized baseline exacerbation). Baseline characteristics were balanced with propensity score matching (1:1). Adjusted risks of exacerbation, pneumonia diagnosis, and COPD and/or pneumonia-related utilization and costs were evaluated. Adjusted exacerbation risk was similar in GOLD A/B and No exacerbation subgroups, and lower in GOLD C/D for FF/UMEC/VI versus TIO/OLO initiators (hazard ratio: 0.87; 95% CI: 0.78, 0.98, p=0.020). Adjusted pneumonia risk was similar between cohorts across the GOLD subgroups. Adjusted COPD and/or pneumonia-related population annualized pharmacy costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators across subgroups, p<0.001.Adjusted COPD and/or pneumonia-related population annualized total healthcare costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators in the GOLD A/B and No exacerbation, subgroups, p<0.001 (cost ratio [95% CI]: 1.25 [1.13, 1.38] and 1.21 [1.09, 1.36], respectively), but similar in the GOLD C/D subgroup. These real-world results support ATS and GOLD recommendations for treating low-exacerbation risk COPD patients with dual bronchodilators and TT for more severe, higher-exacerbation risk COPD patients.

Identifying delirium in advanced dementia in the ECT‐AD clinical trial

AbstractBackgroundDelirium and dementia are common causes of cognitive impairment in older adults and frequently co‐exist. Delirium is associated with poor clinical outcomes when comorbid with dementia. Identifying delirium superimposed on dementia (DSD) is clinically challenging given the overlap in symptoms, including inattention, cognitive impairment, and altered level of consciousness, especially in advanced stages of dementia. Recognition of delirium is also critical in ADRD (Alzheimer’s Disease and Related Dementias) clinical trials for both validity and safety reasons. The ECT‐AD study is one such trial investigating the safety and efficacy of electroconvulsive therapy (ECT) for treatment‐refractory agitation and aggression in individuals with advanced ADRD. Herein we review the Confusion Assessment Method (CAM) for identifying delirium in the ECT‐AD study.MethodInclusion criteria for ECT‐AD are hospitalized individuals diagnosed with ADRD (ages 55–89, MMSE ≤ 15) and refractory agitation/aggression, as measured by the Cohen‐Mansfield Agitation Inventory (CMAI). Procedures for detecting baseline and treatment‐emergent delirium involve a 3‐step approach conducted by raters trained in the CAM, which assesses inattention, disorganized thinking, altered levels of consciousness, and fluctuating mental status. Step 1 involves gathering information from nurse informants regarding the patient’s mental status over the past 24 hours. Step 2 involves collecting observational data through informal patient interaction (e.g., brief conversation). Step 3 is an objective assessment of cognitive status using the Severe Impairment Battery – 8 Item (SIB‐8), while also making qualitative observations about delirium features (e.g., level of consciousness). The rater then codes the CAM and determines delirium status based on these 3 steps.ResultOf our 6 consented subjects, 1 experienced delirium detected by the CAM during the Randomization Phase. The subject received three positive CAMs on consecutive treatment days, citing change in mental status, inability to arouse, restlessness, psychomotor agitation, and swearing. ECT/S‐ECT was held each treatment day and the subject was withdrawn from the Randomization Phase.ConclusionIdentifying DSD is challenging due to overlapping symptoms and the fluctuating nature of delirium. The CAM may be useful in this regard by using a multi‐step approach that incorporates observations from reliable informants, direct patient interactions, and structured cognitive assessments.

Consolidation of High-Risk Acute Promyelocytic Leukemia (APL) in Community Infusion Centers: A Single Center Experience

Intro: APL is one of the most curable forms of acute myeloid leukemia. Whereas all-trans retinoid acid (ATRA) and arsenic trioxide (ATO) are the standard of care for treatment of low/intermediate risk APL (APL0406 trial, LoCoco et al. NEJM 2013), the optimal treatment of high-risk APL remains unclear. In our institution, we use the APML4 regimen (Iland et al. Blood 2012) to treat high-risk APL patients, which uses idarubicin+ATRA followed by ATRA+ATO for induction. Then, there are two consolidation cycles of ATRA+ATO, the first of which is 28 consecutive days of treatment. Consolidation is followed by two years of ATRA + 6-mercaptopurine + methotrexate maintenance (PETHEMA LPA99, Sanz et al. Blood 2003). In the APML4 trial, the outcomes were excellent for all risk groups, particularly for high-risk patients. However, this regimen cannot be administered in community infusion centers (CIC) that are not open on weekends. In addition, the expertise required to give maintenance therapy makes it challenging to administer outside of an academic medical center. Here, we examine outcomes of high-risk APL patients who received induction at our institution to document the types of consolidation regimens they received and their outcomes. In particular, we focus on the outcomes of high-risk APL patients who received induction with idarubicin+ATRA+ATO (as per APML4) at our institution, and then for practical considerations received consolidation with ATRA+ATO (as per APL0406) in the community. Methods: We performed a retrospective analysis of all patients between the ages of 18-89 who were diagnosed with high-risk APL at the Knight Cancer Institute between January 2009 and July 2022. We identified 19 patients with the diagnosis of high-risk APL. One patient died soon after diagnosis due to intracranial bleed (excluded from final analysis). The remainder completed induction and consolidation. Result: Table 1 shows the main clinical features at diagnosis. The most common complications during induction were differentiation syndrome and coagulopathy. All 18 patients achieved complete morphologic remission (CR) at the end of induction but still had detectable PML-RARA by PCR. 4/18 (22%) patients received the APL2000 regimen (Adès et al. JCO 2006), and 1/18 (6%) patient received the PETHEMA regimen (Sanz et al. Blood 2003). All 5 patients were hospitalized for neutropenic fever, which required significant dose reduction and treatment delay. One patient (6%) received induction with ATRA+ATO+gemtuzumab ozogamicin followed by consolidation with ATRA+ATO (Estey et al. Blood 2006). The majority of patients (12/18, 67%) received induction as per APML4 protocol (Table 2). The APL0406 regimen was administered as consolidation in 11/18 (61%) patients; and all patients except one received consolidation at local CIC. Common side effects were headache and nausea, leading to dose reduction in five patients. One patient continued with APML4 consolidation. Molecular CR was confirmed in all patients at the end of consolidation treatment. 13/18 (72%) patients did not receive maintenance therapy after consolidation. All patients were subsequently followed by RT-PCR for PML/RARA for molecular relapse. At the last follow up, all 18 patients remained to be in molecular CR with no relapsed disease. Discussion: The benefit of ATRA+ATO for low/intermediate risk APL patients is well established, but the optimal management of high-risk APL remains a challenge, especially when consolidation is given in CIC. Our series of patients provides real world evidence that ATRA+ATO consolidation as per APL0406 regimen is effective in high-risk APL patients after induction with idarubicin+ATRA+ATO as per the APML4 regimen. Although the numbers are limited, all patients remain in molecular remission as measured from the end of consolidation, similar to the excellent outcomes of low/intermediate risk APL patients. Consolidation was well tolerated, with minimal treatment delays, suggesting that a standard consolidation regimen for low-, intermediate-, and high-risk APL patients can be successfully administered in the community (most centers typically treat 1-2 patients per year with APL). The majority of patients did not receive maintenance therapy but remained in remission, providing further evidence that maintenance therapy is unnecessary with sufficient ATRA+ATO consolidation, and simplifying therapy (Shah et al. Blood 2018). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The biological response of Carica papaya leaves extract to saponin reduction (O/W) emulsion on human bronchial epithelium cell (BEAS-2B)

Carica papaya leaf has a potentially well-known therapeutic effect in accelerating human blood platelet counts against dengue fever and dengue haemorrhagic fever. However, consuming the extract was considered troublesome due to its bitter taste. The fresh papaya leaves were extracted into two types of preparation: a) Fresh Papaya Leaves Extract (FPL) and b) Papaya Leaves with Saponin Reduction Extract (PLSR). This was followed by the determination of the best edible O/W emulsion formulation of both different extracts with virgin coconut oil (VCO) and whey protein (WP) as surfactant. Through Ternary Phase Diagram (TPD), the optimum ratio (w/w) of FPL/PLSR: VCO: WP were 63: 16: 21 and 65: 16: 19 respectively. Both formulas were examined for their physicochemical properties including pH, creaming index (CI), contact angle and droplet size measurement. The human bronchial epithelium cell (BEAS-2B) was treated using both emulsions for 72 hrs of cell growth response (EC50). The result shows that both FPL and PLSR formulations were slightly acidic and exhibited stable emulsion with no creaming formation (CI) up to 24 hrs of storage (25 ℃). Next, FPL emulsion shows 3 times higher wettability and 4 times bigger nanoparticle size than PLSR. These properties can affect the emulsion absorptivity in the targeted cell microenvironment. Remarkably, the BEAS-2B cell viability (%) for each emulsion was relatively elevated within 24 hrs and increased to more than 100 % at 48 and 72 hrs of exposure. This might hugely represent its potential in repairing damaged blood vessels due to dengue haemorrhagic fever. Besides, the EC50 value also indicated low levels of concentration needed to exponentially increase cell growth and safe for dengue fever treatment. For that reason, the recommended effective dosage by the Ministry of Health (Malaysia) (MOH) for both FPL and PLSR emulsions is two tablespoons twice a day for three consecutive days of treatment (equally to the effective dosage of 102 g extract).

Abstract 10389: Interleukin-1 Blockade With Anakinra Restores Cardiac Contractility Reserve and Exercise Capacity in a Mouse Model of Ischemic Heart Failure

Background: Acute myocardial infarction (AMI) is associated with an intense inflammatory response promoting adverse cardiac remodeling, impaired cardiac reserve, and reduced exercise capacity, hallmarks of heart failure. Interleukin-1β (IL-1β) is the prototypical inflammatory cytokine that is increased in AMI and is sufficient to impair cardiac reserve when administered exogenously in mice. Whether blocking IL-1β signaling with recombinant IL-1 receptor antagonist, anakinra, can restore cardiac contractile reserve and improve exercise capacity in AMI is unknown. Methods: We induced ischemic heart failure due to large non-reperfused anterior AMI in mice via surgical permanent ligation of the left anterior descending artery via lateral thoracotomy in 10-week-old male CD1 mice (N=30, 32-37 g in weight) followed for 10 weeks. Anakinra was given as intraperitoneal injection of 10 mg/kg, 0.2 ml, for three consecutive days. Cardiac contractile reserve was measured assessing changes in left ventricular fractional shortening with isoproterenol challenges (N=5). A subgroup of mice that had been previously trained to run on treadmill were used to measure interval changes in exercise capacity 10 weeks after AMI and with three consecutive days of anakinra treatment (N=6). Data are presented as mean and standard error of mean. T-test for paired group analysis was used to compare values. Results: Cardiac contractile reserve was impaired at -10±5% and restored with anakinra given for three days to +49±11% (p=0.008). Exercise capacity was also significantly reduced with AMI at 191±39 m and restored to 247±46 m after anakinra treatment (p=0.03). Conclusion: Ischemic heart failure due to large non-reperfused AMI leads to a severe reduction in cardiac contractility reserve and exercise capacity that are reversed by IL-1 blockade with anakinra.