Successful Therapy Research Articles

Mutations in the kinesin KIF12 promote MASH in humans and mice by disrupting lipogenic enzyme turnover.

As a common cause of liver cirrhosis, metabolic dysfunction-associated steatohepatitis (MASH) is regarded as a target of therapeutic intervention. However, a successful therapy has not yet been found, partly because the molecular pathogenesis is largely elusive. Here we show that KIF12 kinesin suppresses MASH development by accelerating the breakdown of two lipid biosynthesis enzymes, acetyl-CoA carboxylase 1 (ACC1) and pyruvate carboxylase (PC), in hepatocytes. We report three familial early-onset liver cirrhosis pedigrees with homozygous KIF12 mutations, accompanying MASH-like steatosis and cholestasis. The mouse genetic model carrying the corresponding Kif12 nonsense mutation faithfully reproduced the phenotypes as early as between 8 and 10 weeks of age. Furthermore, KIF12-deficient HepG2 cells exhibited significant steatosis, which was ameliorated by overexpressing a proline-rich domain (PRD) of KIF12. We found that KIF12-PRD promotes the degradation of ACC1 and PC, and this effect is likely to be through its direct interaction with these enzymes. Interestingly, KIF12 enhanced the ubiquitination of ACC1 by the E3 ligase COP1 and colocalized with these proteins as seen by super-resolution microscopy imaging. These data propose a role for KIF12 in suppressing MASH by accelerating turnover of lipogenic enzymes.

Susceptibility of Non-Tuberculous Mycobacteria Biofilm to Common Disinfectants in Aquaculture Systems.

Mycobacteriosis is a common and persistent bacterial disease affecting cultured, wild and pet fish. The disease can be caused by various Mycobacterium spp. Currently, depopulation and disinfection are the main recommended measures for containing disease outbreaks, as no vaccines are commercially available, and only a few reports of successful antimicrobial therapies have been made. While disinfectant susceptibility studies have been conducted on planktonic forms of some non-tuberculous mycobacteria (NTM) affecting fish, biofilm-related research remains limited. In this study, biofilm formation of Mycobacterium chelonae, Mycobacterium salmoniphilum, Mycobacterium arcueilense and Mycobacterium marinum isolates recovered from diseased fish were initially evaluated using the minimal biofilm eradication concentration (MBEC) assay system. All Mycobacterium spp. were able to form biofilms within a 2-week period when incubated at 25°C, but M. chelonae, M. salmoniphilum and M. arcueilense produced a faster and greater biofilm than M. marinum. To investigate the susceptibility of mycobacterial biofilms to common disinfectants, mature biofilms were divided into six treatment groups based on disinfectant type and exposure time: povidone-iodine (50 mg L-1 free iodine) and bleach (200 mg L-1 free chlorine) were applied for 30 min each; hydrogen peroxide (3% H2O2) and Virkon Aquatic (10 g L-1) were applied for 15 min each; and 70% ethanol was tested at both 15 and 30 min. Results demonstrated variable susceptibility among species. M. marinum was susceptible to all disinfectants, while M. arcueilense was susceptible to bleach, povidone-iodine and 70% ethanol (30-min exposure). None of the tested disinfectants at recommended doses effectively eradicated M. chelonae or M. salmoniphilum biofilms. These findings underscore species-specific differences in biofilm formation and resistance, emphasising the critical need for robust disinfection protocols in aquaculture settings to prevent mycobacteriosis transmission. Further research is essential to understand the mechanisms underlying disinfectant resistance among NTMs, optimise disinfection strategies and ensure the health and biosecurity of aquaculture facilities.

From natural defenders to therapeutic warriors: NK cells in HIV immunotherapy.

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells both play essential roles in controlling viral infections by eliminating virus-infected cells. Unlike CTLs, which require priming and activation by antigen-presenting cells, NK cells possess a remarkable capacity to mount a rapid antiviral immune response immediately after infection. Additionally, they can bolster the adaptive immune system by secreting cytokines and directly interacting with other immune cells. However, during chronic human immunodeficiency virus (HIV) infection, various immune cells, including NK cells, experience functional impairments. This has led to the exploration of NK cell-based immunotherapy as a promising strategy to reverse these dysfunctions and contribute to the pursuit of a functional cure for HIV. Building on the success of NK cell therapies in cancer treatment, these approaches offer significant potential for transforming the HIV cure field. This review provides a comprehensive overview of the latest advances in NK cell-based immunotherapy for HIV, outlining the progress made and the key challenges that must be overcome to achieve a functional cure for people living with HIV.

Antimicrobial Resistance in Pasteurella multocida Isolates from Bovine Mastitis Can Be Associated with Multidrug-Resistance-Mediating Integrative and Conjugative Elements (ICEs)

Background/Objectives: Pasteurella multocida commonly colonizes the bovine respiratory tract and can occasionally cause intramammary infections. Here, eight P. multocida isolates from clinical cases of bovine mastitis were investigated for their molecular characteristics as well as phenotypic and genotypic antimicrobial resistance (AMR) properties. Methods: The isolates originated from quarter milk samples obtained in Germany for diagnostic purposes. Antimicrobial susceptibility testing (AST) by broth microdilution was performed according to the Clinical and Laboratory Standards Institute. Closed whole-genome sequences were generated by hybrid assembly of Illumina MiSeq short-reads and Oxford Nanopore MinION long-reads, followed by consecutive sequence analysis. Results: The P. multocida isolates belonged either to capsular:lipopolysaccharide type A:3 (n = 7) or A:6 (n = 1), and multi-locus sequence types 1 (n = 7) or 7 (n = 1). Seven isolates carried AMR genes, such as mef(C), mph(G), strA, strB, aphA1, aadA31, tet(H), tet(Y), floR, catA3, and sul2, as part of an integrative and conjugative element (ICE). These mobile genetic elements, 58,382–78,401 bp in size, were highly similar to the ICEs Tn7406 or Tn7407 that have been previously described in bovine Mannheimia haemolytica and P. multocida, respectively. Moreover, the isolates showed elevated minimal inhibitory concentrations corresponding to the identified AMR determinants. Conclusions: Molecular typing and ICE organization suggest the bovine respiratory tract as reservoir of the investigated mastitis-associated P. multocida. Horizontal cross-genus transfer of multidrug-resistance-mediating ICEs seems to occur under in vivo conditions among different pathogens from cattle in Germany, which underlines the importance of pathogen identification followed by AST for successful bovine mastitis therapy.

Epilepsia em cão

This work aimed to report the case of a patient who was presented at the Veterinary Clinic of the Pontifical Catholic University of Campinas (São Paulo, Brazil), in November 2023, with a history of epilepsy. Epilepsy is a disease characterized by the occurrence of convulsive crises, and which has been frequently found in the veterinary routine. Neurological disorders are complex to identify and treat, and epilepsy is an example of this. The difficulty begins with the diagnosis, where the identification, or lack thereof, of convulsive crises can depend greatly on the guardian's perception and report. Furthermore, the list of differential diagnoses is extensive and the elimination process and search for a cause can take time. Regarding treatment, there are few drugs with proven efficacy nowadays, with phenobarbital and potassium bromide being most relevant in the treatment of epilepsy. Even with the institution of drug therapy, there are several factors that interfere with the assertiveness of the treatment, from the guardian's compliance in the administration or carrying out of monitoring exams, to the receptivity and response of each organism to medications and dosage. Success in therapy can be achieved when the patient presents a decrease in the frequency, duration and intensity of episodes, as complete interruption is not commonly seen.

Gold Mesoporous Silica-Coated Nanoparticles for Quantifying and Qualifying Mesenchymal Stem Cell Distribution; a Proof-of-Concept Study in Large Animals.

Mesenchymal stem cells (MSCs) have demonstrated promising therapeutic potential across a wide range of diseases including (multi) organ injury in neonates. Despite the reported preclinical successes of MSC therapy, a major challenge in their clinical translation is a limited understanding of their biodistribution after administration. This knowledge gap needs to be addressed to allow clinical implementation. Accordingly, in this study, we propose that silica-coated gold nanoparticles (AuMS) are a promising tool for in vivo MSC tracing. This study explores the use of AuMS for both qualitative and quantitative MSC tracking in vivo after intravenous (I.V.) administration in a translational ovine model of preterm birth. Additionally, we assess the impact of AuMS labeling on the immunomodulatory functions of MSC, which play an important role in the therapeutic potency of these cells. Quantitative and qualitative assessment of AuMS-labeled MSC was performed in vivo using fluorescent microscopy and inductively coupled plasma mass spectrometry (ICP-MS), respectively. AuMS localization in the liver, spleen, and lung was demonstrated. In vitro studies showed that AuMS cellular uptake occurs within 6 h and remains internalized up to 72 h. Labeled MSC maintained their immune phenotype and did not alter their immunomodulatory capacity and proliferation abilities. Overall, we demonstrate that AuMS is a promising, biocompatible nanoprobe for MSC tracing up to 72 h post-I.V. administration.

Liver cancer risk and changes in lifestyle habits after successful hepatitis C virus therapy post-DAA HCV therapy: lifestyle changes and liver cancer risk

BackgroundThe eradication of the Hepatitis C Virus (HCV) reduce the risk of liver cancer (LC), but lifestyle changes after cure may counterbalance its benefit. Our study investigates lifestyle changes that occur in HCV patients with Sustained Virological Response (SVR) after direct-acting antiviral (DAA) treatment.MethodsIn this prospective, single-center study, HCV patients with advanced liver disease (F3/F4) treated and cured with DAA were invited to fill a lifestyle habits questionnaire in and perform abdominal ultrasound (US), blood extraction and anthropometric measurements within the 1st month after SVR and every 6 months thereafter until 48 months of follow-up, LC development, death, or loss to follow-up.ResultsThis prospective cohort included 182 patients with SVR after DAA in this first analysis through the 4 years of follow-up. At the time of SVR, 65.9% had cirrhosis, median BMI was 27.1 kg/m2, 74.2% were overweight or obese and 6.6% had an US with hepatic steatosis. Within a year of SVR, 9% of males and 4% of females progressed from normal weight to overweight/obesity and 19.4% increased alcohol consumption. At 48 months, there were statistically significant increases in BMI (0.75, p = 0.001) and alcohol consumption (6.4% p = 0.007).ConclusionsIn this prospective cohort, successful HCV therapy was followed by significant changes in lifestyle habits translating into increases in BMI and alcohol consumption. These post-SVR changes raise concerns that the chemopreventive benefits of HCV cure may be counterbalanced by increased risks of liver disease progression and LC development from metabolic risk factors and alcohol use. Post-SVR, patients may benefit from intensive counseling and pharmacotherapy to address obesity and alcohol use.Trial registration/ clinical trial numberNot applicable.

Ophthalmic In Situ Nanocomposite Gel for Delivery of a Hydrophobic Antioxidant

The topical administration of in situ hydrogels for ocular pathologies is a promising application strategy for providing high effectiveness and patient compliance. Curcumin, a natural polyphenol, possesses all the prerequisites for successful therapy of ophthalmic diseases, but unfortunately its physicochemical properties hurdle the practical use. Applying a composite in situ thermoresponsive hydrogel formulation embedded with polymer nanoparticles is a potent strategy to overcome all the identified drawbacks. In the present work we prepared uniform spherical nanoparticles (296.4 ± 3.1 nm) efficiently loaded with curcumin (EE% 82.5 ± 2.3%) based on the biocompatible and biodegradable poly-(lactic-co-glycolic acid). They were thoroughly physicochemically characterized in terms of FTIR, SEM, TGA, and DLS, in vitro release following Fickian diffusion (45.62 ± 2.37%), and stability over 6 months. Their lack of cytotoxicity was demonstrated in vitro on HaCaT cell lines, and the potential for antioxidant protection was also outlined, starting from concentrations as low as 0.1 µM and reaching 41% protection at 5 µM. An in situ thermoresponsive hydrogel (17% w/v poloxamer 407 and 0.1% Carbopol) with suitable properties for ophthalmic application was optimized with respect to gelation temperature (31.40 ± 0.36 °C), gelling time (8.99 ± 0.28 s) upon tears dilution, and gel erosion (90.75 ± 4.06%). Upon curcumin-loaded nanoparticle embedding, the in situ hydrogels demonstrated appropriate pseudoplastic behavior and viscosity at 35 °C (2129 ± 24 Pa∙s), 6-fold increase in the permeation, and prolonged release over 6 h.

CAR T-cell Therapy Landscape in Pediatric, Adolescent and Young Adult Oncology - A Comprehensive Analysis of Clinical Trials.

Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a transformative approach in cancer treatment, particularly for hematologic malignancies. This therapy involves the genetic modification of patients' T-cells to target specific tumor antigens, bypassing the traditional MHC-TCR-mediated recognition. This innovation marks a significant step toward personalized medicine and precision oncology. In the pediatric, adolescent, and young adult (P-AYA) populations, Tisagenlecleucel (Kymriah®) exemplifies the success of CAR T-cell therapy, demonstrating significant efficacy in treating relapsed or refractory acute lymphoblastic leukemia (r/r ALL). However, the development of CAR T-cell therapies for P-AYA patients has not progressed as rapidly as for adults, with only one FDA approval for pediatric applications compared to six for adults up to 2024. Several challenges hinder the development of pediatric CAR T-cell therapies, including complex production logistics, limited clinical site access, restrictive patient eligibility criteria, and financial constraints, necessitating more effective incentives for pediatric oncology drug development independent of adult indications. To assess the current landscape of CAR T-cell therapy in P-AYA oncology, we conducted a comprehensive review of clinical trials registered on ClinicalTrials.gov up to May 2024. Our analysis included 77 trials exclusively targeting the P-AYA population from an initial pool of 40,690 studies filtered by age, dates, and specific criteria related to CAR T-cell interventions in cancer therapy. We found that 45% of these trials originated from the USA and 30% from China. The data retrieved from these trials provided insights into various aspects, including histological categories, antigenic targets, CAR-T generations, costimulatory domains, manufacturing processes, geographical distribution, and funding sources. This review highlighted a predominant focus on hematologic malignancies, particularly B-cell acute lymphoblastic leukemia (B-ALL), with significant attention to dual antigen targeting (CD19 and CD22) to address resistance mechanisms. Emerging targets such as GD2 for solid tumors and B7-H3 for various cancers also showed promise. Additionally, most trials still utilize second-generation CAR-T constructs with 4-1BB costimulatory domains, reflecting a conservative approach in pediatric populations. Our findings underscore the disparity in CAR T-cell therapy development between pediatric and adult populations, driven by distinct biological, ethical, and economic considerations. Pediatric cancers require specialized treatments tailored to the unique biology and genetic makeup of pediatric oncology. However, research and drug development have historically focused less on pediatric needs. Despite legislative efforts to promote pediatric oncology drug development, significant gaps remain. Clinical trials for P-AYA populations face challenges in patient enrollment, trial design, and funding, often relying on academic and non-profit institutions. Addressing these barriers is critical for advancing CAR T-cell therapy in pediatric oncology, improving outcomes, and ensuring equitable access to innovative treatments for these vulnerable populations. This review aims to inform future research and policy decisions, promoting advancements in CAR T-cell therapy for P-AYA cancer patients.

Dental Pulp Stem Cells (DPSCs), Stem Cells From Human Exfoliated Deciduous Teeth (SHEDSCs), and Periodontal Ligament Stem Cells (PDLSCs) Isolation, Characterization and the Effectiveness of Allantoin as Bioactive Molecule for Dental Regeneration.

Dental stem cells are valuable tools in regenerative medicine due to their pluripotency and self-renewal properties. This study aimed to investigate the effects of allantoin (Al) on Dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDSCs), and periodontal ligament stem cells (PDLSCs) regarding cytotoxicity, proliferation, wound healing, and osteogenic differentiation. Human dental stem cells were isolated from three dental tissues using the explant culture method and cultured in DMEM-F12 medium supplemented with 15% fetal bovine serum (FBS) and antibiotics. The cytotoxicity and proliferation of allantoin were assessed using the XTT cell viability assay at concentrations ranging from 0,25 to 5 mg/mL. Wound healing was evaluated through a scratch assay at 1 mg/mL, and osteogenic differentiation was assessed using Alizarin Red S staining at 0,5 mg/mL and 1 mg/mL. Al exhibited no cytotoxic effects across the tested concentrations. It enhanced cell proliferation, particularly in SHEDSCs at 5 mg/mL. DPSCs also showed significant improvement in wound healing in the scratch assay. At 1 mg/mL, Al inhibited osteogenic differentiation in DPSCs and PDLSCs, as indicated by reduced mineralization. Al shows potential as a non-cytotoxic agent for enhancing the proliferation of dental stem cells, especially SHEDSCs. However, its limited effect on wound healing of SHEDSCs and PDLSCs and inhibition of osteogenic differentiation at higher concentrations suggest that further optimization is required for its application in bone regeneration. Evaluation of the effects of plant-based therapeutic compounds on various types of dental stem cells may have the potential to increase the success of stem cell-based therapies in clinical applications in regenerative dentistry.

Network analyses of brain tumor multiomic data reveal pharmacological opportunities to alter cell state transitions

Glioblastoma Multiforme (GBM) remains a particularly difficult cancer to treat, and survival outcomes remain poor. In addition to the lack of dedicated drug discovery programs for GBM, extensive intratumor heterogeneity and epigenetic plasticity related to cell-state transitions are major roadblocks to successful drug therapy in GBM. To study these phenomenon, publicly available snRNAseq and bulk RNAseq data from patient samples were used to categorize cells from patients into four cell states (i.e., phenotypes), namely: (i) neural progenitor-like (NPC-like), (ii) oligodendrocyte progenitor-like (OPC-like), (iii) astrocyte-like (AC-like), and (iv) mesenchymal-like (MES-like). Patients were subsequently grouped into subpopulations based on which cell-state was the most dominant in their respective tumor. By incorporating phosphoproteomic measurements from the same patients, a protein–protein interaction network (PPIN) was constructed for each cell state. These four-cell state PPINs were pooled to form a single Boolean network that was used for in silico protein knockout simulations to investigate mechanisms that either promote or prevent cell state transitions. Simulation results were input into a boosted tree machine learning model which predicted the cell states or phenotypes of GBM patients from an independent public data source, the Glioma Longitudinal Analysis (GLASS) Consortium. Combining the simulation results and the machine learning predictions, we generated hypotheses for clinically relevant causal mechanisms of cell state transitions. For example, the transcription factor TFAP2A can be seen to promote a transition from the NPC-like to the MES-like state. Such protein nodes and the associated signaling pathways provide potential drug targets that can be further tested in vitro and support cell state-directed (CSD) therapy.

Integrated U-Net segmentation and gated recurrent unit classification for accurate brain tumor diagnosis from magnetic resonance imaging images

Early diagnosis and proper grouping of tumors in the brain are critical for successful therapy and positive outcomes for patients. This work proposes a complete technique for identifying brain tumors that employ sophisticated artificial intelligence methodologies and achieve an accuracy rate of 97.18%. The work makes use of the brain tumor magnetic resonance imaging (MRI) collection in Kaggle, which has 723 MRI scans classified as glioma, meningioma, pituitary tumor, and no tumor. These images are initially preprocessed, which includes scaling to a homogeneous size normalizing, and removal of noise to ensure uniformity and clarity. To improve the information set, generative adversarial networks (GANs) are used to perform data augmentation, producing artificial pictures that improve the database variety and resilience. To achieve exact cancer localization, the U-Net construction, recognized for its encoder-decoder design and skip links, is used to divide up tumor areas across images generated by MRI. The image segments are then input into gated recurrent units (GRUs), to analyze a collection of features to capture periods and differences between segments. The last classification is accomplished using an entirely linked layer and then a softmax stimulation, which provides the tumors classes. This method helps for medical experiments and clinical methods.

Excision of HIV-1 Provirus in Human Primary Cells with Nanocapsuled TALEN Proteins.

Despite the tremendous success of combination antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV) infection, the durability and persistence of latent reservoirs of HIV-infected cells in HIV-infected patients remain obstacles to achieving HIV cure. While technically challenging, the most direct means to eradicate latent reservoirs is to destroy the HIV provirus, thus ensuring that HIV virions are not produced while preserving resident cells. Transcription activator-like effector nucleases (TALEN)─a genome editing method with high DNA targeting efficiency─have been investigated as a potential gene therapy by disrupting the HIV-1 coreceptor CCR5 genes in HIV target cells or HIV proviral DNA in infected cells. However, the transduction and editing efficiencies are low in primary cells and vary by cell type. Using a nanotechnology platform, which we term nanocapsules, the TALEN protein can be effectively delivered into primary cells and escape from endosome/lysosome sequestration. We report that TALEN nanocapsules can effectively mutagenize the HIV-1 proviral DNA integrated into two primary HIV-1 reservoir cells─T cells and macrophages, such that replication and/or reactivation from latency is aborted. We envision that this study provides a useful platform to deliver a wide range of DNA-modifying enzymes for effective HIV therapy.

Multi-omics dissection of metabolic dysregulation associated with immune recovery in people living with HIV-1

BackgroundDespite the success of antiretroviral therapy (ART) in suppressing HIV-1 replication, some people living with HIV-1 (PLWH) fail to achieve an optimal recovery of CD4 T cells, and precise metabolic regulation underlying immune recovery remained poorly understood.MethodsIn this cross-sectional study, mass spectrometry was used for quantitative analysis of plasma metabolome and lipidome in 24 treatment-naïve PLWH (TNs), 33 immunological responders (IRs), 35 immunological non-responders (INRs), and 16 healthy controls (HCs). The data were analyzed using the Mann–Whitney U-test, Kruskal–Wallis test, Spearman correlation, and LASSO regression analysis.ResultsSignificant metabolic dysregulation was observed in TNs, IRs and INRs compared to HCs. In TNs, metabolomic analysis revealed increased levels of 3-hydroxyoctanoic acid, 3-oxododecanoic acid, 5-hydroxy-L-tryptophan, 5-hydroxyindoleacetic acid, L-kynurenine, oleoylcarnitine, and pseudouridine that were positively correlated with CD8 T cell activation and inflammation-related markers, and decreased levels of phosphorylcholine, ribothymidine, and thymine that were negatively correlated. Notably, 3-hydroxyoctanoic acid and thymine were consistently associated with CD4 T cell counts and inflammation-related markers in PLWH, regardless of ART. Pathway analysis uncovered the biosynthesis of unsaturated fatty acids as the major dysregulated pathway in TNs, IRs, and INRs, while primary bile acid biosynthesis was the dysregulated pathway specifically in INRs. Lipidomic analysis indicated higher plasma triacylglycerols, free fatty acids, ceramide, and monosialodihexosyl gangliosides (GM3) in TNs, IRs, and INRs compared to HCs. Pathway enrichment and differential correlation analyses underscore perturbed systemic lipid metabolism in treatment response to ART, possibly mediated by host-commensal metabolic interactions. Ultimately, we identified two panels, one consisting of 9 metabolites and another of 8 lipids, that can effectively distinguish INRs from IRs.ConclusionsMetabolic aberrations induced by chronic HIV-1 infection persist and do not recover with ART. Abnormal primary bile acid biosynthesis pathway and levels of DHA-containing lipids are closely associated with CD4 T cell recovery. These finding provide new intervention targets to achieve better immune recovery in PLWH.

Efficacy of Peritoneal Dialysis in Acute Kidney Injury in Neonates with Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia.

We aimed to evaluate the efficacy of peritoneal dialysis (PD) in hypoxic-ischemic acute kidney injury (AKI) in newborns with hypoxic-ischemic encephalopathy (HIE) who underwent therapeutic hypothermia (TH). This was a retrospective study including the newborns with HIE/TH who developed hypoxic-ischemic AKI and underwent PD between January 2022 and June 2024. The blood test results obtained before starting PD were compared with the blood test results obtained just before the decision to terminate PD or, in case of death, with the final blood test results obtained before death. Twenty-one newborns were included in the study. Four (19%) of these newborns were diagnosed with moderate HIE, and 17 (81%) were diagnosed with severe HIE. The median gestational age of the patients was 38 (36-39) weeks, and the mean birth weight was 3083 ± 494 g. The median postnatal day when PD started was 3 (2-4) days and its duration was 7 (4-10) days. All patients had fluid overload as an indication for PD dialysis, and fluid overload was accompanied by hyperkalemia in 8 (38.1%) patients. After PD, blood pH, bicarbonate, and sodium values increased significantly (p ≤ 0.001, 0.009, <0.001, respectively), and potassium, phosphorus, and creatinine values decreased significantly (p ≤ 0.001, <0.001, 0.031, respectively) compared with the predialysis values. PD corrects acidosis and electrolyte imbalance and may be considered as a successful renal replacement therapy for hypoxic-ischemic AKI in neonates with HIE/TH, especially in units with limited resources.

Revisiting substance P in migraine: a methodological approach inspired by anti-CGRP and anti-PACAP success

Substance P, previously dismissed as a therapeutic target for migraine due to the failure of neurokinin-1 receptor antagonists, warrants renewed attention. Building on the success of therapies targeting the calcitonin gene-related peptide (CGRP) system and pituitary adenylate cyclase-activating peptide (PACAP) in migraine prevention, which highlight the importance of targeting peptides, this proposal reexamines substance P as a mediator in migraine pathophysiology. Using an established methodological framework, migraine-inducing properties of substance P can be evaluated through randomized, double-blind, placebo-controlled crossover studies involving healthy volunteers and individuals with a history of migraine. This approach aims to establish proof of concept for substance P’s role in migraine, laying the groundwork for investigations with animal and cell-based models and advancing the development of innovative treatments for patients refractory to current therapies.

Development of medication reminder WhatsApp Bot application to improve medication adherence in pregnant women with hypertension

Background: Pregnant women's compliance with taking medication regularly is essential and supports the success of therapy. If pregnant women do not comply with taking medication, this can hurt the development of the disease and cause unexpected complications. Non-communicable diseases cause most cases of death in pregnant women. This is the basis for researchers to create a medication reminder system.Purpose: This research aims to develop a WhatsApp Bot application, WhatsApp Bot, that reminds users when to take medication. Method: This study employed Research and development, which consisted of four stages: Literature Study, Development Stage, Validity Expert, and Trial.Results: A system that health workers can use in primary health facilities to remind them when to take medication has been successfully created. Performance test of the medication reminder system with a high % accuracy rate of 98% (MAPE value 9.05%).Conclusion: This application is beneficial for pregnant women to remind them to take medication to increase compliance.

Long-term exposure therapy outcome in phobia and the link with behavioral and neural indices of extinction learning.

Extinction learning is regarded as a core mechanism underlying exposure therapy. Under this assumption, studies have looked at the predictive value of the extinction learning paradigm for exposure therapy outcomes. However, predicting factors of long-term exposure therapy success have not been established. Participants with a specific phobia (SP) for spiders were included in a double-blind randomized controlled trial. Participants were randomly assigned to receive exposure therapy (n=25, 24 females) or an active control intervention, progressive muscle relaxation (PMR; n=18, 15 females). Symptom levels were measured with the Fear of Spiders questionnaire (FSQ) at baseline (T0), after the intervention (T1), and at six- (T2) and twelve (T3) months follow-up. At baseline, participants completed a three-day fMRI fear conditioning, extinction learning, and extinction recall paradigm. Indices of extinction were defined as self-reported threat expectancy and fear, and neural activation during stimulus presentations and threat omission in the ventromedial prefrontal cortex and nucleus accumbens, based on prior data. Mixed model analysis revealed that the exposure therapy group had an overall stronger decrease in phobic symptoms over time than the PMR group (β=10.95, p<.001). However, none of the indices of extinction learning were predictive for FSQ scores after exposure therapy at the longest follow-up measurement (T3). In sum, the current results show the long-term effectiveness of a single session of exposure therapy for reducing a specific fear of spiders but no baseline characteristics were identified that predicted individual differences in exposure therapy success after one year.

A strain-based classification is associated with therapy success in cardiac resynchronization therapy-eligible patients

Abstract Introduction Echocardiography-derived septal strain patterns stages are associated with a stepwise increase in survival for each increment in strain stage among patients treated with cardiac resynchronization therapy (CRT). However, it is unknown whether the strain stages could also predict survival in conservatively-treated (i.e. not CRT-implanted) patients. Purpose This study aims to investigate the interplay between septal strain patterns and long-term survival in both CRT- and conservatively-treated patients. Methods In this multicentre study, CRT-eligible patients from six European centres underwent speckle-tracking strain analysis on echocardiography. CRT-treated patients (CRT) were enrolled prospectively and assessed prior to device implantation. Conservatively-treated patients (CON) were assessed retrospectively. Dyssynchrony was graded through analysis of septal strain curves, categorizing patients into five distinct patterns, denoted as strain Stage-0 (no dyssynchrony) through strain Stage-4 (severe dyssynchrony) (Fig. A). The study endpoint was all-cause mortality. Results A total of 267 CRT patients (69% males, 89% left bundle branch block (LBBB) and QRS 166±20 ms) and 167 CON patients (69% males, 87% LBBB, QRS 155±25 ms) were included. Median follow-up time was 49 (40-57) months. CON patients within the highest strain stages had the worst outcome, whereas CRT-treated patients within the highest strain stages had the best survival (Fig. B). A stepwise increase in survival difference was observed between CRT and CON patients for each increment in strain stage (Fig. B-F). Hazard ratios (HR) were: Stage-0: 1.42 (95% CI: 0.59-3.44, p=0.436) / Stage-1: 2.63 (95% CI: 1.19-5.82, p=0.017) / Stage-2: 3.93 (95% CI: 1.20-12.83, p=0.024) / Stage-3: 5.74 (95% CI: 1.72-19.19, p=0.005) and Stage-4: 16.49 (95% CI: 4.84-56.21, p&amp;lt;0.001). Conclusions The strain stages demonstrated a strong survival benefit for CRT-treated compared to conservatively-treated, but CRT-eligible patients. Patients with more severe dyssynchrony (highest strain stages) have most benefit from CRT implantation. These findings underscore the potential value of the strain stages in refining risk stratification and patient selection of CRT.

P-1113. Treatment Patterns and Clinical Outcomes in Hospitalized Patients with Febrile Neutropenia treated with Ceftolozane/Tazobactam: A Subgroup Analysis of the SPECTRA study

Abstract Background This sub-group analysis of the Study of Prescribing Patterns and Effectiveness of Ceftolozane/Tazobactam(C/T) Real-world Analysis (SPECTRA) described treatment patterns and outcomes in hospitalized patients with Febrile Neutropenia (FN).Table 1.Treatment patterns of Febrile Neutropenia by C/T and C/T Treatment duration and All-Cause In-Hospital Mortality (ACHM)Abbreviations: CRI= Chronic Respiratory Infection cIAI= Complicated Intra-abdominal Infection cUTI= Complicated Urinary Tract Infection (1) For patients aged 90 or older the HCP was asked not to enter the exact age and to check a specific box. Therefore, patients aged 90 or older are included in 'Missing' and are not taken into account in the calculation of mean, median, etc. (2) Several indications may have been reported for the same patient. (3) A patient is counted once for each single indication or combination of indications. Methods SPECTRA was a multicenter, observational study, in hospitalized adult patients treated with C/T for ≥48 hours in 7 countries (n=617). Medical records were extracted, covering 6 months prior to the index date, up to 30 days after the last dose of C/T or until death. Descriptive statistics were reported here on treatment patterns, all-cause in-hospital mortality (ACHM), clinical success and microbiologic response in cases of Febrile Neutropenia (FN, n=38).Table 2.Clinical Success, Microbiologic Response, and Duration of GN antibacterial therapy (days) between Neutropenic and non-Neutropenic patients1Analysis includes only those with known status for clinical success, and only those with known status for microbiological response. Responses of 'Unknown' are considered as missing data. Microbiological response was defined as negative culture result at site of index infection with same organism post C/T administration. Results The median duration of C/T treatment was 8 days, median time from index hospitalization admission to C/T initiation was 18 days, and from the first microbiological sample to C/T initiation 3.5 days (Table 1). ACHM was 9.2% (n=12). Clinical success was 69.4% (n=25) (Table 2). 63% of the patients (n=24) received suboptimal doses for treatment. MDR Pseudomonas aeruginosa and, ESBL-producing Enterobacterales were isolated in 15 and 4 patients, respectively. One had a clinical diagnosis of both pneumonia and sepsis, 2 patients with pneumonia, 4 with respiratory related infections, 1 with skin infection, 3 with sepsis, 1 with cIAI, and 2 with cUTI, in addition to FN. Microbiologic response was achieved for 30.6% of the patients, who received a median of 17 days of GN antibacterial therapy.Table 3Appropriate* Dose of C/T by Indication for Index Event*If the dose received was different (lower or higher) from the appropriate dose as defined, then the patient was considered as not having received the appropriate dose. If the dose received was different (lower or higher) from the appropriate dose on the first day but was then adjusted to the appropriate dose, then the patient was considered as having received the appropriate dose. For patients having both respiratory and non-respiratory infection, the appropriate dose for respiratory infection (=the highest dose) was considered as the appropriate dose for the patient. Conclusion These findings demonstrate potential new findings for the treatment of febrile neutropenia. However, further research is needed to explore its full potential and optimize dosing strategies for improved outcomes. Disclosures Yanbing Zhou, PhD, Merck: I am a full time Merck Employee and own stocks in the retirement plan provided by Merck.|Merck: Stocks/Bonds (Public Company) David Paterson, bioMerieux: Grant/Research Support|bioMerieux: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Grant/Research Support|Shionogi: Honoraria Florian Thalhammer, MD, MSD: Advisor/Consultant Stefan Kluge, Prof. Dr. med., Merck &amp; Co: Advisor/Consultant|Merck &amp; Co: Board Member Mike Allen, PhD, Merck: I am a full time Merck Employee and own stocks in the retirement plan provided by Merck.|Merck: Stocks/Bonds (Public Company) Brune Akrich, MD, Merck: I am a full time Merck Employee and own stocks in the retirement plan provided by Merck.|Merck: Stocks/Bonds (Public Company) Emre Yucel, PhD, Merck: I am a full time Merck Employee and own stocks in the retirement plan provided by Merck.|Merck: Stocks/Bonds (Public Company)