Days Treatment Research Articles

European S2k guidelines for hidradenitis suppurativa/acne inversa part 2: Treatment.

This second part of the S2k guidelines is an update of the 2015 S1 European guidelines. These guidelines aim to provide an accepted decision aid for the selection, implementation and assessment of appropriate and sufficient therapy for patients with hidradenitis suppurativa/acne inversa (HS). The chapters have been selected after a Delphi procedure among the experts/authors. Certain passages have been adopted without changes from the previous version. Potential treatment complications are not included, being beyond the scope of these guidelines. Since the S1 guidelines publication, validation of new therapeutic approaches has almost completely overhauled the knowledge in the field of HS treatment. Inflammatory nodules/abscesses/draining tunnels are the primary lesions, which enable the classification of the disease severity by new validated tools. In relation to the degree of detectable inflammation, HS is classified into the inflammatory and the predominantly non-inflammatory forms. While the intensity of the inflammatory form can be subdivided by the IHS4 classification in mild, moderate and severe HS and is treated by medication accordingly, the decision on surgical treatment of the predominantly non-inflammatory form is based on the Hurley stage of the affected localization. The effectiveness of oral tetracyclines as an alternative to the oral combination of clindamycin/rifampicin should be noted. The duration of systemic antibiotic therapy can be shortened by a 5-day intravenous clindamycin treatment. Adalimumab, secukinumab and bimekizumab subcutaneous administration has been approved by the EMA for the treatment of moderate-to-severe HS. Various surgical procedures are available for the predominantly non-inflammatory form of the disease. The combination of a medical therapy to reduce inflammation with a surgical procedure to remove irreversible tissue damage is currently considered a holistic therapeutic approach. Suitable therapeutic options while considering HS severity in the therapeutic algorithm according to standardized criteria are aimed at ensuring a proper therapy.

Colchicine-Induced Tetraploidy in Protocorms of Aerides rosea Lodd. ex Lindl. and Paxton. and Its Identification

Aerides rosea (Orchidaceae) boasts high ornamental value due to its pleasant aroma, foxtail spike, and elegant floral morphology. Inducing A. rosea to become tetraploid enhances horticultural traits and facilitates fertile intergeneric hybrids through crosses with other market-available tetraploid species. The experimental design involved the application of colchicine at varying concentrations—0.05%, 0.1%, and 0.2%—to a solid medium. Exposure durations were 5, 10, and 15 days, with treatments conducted under sterile conditions on 6-week-old protocorms post-germination. Results indicated that the protocorms were sensitive to colchicine concentrations exceeding 0.05%, with high concentrations leading to a mortality rate exceeding 50%. Flow cytometry (FCM) with 4′,6-diamidino-2-phenylindole (DAPI) staining confirmed a doubling of chromosome numbers in tetraploid plants (2n = 4x = 76) compared to diploid controls (2n = 2x = 38). Induction efficiency was significantly influenced by colchicine concentration and treatment duration. A 10-day treatment with 0.2% colchicine yielded a 70.00% tetraploid induction rate; however, considering protocorm survival, a 5-day treatment with 0.05% colchicine was preferable, achieving a 63.55% survival rate and a 56.67% tetraploid induction rate. Tetraploid plants exhibited distinct morphological traits, such as a more compact growth habit, thicker leaves, and increased stem and root thickness. Leaf morphology changes included larger stomata with reduced density, denser spongy mesophyll, and more pronounced venation. Tetraploids also demonstrated a 1.94-fold increase in genome size compared to diploids. The tetraploid genotypes developed in this study hold significant potential for future Aerides breeding programs.

Double-blind, placebo-controlled trial of the efficacy and safety of azelastine hydrochloride in children with perennial allergic rhinitis.

Allergic rhinitis (AR) affects up to 40% of the pediatric population. The US practice parameter recommends the use of INAH or INCS as first-line therapy for the treatment of AR. Although not directly targeted to children, the recent US Practice Parameters proposed intranasal antihistamines as first-line therapy whereas the ARIA guidelines did not. This was a randomized, double-blind, parallel-group study with a duration of 28 days. It compared Azelastine hydrochloride 0.10% and 0.15% to placebo of one spray per nostril twice daily in pediatric subjects with moderate-to-severe symptomatic perennial allergic rhinitis (PAR). A total of 486 subjects were included in the study. The change from baseline rTNSS was statistically significant for 0.15% AZE (P = .005) and 0.10% AZE (P = .015) vs. placebo. 0.15% AZE showed an LS mean change of -3.45 (20.2%) over the 28-day treatment period from a baseline value of 16.60 in rTNSS. 0.10% AZE showed an LS mean change of -3.37 (20.5%) over the 28-day treatment period from a baseline value of 16.35 in rTNSS. Somnolence was reported by one patient in the 0.1% group and one placebo patient (both of mild severity and unlikely to be related to treatment). None of the patients reported fatigue. 0.15% AZE significantly improved the overall rTNSS compared with placebo over the 28-day study period. 0.15% AZE was well tolerated in this study.

Preventing epileptogenesis by interaction between inositol isomers and proteins.

Inositols play significant roles in biological systems. Myo-inositol (MI), the most prevalent isomer, functions as an osmolyte and mediates cell signal transduction. Other notable isomers include Scyllo-inositol (SCI) and D-Chiro-inositol (DCHI). Our previous investigations have highlighted MI's potential antiepileptogenic effects, although its exact mechanisms of action during epileptogenesis remain unclear. A critical, unexplored area is how inositols interact with proteins. Additionally, the antiepileptogenic capabilities of SCI and DCHI have yet to be determined. This study seeks to address these gaps. Inositol interacting proteins were identified by cellular thermal shift assay. Status epilepticus (SE) in rats was induced using kainic acid (KA), followed by a 28-day treatment with either MI, SCI, DCHI, or saline. The duration and frequencies of behavioral spontaneous recurrent seizures (SRS) were scored for 8 weeks by 24 h video monitoring system. The effects of inositol treatment on spatial learning and memory deficits associated with epileptogenesis were evaluated by Morris water maze test. The changes in protein amounts were studied by Western immunoblotting. We identified several proteins that interact with inositols, noting both commonalities and isomer-specific associations. For the first time, we demonstrated that the treatment with SCI and DCHI, alongside MI, significantly reduces the frequency and duration of behavioral SRS in a KA-induced post-status epilepsy model in rats. This reduction persisted for 4 weeks post-treatment. Moreover, all three inositol isomers mitigated spatial learning and memory deficits associated with epileptogenesis. Alterations in the inositol interacting proteins: alpha synuclein and 14-3-3 theta were further examined 8 weeks post-SE in the hippocampus and neocortex of rats. Myo-inositol, SCI and DCHI interact with a number of proteins involved in different biological pathways. All studied inositol isomers express long-term beneficial effects on KA-induced SRS and the associated comorbidities. Inositols can be successfully used in the future for translational research. Epilepsy is a common neurological disorder characterized by spontaneous recurrent seizures and a range of associated comorbidities. The process that leads to the development of epilepsy is called epileptogenesis, and currently, no medication can effectively prevent it. Our study investigated the effects of a group of compounds-myo-inositol, scyllo-inositol, and D-chiro-inositol-that have potential antiepileptogenic properties on epilepsy induced by kainic acid. We found that: (i) the three inositol isomers share some common target proteins and also have unique ones and (ii) all of them counteract epileptogenesis and the related cognitive impairments.

Apomorphine for prolonged disorders of consciousness: a multimodal open-label study

Apomorphine is a dopaminergic candidate therapy to improve recovery in patients with prolonged disorders of consciousness (PDoC). Behavioural improvements were previously described in non-controlled case series, but its efficacy and neural mechanisms remain largely unknown. This open-label controlled study using multimodal outcome measures investigates the action of apomorphine in severely brain-injured patients. Thirteen PDoC patients received 30-day subcutaneous apomorphine treatment (n=6) or standard care (control group, n=7) in a neurological rehabilitation centre between February 2018 and January 2021. The apomorphine group was monitored 30 days before treatment initiation, during treatment and one year after treatment. Primary outcome measure was defined as changes in behavioural diagnosis using the Coma Recovery Scale-Revised (CRS-R). CRS-R index, recovery of new conscious behaviours, DoC-feeling scores, high-density electroencephalography, and fluorodeoxyglucose positron emission tomography were employed as secondary outcome measures. The control group was monitored with repeated CRS-R only. Registration: EudraCT 2018-003144-23; Clinicaltrials.govNCT03623828. Groups (apomorphine vs. control: odds ratio 8.9, 95% CI 3.3-17.8) and study phase (treatment vs. baseline, apomorphine group only: odds ratio 3.9, 95% CI 1.5-10.1) significantly influenced positive changes in behavioural diagnosis. At one-year post-injury, 4/6 patients in the apomorphine group and 1/7 patients in the control group had improved their diagnosis. Similarly, CRS-R index was significantly influenced by study phase (treatment vs. baseline). All items on the DoC-feeling score were rated higher after treatment than before by both family and medical staff. Patients in the apomorphine group recovered more conscious behaviours than control patients. Alpha-band whole-brain connectivity and participation coefficient, as well as alpha-band parieto-temporal connectivity and frontal participation coefficient were higher after treatment than at baseline. Whole-brain metabolism increased by a relative mean of 13.8% after treatment compared to baseline, with a significant effect of timing (pre-vs. post-treatment scans) on regional SUV. Long-lasting consciousness improvements were observed in patients treated with apomorphine, compared to controls and compared to baseline. Changes in brain connectivity and metabolism were observed after treatment, providing insights into possible neurophysiological mechanisms and target areas. This open-label study confirmed the feasibility and safety of apomorphine treatment, which may represent a key therapeutic option for PDoC. University and University Hospital of Liege, Belgian National Funds for Scientific Research, Fund Generet of the King Baudouin Foundation, AstraZeneca Foundation, Leon Fredericq Foundation and NeuroHealing Pharmaceuticals Inc.

Obsessive-compulsive Disorder: Exposure Treatment and special Features of concentrated Treatment

Obsessive-compulsive disorder (OCD) is often associated with great suffering for both the affected individual as well as their relatives. The treatment of choice for OCD is cognitive behavioural therapy (CBT) with exposure and response prevention. Exposurebased treatment is offered in a concentrated, high-frequency format over four consecutive days in the Bergen 4-Day Treatment (B4DT). This article presents the procedure and effectiveness of this concentrated exposure treatment.

Effects of 0.024% latanoprostene bunod on intraocular pressure and pupil diameter in normal cats and cats with congenital glaucoma.

To evaluate the effects of latanoprostene bunod on intraocular pressure (IOP) and pupil diameter (PD) in normal cats and cats with feline congenital glaucoma (FCG). Five normal and 5 FCG cats. This masked, controlled crossover study comprised a 1-day Pre-treatment phase followed by two 10-day Treatment phases, each followed by a 10-day Recovery phase. During treatment, all cats received twice daily 0.005% latanoprost (LAT) or 0.024% latanoprostene bunod (LBN) in a randomized eye. Following Recovery, the same eye was treated with the opposite drug. Contralateral eyes served as saline-treated controls. Intraocular pressure and PD measurements were performed three times daily during all study phases. Data were analyzed via constrained longitudinal data analysis models. Neither drug significantly reduced IOP in normal cats. In FCG cats, statistically significant reductions in mean (95% CI) IOP were observed relative to controls 4 h after LAT and LBN treatment (-5.5 mmHg [-8.4, -2.5], p < .001, -7.2 mmHg [-10.2, -4.3], p < .001, respectively). These differences represented 28.4% and 37.9% IOP reductions, respectively. Mean IOP reduction after 4 h was significantly greater with LBN treatment compared to LAT (-1.8 mmHg [-3.2, -0.4], p = .012). However, these IOP reductions were not considered clinically significant. Both drugs similarly reduced PD in normal and FCG cats. Transient IOP reduction was observed after topical administration of LAT and LBN in FCG cats; and mean IOP difference was statistically significantly greater in LBN-treated eyes. However, the apparent enhanced hypotensive effect of LBN is not clinically significant.

Gastrointestinal health anti-diarrheal mixture relieves spleen deficiency-induced diarrhea through regulating gut microbiota.

This study evaluated the therapeutic efficacy of the gastrointestinal health anti-diarrheal mixture (GHAM) on diarrhea induced by spleen deficiency, focusing on its modulation of gut microbiota. Using specific pathogen-free Wistar rats, a spleen deficiency model was created through senna leaf gavage. Rats were divided into control, model, positive control, and GHAM treatment groups. After a 14-day treatment, fecal samples were analyzed via 16S rDNA sequencing to assess microbiota alterations. GHAM significantly mitigated diarrhea and enhanced food intake and fecal quality. It increased the abundance of beneficial bacteria, such as Romboutsia and Clostridium_sensu_stricto_1, and decreased the levels of diarrhea-associated bacteria, such as Prevotellaceae and Bacillus, thereby improving microbiota functionality. GHAM's modulation of gut microbiota structure and function effectively alleviated spleen deficiency-induced diarrhea, positioning it as a potential natural herbal treatment for gastrointestinal ailments. This study lays the groundwork for further exploration of GHAM's regulatory impact on gut health.

Bivalent CD47 Immunotoxin for Targeted Therapy of T-Cell Acute Lymphoblastic Leukemia

CD47 is overexpressed on the surface of many types of cancer cells, including T-cell acute lymphoblastic leukemia (T-ALL) cells. In this study, we have developed a diphtheria toxin-based bivalent anti-human CD47 immunotoxin (bi-CD47-IT) for the targeted therapy of CD47+ cancers using a unique diphtheria toxin-resistant yeast Pichia pastoris expression system. Bi-CD47-IT demonstrated compelling in vivo efficacy in multiple T-ALL cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. Bi-CD47-IT significantly prolonged the median survival of the tumor-bearing mice and highly effectively depleted the T-ALL blast cells in the peripheral blood, spleen, liver, bone marrow, brain, and spinal cord in the T-ALL CDX and PDX mouse models. Bi-CD47-IT cured 60% of tumor-bearing mice in a T-ALL Molt-4 CDX mouse model. Because CD47 is also expressed on normal tissues, including red blood cells and lymphocytes, specificity is a concern. We thus analyzed the in vitro binding avidity and hemagglutination of bi-CD47-IT in human red blood cells, finding no binding or hemagglutination. We further performed a toxicity study of bi-CD47-IT in humanized mice, which showed that bi-CD47-IT transiently depleted the human lymphocytes for ∼4 weeks after the 10-day treatment. No clinical adverse events were observed. As a result, bi-CD47-IT appears to possess the “optimal” binding avidity, with effective binding to human CD47+ T-ALL tumor cells, no binding to human red blood cells and weak binding to human lymphocytes. We believe that bi-CD47-IT is a promising and safe therapeutic drug candidate for the targeted therapy of CD47+ cancers.

The influence of secondary aging on the microstructure and corrosion resistance of Al-Zn-Mg-Cu alloy

In this study, through process optimization, we successfully identified a 7-day T6I4 secondary low-temperature aging treatment that significantly enhances the corrosion resistance of Al-Zn-Mg-Cu alloys. Microstructural analysis revealed that the Guinier-Preston (GP) zones and η' phases, are uniformly dispersed within the aluminum matrix after this treatment, effectively reducing the width of the precipitate-free zone (PFZ), thereby significantly lowering the risk of intergranular corrosion. Electrochemical testing results indicate that the alloy treated with this process exhibits superior electrochemical corrosion resistance, characterized by the highest charge transfer resistance (Rct) and the lowest corrosion current density (Icorr). Furthermore, long-term corrosion experiments have provided an in-depth understanding of the alloy's corrosion durability mechanisms under optimal process conditions. Density Functional Theory (DFT) calculations have further elucidated the work function and surface energy of the precipitates, providing a theoretical foundation for the enhancement of alloy performance.

Results of a Phase 2 Multicenter Study to Evaluate the Efficacy of VP-315, an Investigational Therapy for Basal Cell Carcinoma

Introduction: VP-315 is an intratumorally injected, chemotherapeutic oncolytic peptide in development as a non-surgical immunotherapeutic agent to be utilized as first line therapy in a primary or neoadjuvant setting for patients with basal cell carcinoma (BCC). Objective: In Part 2 of this study, the secondary objective was to evaluate the effect of various dosing regimens on the antitumor efficacy of VP-315 in a larger population of adult subjects with biopsy proven BCC. Methods: Eighty-two (82) subjects with up to 2 target BCC tumors (total 91 tumors) were treated intratumorally with VP-315 for up to 2 weeks. Cohort 3 was not enrolled based on results from Cohorts 1-2. Each 7-day treatment week was comprised of 2 or 3 consecutive treatment days followed by a no-treatment period of at least 4 days. Dosing scheme: Cohort 1: (n=6) Tumor injected 3 days consecutively (3X/week 4 mg loading dose Day 1 followed by 8 mg dose). Cohort 2: (n=3) Tumor injected 3 days consecutively (3X/week 8 mg dose). Cohort 4: (n=36) Each tumor was injected 2 days consecutively (2X/week 8 mg split dose*). Cohort 5: (n=37) Each tumor was injected 3 days consecutively (3X/week 8 mg split dose*). * Dose split into 2 injections, 30% injected initially; 70% injected 15-30 minutes later. Efficacy endpoints included histological clearance of target tumor(s) and estimate of remaining tumor volume (tumor size reduction) at excision (Week 12-13). Results: Eighty-two (82) subjects (n=92 lesions) completed treatment for BCC with VP-315 in Part 2. Approximately 51% of tumors achieved complete histologic clearance. All tumors treated had a reduction in tumor size. Overall tumor size reduction was 86%. Tumor size reduction in subjects who still had any residual tumor was 71%. Conclusion: Complete histological clearance in a majority of VP-315 treated tumors could eliminate the need for surgical intervention in those patients in clinical practice. In subjects with residual tumor burden, the substantial reduction in tumor size after VP-315 treatment would markedly reduce the surgical incision area and the amount of potential post-surgical scarring. Based on the favorable results, further research using VP-315 as a potential non-surgical immunotherapy for BCC as a first line therapy in a primary or neoadjuvant setting is warranted.

Results of a Phase 2 Multicenter Study Evaluating the Safety and Tolerability of VP-315, an Investigational Therapy for Basal Cell Carcinoma

Introduction VP-315 is an intratumorally injected, chemotherapeutic oncolytic peptide in development as a non-surgical immunotherapeutic agent to be utilized as first line therapy in a primary or neoadjuvant setting for patients with basal cell carcinoma (BCC). Objective In Part 2 of this study, the primary objective was to determine the optimal dosing regimen for VP-315 by exploring the effects of various dosing schemes on the safety and tolerability of VP-315 in a larger population of subjects with biopsy proven BCC. Methods Eighty-two (82) subjects with up to 2 target BCC tumors (total 91 tumors) were treated intratumorally with VP-315 for up to 2 weeks. Cohort 3 was not enrolled based on results from Cohorts 1-2. Each 7-day treatment week was comprised of 2 or 3 consecutive treatment days followed by a no-treatment period of at least 4 days. Dosing scheme: Cohort 1: (n=6) Tumor injected 3 days consecutively (3X/week 4 mg loading dose Day 1 followed by 8 mg dose). Cohort 2: (n=3) Tumor injected 3 days consecutively (3X/week 8 mg dose). Cohort 4: (n=36) Each tumor was injected 2 days consecutively (2X/week 8 mg split dose*). Cohort 5: (n=37) Each tumor was injected 3 days consecutively (3X/week 8 mg split dose*). * Dose split into 2 injections, 30% injected initially; 70% injected 15-30 minutes later. Safety and tolerability were assessed by documenting the occurrence of Treatment Related Adverse Events (TRAEs), including those of special interest, Treatment Related Serious Adverse Events (TRSAEs), discontinuations due to AEs and expected treatment-related cutaneous reactions including tumor necrosis. Results All 82 subjects completed one of the VP-315 treatment regimens for BCC. TRAEs were mostly mild to moderate. AEs included injection site pain (mild 13.4%, moderate 12.2%, severe 1.2%), hypertension (mild 4.9%), hypotension (mild 4.9%), erythema (mild 1.2%, moderate 2.4%), and headache (mild 2.4%). Expected cutaneous reactions were observed. No TRSAEs were reported. Conclusion VP-315 treatment was shown to be safe and well-tolerated when administered once daily 2-3 times per week per tumor for up to 2 weeks using a split dose approach. Given its favorable safety profile, VP-315 warrants continued research as a potential non-surgical immunotherapy for BCC as a first line therapy in a primary or neoadjuvant setting. Sponsored by Verrica Pharmaceuticals Inc.

Psychometric assessment of a Chinese version of a mindfulness practice quality measurement tool

BackgroundMindfulness training is increasingly popular in China. The challenge of evaluating mindfulness practice objectively and accurately has attracted research attention. However, previous studies in China focused primarily on the quantity rather than the quality of mindfulness training. The Practice Quality - Mindfulness (PQ-M) can provide a solution. Consequently, the present study aimed to validate and assess the internal consistency and construct validity of the Chinese version of the Practice Quality - Mindfulness (Ch-PQ-M) in a non-clinical sample.MethodsOne hundred and sixty participants (female:81) were recruited to practice 20 min of mindfulness training daily for four consecutive days and to complete the Ch-PQ-M, the State Anxiety Inventory, and the Peace of Mind Scale immediately after each mindfulness practice. The Five Facet Mindfulness Questionnaire, the Trait Anxiety Inventory, and the Positive and Negative Affect Scale were administered pre- and post- 4-day treatment. Construct validity (confirmatory factor analysis), internal consistency, test–retest reliability, predictive validity and construct validity were examined.ResultsCh-PQ-M demonstrated acceptable internal consistency and test–retest reliability. Confirmatory factor analysis supported the established two-factor model (perseverance and receptivity). The Ch-PQ-M attention score was significantly associated with changes of trait anxiety. It improved with short-term mindfulness practice. The perseverance score consistently correlates with scores on peace of mind, state anxiety, trait anxiety, and observe and nonreactivity. The receptivity score remains consistently correlated with the nonjudging. These findings suggest that Ch-PQ-M is a valid instrument for evaluating individual mindfulness quality for a single-session practice.ConclusionsOur findings suggest that Ch-PQ-M (especially for the Ch-PQ-M perseverance score) has acceptable psychometric properties and is a reliable and valid instrument for assessing mindfulness practice quality in the Chinese cultural context.

Precipitation Patterns and Their Role in Modulating Nitrous Oxide Emissions from Arid Desert Soil

Nitrous oxide (N2O) ranks as the third most significant greenhouse gas, capable of depleting the ozone layer and posing threats to terrestrial ecosystems. Climate change alters precipitation variability, notably in terms of frequency and magnitude. However, the implications of precipitation variability on N2O emissions and the underlying mechanisms remain inadequately understood. In this study, employing laboratory incubation methods on three representative sandy soil types (sandy soil, shrub soil, and crust soil), we examined the impacts of diverse precipitation levels (5 mm and 10 mm) and frequencies (7 days and 14 days) on N2O emissions from these soil types. This study aims to clarify the complex connections between soil N2O emission fluxes and soil physicochemical properties in the soil environment. Our findings reveal that the N2O emission flux exhibits heightened responsiveness to 5 mm precipitation events and a 14-day precipitation frequency, and compared to other treatments, the 5 mm precipitation and 14-day precipitation frequency treatment resulted in a 20% increase in cumulative nitrous oxide emissions. Consequently, cumulative N2O emissions were notably elevated under the 5 mm precipitation and 14-day precipitation frequency treatments compared to the other experimental conditions. The N2O emission flux in sandy soil displayed a positive correlation with available phosphorus (AP) and a negative correlation with pH, primarily attributed to the exceedingly low AP content in sandy soil. In shrub soil, the soil N2O emission flux exhibited a significant positive correlation with NH4+-N and a negative correlation with NO3−-N. Conversely, no significant correlations were observed between soil N2O emission flux and soil physicochemical properties in crust soil, underscoring the importance of considering plant–soil microbial interactions. Our findings suggest that soil nitrous oxide emissions in arid and semi-arid regions will be particularly responsive to small and frequent rainfall events as precipitation patterns change in the future, primarily due to their soil physicochemical characteristics.

Case Study on Management of Overweight (Sthoulya) through Ayurveda

ABSTRACT Modernization, affluence, and advancements in science and technology have led to increasingly sedentary lifestyles. This unintentionally invites a range of health issues, one of which is Sthoulya (overweight), which can affect physical, mental, and social health. Sthoulya refers to an individual who has excessive fat and flesh accumulation, causing a disproportional enlargement of the buttocks, belly, and breasts without a corresponding increase in energy. A 38-year-old female patient presented with weight gain, excessive hunger, sleep and sweating, lack of enthusiasm, and bad body odor. Before and after therapy, the patient was assessed for subjective and objective characteristics. There was an improvement in subjective parameters, anthropometric measurements, body mass index (BMI), and body weight after treatment. The combination therapy comprising Tryushanadi Guggul, Udvartan with Vacha Churna, and Peti Sweda demonstrated effectiveness in improving the lipid profile and anthropometric measurements of the patient over a 30-day treatment period.

DDEL-17. INTRA-TUMORAL CONVECTION ENHANCED DELIVERY OF DEXAMETHASONE REDUCES INFLAMMATORY SIGNATURES AND EXTENDS SURVIVAL IN GBM MODEL

Abstract Dexamethasone is the most widely utilized drug for glioblastoma (GBM). However, systemic delivery of dexamethasone in GBM patients is associated with significant side effects and increasing doses with worse survival. Convection-enhanced delivery (CED) can deliver high doses of immunotherapy directly into the tumor microenvironment (TME) while avoiding systemic toxicity. Here, we report that high doses of dexamethasone can be delivered locally by CED without side effects and increase survival in a GBM model along with reduced inflammatory myeloid signatures. We investigated CED of dexamethasone treatment on survival(n=40), adverse side effects, and the immunological TME through peripheral analyses, liquid chromatography–mass spectrometry, and histology in a preclinical syngeneic mouse model. Additionally, we assessed the transcriptional responses of human GBM slices and stem-cell-derived human microglia after steroid treatment through bulk and single-cell RNA sequencing. We found that 7-day treatment with CED of dexamethasone produced a significant survival advantage in glioma-bearing mice compared to non-treated control(p=0.03). Systemic dexamethasone achieved low levels of drug in the TME and caused dysregulated blood glucose, blood counts, and peripheral organ weights, while high CED doses avoided these side effects(p&amp;lt; 0.05 each). Steroid treatment of acute GBM slices and lipopolysaccharide-activated microglia in-vitro both reversed inflammatory myeloid signatures associated with poor survival and recurrence on RNA sequencing analyses. We demonstrate the preclinical efficacy of delivering high local doses of dexamethasone in a GBM model through CED and observed prolonged survival along with reduced adverse inflammatory myeloid signatures. No side effects were demonstrated after chronic CED treatment of dexamethasone while systemic delivery achieved poor tumor penetration and caused known hematologic and metabolic side effects supporting the potential to optimize the clinical use of this therapy. CED of dexamethasone provides us a new treatment paradigm to locally control inflammatory signatures in the glioma TME in a controlled fashion.

Efficacy of compound sodium acetate Ringer’s solution in early fluid resuscitation for children with septic shock: a preliminary retrospective cohort study

BackgroundThe effectiveness of acetated Ringer’s solution in pediatric shock has received little attention. This study aimed to assess the clinical outcomes of using compound sodium acetate Ringer’s solution (AR) for fluid resuscitation in children with septic shock.MethodsWe retrospectively analyzed the clinical data of children with septic shock admitted to the pediatric intensive care unit of the Affiliated Hospital of Southwest Medical University from December 2019 to January 2023. Based on the resuscitation fluid administered, the participants were categorized into the compound AR and normal saline (NS) groups. We compared blood circulation conditions, internal environment parameters (arterial blood pH, lactic acid, serum sodium, chloride, calcium, magnesium, potassium, and blood glucose), and 28-day clinical outcomes between the two groups.ResultsThis study included 40 children, with 13 and 27 in the compound AR and NS groups, respectively. The two groups showed no significant differences in sex, age, body weight, body mass index, primary inflammation level, or Pediatric Sequential Organ Failure Assessment on admission. Similarly, no significant difference was observed in resuscitation fluid volume administered during the first hour (compound AR group: 250.00 mL [100.00, 390.00]; NS group: 250.00 mL [100.00, 500.00]). The total amount of crystalloid and colloid fluids administered within 24 h, vasoactive drug use, and blood pressure recovery post-resuscitation did not significantly differ between the groups. However, at 6 h post-resuscitation, the compound AR had considerably lower lactate level than the NS group (1.12 vs. 2.20 mmol/L). There were no significant differences in arterial blood pH, serum sodium, chloride, calcium, magnesium, potassium, and blood glucose levels between the groups. After treatment, in the compound AR group, 3 patients died, 2 improved, and 8 were cured. In the NS group, 7 patients died, 8 improved, and 12 were cured. The 28-day treatment outcomes (mortality rate, improvement rate, cure rate, or side effects) showed no significant differences between the groups.ConclusionsCompound AR was as effective as NS as a resuscitation fluid in pediatric septic shock, demonstrating similar intravascular volume restoration and hemodynamic stability maintenance. However, it caused a faster decline in arterial lactate levels without obvious side effects.

Clinical Impact of High-dose Esomeprazole-amoxicillin Dual Therapy as Rescue Treatment for Helicobacter pylori Infection: A Prospective, Multicenter, Randomized Trial.

This study aimed to compare the effectiveness and safety of high-dose dual therapy (HDDT) using esomeprazole and amoxicillin to furazolidone-based quadruple therapy (FBQT) in treating nonresponsive patients with Helicobacter pylori (H. pylori) infection. A total of 209 patients with H. pylori infection, who had previously received ineffective treatment and visited an outpatient clinic, were randomly assigned to either the HDDT or FBQT groups. All patients underwent a 14-day treatment regimen, and the success rates of H. pylori eradication and safety of the treatment regimens were assessed 4 weeks posttreatment. Following the 14-day treatment period, the intention-to-treat (ITT) analysis revealed eradication rates of 93.6% for HDDT and 86.9% for FBQT. In the per-protocol (PP) analysis, eradication rates were 94.5% for HDDT and 88.7% for FBQT. No significant difference in eradication rates was observed between the two groups. HDDT exhibited significantly lower rates of adverse reactions (9.1% in ITT and 9.2% in PP) compared with FBQT (58.6% in ITT and 59.8% in PP). Multivariate analysis identified interval time, alkaline phosphatase, and serum creatinine level as factors influencing the eradication rate. The area under the receiver operating curve of the interval time between the FBQT group and the HDDT group and the success of H. pylori eradication were 0.622 and 0.578, respectively. The optimal salvage treatment intervals were determined as 6 months for FBQT and 1 year for HDDT. HDDT using high-dose esomeprazole and amoxicillin demonstrated efficacy in treating H. pylori infection, with the added benefits of reduced side effects and improved medication compliance compared with FBQT. HDDT can be considered a rescue treatment option when other methods fail, with treatment intervals optimized accordingly.

CVN424, a GPR6 inverse agonist, for Parkinson's disease and motor fluctuations: a double-blind, randomized, phase 2 trial

CVN424 is a GPR6 inverse agonist that provides selective pharmacological control of the indirect striatopallidal pathway. We assessed the safety and efficacy of CVN424 as an adjunctive treatment to levodopa for reducing OFF-time in individuals with Parkinson's disease (PD) experiencing motor-fluctuations. This was a randomised, double-blind, placebo-controlled study conducted at 21 sites across the United States to evaluate two doses of CVN424 (NCT04191577). Patients with PD (Hoehn and Yahr stages 2-4) who were on a stable dose of levodopa and experiencing ≥2h of daily OFF-time were randomised (1:1:1) to receive either once-daily CVN424 (50mg or 150mg) or placebo for a 28-day treatment period. The primary endpoints were safety and tolerability. The key secondary endpoint was the change from baseline to Day 27 in OFF-time. The study was conducted from December 23, 2019, to October 14, 2021. Out of 198 participants screened, 141 eligible participants were randomised to one of the three treatment groups (n=47 per group), and 127 participants completed the 28-day treatment period. The most common treatment emergent adverse events (TEAEs) were headache (2% with CVN424 50mg, 9% with CVN424 150mg, and 2% with placebo) and nausea (4% with CVN424 50mg, 6% with CVN424 150mg and 2% with placebo). No serious treatment-related adverse events were reported. On Day 27, the mean±standard deviation (SD) change from baseline in daily OFF-time was-1.3±3.0h in the CVN424 50mg group,-1.6±2.5h in the CVN424 150mg group, and-0.5±2.9h in the placebo group. The placebo-adjusted LS mean±standard error (SE) treatment difference was significant for the CVN424 150mg dose (1.3±0.56h, [95 CI%-2.41 to-0.19], nominal p=0.02). Treatment with CVN424 was safe and well-tolerated. Despite the short study duration and small sample size, the 150mg CVN424 dose provided a clinically meaningful reduction in daily OFF-time. This study supports the development of CVN424 for the treatment of PD. Cerevance.

Unraveling Cecal Alterations in Clostridioides difficile Colonized Mice through Comprehensive Metabolic Profiling.

The disruption of gut microbiota caused by antibiotics favors the intestinal colonization of Clostridioides difficile - a Gram-positive, spore-forming anaerobic bacterium that causes potentially fatal gastrointestinal infections. In an endeavor to elucidate the complexities of the gut-brain axis in the context of Clostridium difficile infection (CDI), a murine model has been used to investigate the potential effects of antibiotic administration and subsequent colonization by C. difficile, as well as the impact of three different 10-day treatments (metronidazole, probiotics, and fecal microbiota transplantation), on the cecal metabolome for the first time. This follows our previous research which highlighted the metabolic effect of CDI and these treatments in the brain and employs the same four different metabolomics-based methods (targeted GC-MS/MS, targeted HILIC-MS/MS, untargeted RP-LC-HRMS/MS and untargeted GC-MS). A total of 286 unique metabolites have been identified in the mouse cecal profiles and statistical analysis revealed that CDI, as well as the subsequent treatments, significantly alters cecal metabolites and lipids implicated in various biochemical pathways centered around amino acid metabolism, glycerophospholipid metabolism, and central carbon metabolism. To our knowledge, this study represents the first exploration of the effects of C. difficile-induced colitis and potential treatments on the cecal tissue metabolome.