Combination of Tramiprosate, Curcumin, and SP600125 Reduces the Neuropathological Phenotype in Familial Alzheimer Disease PSEN1 I416T Cholinergic-like Neurons.

Familial Alzheimer's disease (FAD) is a complex and multifactorial neurodegenerative disorder for which no curative therapies are yet available. Indeed, no single medication or intervention has proven fully effective thus far. Therefore, the combination of multitarget agents has been appealing as a potential therapeutic approach against FAD. Here, we investigated the potential of combining tramiprosate (TM), curcumin (CU), and the JNK inhibitor SP600125 (SP) as a treatment for FAD. The study analyzed the individual and combined effects of these two natural agents and this pharmacological inhibitor on the accumulation of intracellular amyloid beta iAß; hyperphosphorylated protein TAU at Ser202/Thr205; mitochondrial membrane potential (ΔΨm); generation of reactive oxygen species (ROS); oxidized protein DJ-1; proapoptosis proteins p-c-JUN at Ser63/Ser73, TP53, and cleaved caspase 3 (CC3); and deficiency in acetylcholine (ACh)-induced transient Ca2+ influx response in cholinergic-like neurons (ChLNs) bearing the mutation I416T in presenilin 1 (PSEN1 I416T). We found that single doses of TM (50 µM), CU (10 µM), or SP (1 µM) were efficient at reducing some, but not all, pathological markers in PSEN 1 I416T ChLNs, whereas a combination of TM, CU, and SP at a high (50, 10, 1 µM) concentration was efficient in diminishing the iAß, p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 markers by -50%, -75%, -86%, and -100%, respectively, in PSEN1 I417T ChLNs. Although combinations at middle (10, 2, 0.2) and low (5, 1, 0.1) concentrations significantly diminished p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 by -69% and -38%, -100% and -62%, -100% and -62%, respectively, these combinations did not alter the iAß compared to untreated mutant ChLNs. Moreover, a combination of reagents at H concentration was able to restore the dysfunctional ACh-induced Ca2+ influx response in PSEN 1 I416T. Our data suggest that the use of multitarget agents in combination with anti-amyloid (TM, CU), antioxidant (e.g., CU), and antiapoptotic (TM, CU, SP) actions might be beneficial for reducing iAß-induced ChLN damage in FAD.

Psychosocial and medication interventions to stop or reduce alcohol consumption during pregnancy.

BACKGROUND: Despite the known harms, alcohol consumption is common in pregnancy. Rates vary between countries, and are estimated to be 10% globally, with up to 25% in Europe. OBJECTIVES: To assess the efficacy of psychosocial interventions and medications to reduce or stop alcohol consumption during pregnancy. SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Group Specialised Register (via CRSLive), Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, Web of Science, and PsycINFO, from inception to 8 January 2024. We also searched for ongoing and unpublished studies via ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). All searches included non-English language literature. We handsearched references of topic-related systematic reviews and included studies. SELECTION CRITERIA: We included randomised controlled trials that compared medications or psychosocial interventions, or both, to placebo, no intervention, usual care, or other medications or psychosocial interventions used to reduce or stop alcohol use during pregnancy. Our primary outcomes of interest were abstinence from alcohol, reduction in alcohol consumption, retention in treatment, and women with any adverse event. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: We included eight studies (1369 participants) in which pregnant women received an intervention to stop or reduce alcohol use during pregnancy. In one study, almost half of participants had a current diagnosis of alcohol use disorder (AUD); in another study, 40% of participants had a lifetime diagnosis of AUD. Six studies took place in the USA, one in Spain, and one in the Netherlands. All included studies evaluated the efficacy of psychosocial interventions; we did not find any study that evaluated the efficacy of medications for the treatment of AUD during pregnancy. Psychosocial interventions were mainly brief interventions ranging from a single session of 10 to 60 minutes to five sessions of 10 minutes each. Pregnant women received the psychosocial intervention approximately at the end of the first trimester of pregnancy, and the outcome of alcohol use was reassessed 8 to 24 weeks after the psychosocial intervention. Women in the control group received treatment as usual (TAU) or similar treatments such as comprehensive assessment of alcohol use and advice to stop drinking during pregnancy. Globally, we found that, compared to TAU, psychosocial interventions may increase the rate of continuously abstinent participants (risk ratio (RR) 1.34, 95% confidence interval (CI) 1.14 to 1.57; I2 =0%; 3 studies; 378 women; low certainty evidence). Psychosocial interventions may have little to no effect on the number of drinks per day, but the evidence is very uncertain (mean difference -0.42, 95% CI -1.13 to 0.28; I2 = 86%; 2 studies; 157 women; very low certainty evidence). Psychosocial interventions probably have little to no effect on the number of women who completed treatment (RR 0.98, 95% CI 0.94 to 1.02; I2 = 0%; 7 studies; 1283 women; moderate certainty evidence). None of the included studies assessed adverse events of treatments. We downgraded the certainty of the evidence due to risk of bias and imprecision of the estimates. AUTHORS' CONCLUSIONS: Brief psychosocial interventions may increase the rate of continuous abstinence among pregnant women who report alcohol use during pregnancy. Further studies should be conducted to investigate the efficacy and safety of psychosocial interventions and other treatments (e.g. medications) for women with AUD. These studies should provide detailed information on alcohol use before and during pregnancy using consistent measures such as the number of drinks per drinking day. When heterogeneous populations are recruited, more detailed information on alcohol use during pregnancy should be provided to allow future systematic reviews to be conducted. Other important information that would enhance the usefulness of these studies would be the presence of other comorbid conditions such as anxiety, mood disorders, and the use of other psychoactive substances.

Electrochemical Behavior of Janus Kinase Inhibitor Ruxolitinib at a Taurine-Electropolymerized Carbon Paste Electrode: Insights into Sensing Mechanisms.

Ruxolitinib (RXL) is a Janus kinase inhibitor used for treating intermediate- or high-risk myelofibrosis. This study presents an electrode modified with electrochemically polymerized taurine on a carbon paste electrode via cyclic voltammetry (CV). The surface characterization of the poly(taurine)-CP electrode was evaluated by using electrochemical (electrochemical impedance spectroscopy─EIS, CV), morphological (scanning electron microscope─SEM), and spectroscopic (Fourier-transform infrared spectroscopy─FT-IR) techniques. Under optimized conditions, RXL exhibited good linearity within the 0.01-1.0 µM concentration range, with a limit of detection (LOD) of 0.005 µM. The proposed electrochemical sensor demonstrated excellent selectivity, accuracy, precision, and repeatability. Furthermore, it effectively detected RXL in human urine and pharmaceutical samples.

Disentangling the formation, mechanism, and evolvement of the covalent methanesulfonyl fluoride acetylcholinesterase adduct: Insights into an aged-like inactive complex susceptible to reactivation by a combination of nucleophiles.

Chemical warfare nerve agents and pesticides, known as organophosphorus compounds inactivate cholinesterases (ChEs) by phosphorylating the serine hydroxyl group located at the active site of ChEs. Over the course of time, phosphorylation is followed by loss of an organophosphate-leaving group and the bond with ChEs becomes irreversible, a process known as aging. Differently, structurally related irreversible catalytic poisons bearing sulfur instead of phosphorus convert ChEs in its aged form only by covalently binding to the key catalytic serine. Kinetic and crystallographic studies of the interaction between Torpedo californica acetylcholinesterase (TcAChE) and a small organosulfonate, methanesulfonyl fluoride (MSF), indeed revealed irreversibly methylsulfonylated serine 200, to be isosteric with the bound aged sarin/soman analogues. The potent bulky reversible inhibitor 7-bis-tacrine (BTA) adopts, in the active site of the crystal structure of the MSF-enzyme adduct, a location and an orientation that closely resemble the one being found in the crystal structure of the BTA-enzyme complex. Remarkably, the presence of BTA accelerates the rate of methanesulfonylation by a factor of two. This unexpected result can be explained on the basis of two facts: i) the steric hindrance exerted by BTA to MSF in accessing the active site and ii) the acceleration of the MSF-enzyme adduct formation as a consequence of the lowering of the rotational and translational degrees of freedom in the proximity of the catalytic serine. It is well known that pralidoxime (2-Pyridine Aldoxime Methyl chloride, 2-PAM) alone or in the presence of the substrate acetylcholine cannot reactivate the active site serine of the TcAChE-MSF adduct. We show that the simultaneous presence of 2-PAM and the additional neutral oxime, 2-[(hydroxyimino)methyl]-l-methylimidazol (2-HAM), triggers the reactivation process of TcAChE within the hour timescale. Overall, our results pave the way toward the likely use of a cocktail of distinctive oximes as a promising recipe for an effective and fast reactivation of aged cholinesterases.

Catheter salvage or removal in catheter-related bloodstream infections with Staphylococcus aureus in children with chronic intestinal failure receiving home parenteral nutrition and the use of prophylactic taurolidine catheter lock solution: A descriptive cohort study.

BACKGROUND: Children with chronic IF require long-term home parenteral nutrition (HPN), administered through a central venous catheter. Catheter-related bloodstream infection (CRBSI) with Staphylococcus aureus is known to be a serious infection with a high mortality rate and risk of complications. A standardized protocol on the management of S aureus CRBSIs in children receiving HPN is lacking. The aim of this study is to evaluate the effectiveness and safety of the current management in an HPN expertise center in the Netherlands. METHODS: We performed a retrospective descriptive cohort study between 2013 and 2022 on children 0-18 years of age with chronic IF requiring long-term HPN. Our primary outcomes were the incidence of S aureus CRBSI per 1000 catheter days, catheter salvage attempt rate, and successful catheter salvage rate. Our secondary outcomes included complications and mortality. RESULTS: A total of 74 patients (39 male; 53%) were included, covering 327.8 catheter years. Twenty-eight patients (38%) had a total of 52 S aureus CRBSIs, with an incidence rate of 0.4 per 1000 catheter days. The catheter salvage attempt rate was 44% (23/52). The successful catheter salvage rate was 100%. No relapse occurred, and no removal was needed after catheter salvage. All complications that occurred were already present at admission before the decision to remove the catheter or not. No patients died because of an S aureus CRBSI. CONCLUSION: Catheter salvage in S aureus CRBSIs in children receiving HPN can be attempted after careful consideration by a multidisciplinary team in an HPN expertise center.

A-series agent A-234: initial in vitro and in vivo characterization.

A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 µM and HssBChE IC50 = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.

Uptake of community health care provision by community health entrepreneurs for febrile illness and diarrhoea: a cross-sectional survey in rural communities in Bunyangabu district, Uganda.

OBJECTIVE: To assess the uptake of services provided by community health workers who were trained as community health entrepreneurs (CHEs) for febrile illness and diarrhoea. DESIGN: A cross-sectional survey among households combined with mapping of all providers of basic medicine and primary health services in the study area. PARTICIPANTS: 1265 randomly selected households in 15 rural villages with active CHEs. SETTING: Bunyangabu district, Uganda. OUTCOME MEASURES: We describe the occurrence and care sought for fever and diarrhoea in the last 3 months by age group in the households. Care provider options included: CHE, health centre or clinic (public or private), pharmacy, drug shop and other. Geographic Information Ssystem (GIS)-based geographical measures were used to map all care providers around the active CHEs. RESULTS: Fever and diarrhoea in the last 3 months occurred most frequently in children under 5; 68% and 41.9%, respectively. For those who sought care, CHE services were used for fever among children under 5, children 5-17 and adults over 18 years of age in 34.7%, 29.9% and 25.1%, respectively. For diarrhoea among children under 5, children 5-17 and adults over 18 years of age, CHE services were used in 22.1%, 19.5% and 7.0%, respectively. For those who did not seek care from a CHE (only), drug shops were most frequently used services for both fever and diarrhoea, followed by health centres or private clinics. Many households used a combination of services, which was possible given the high density and diversity of providers found in the study area. CONCLUSIONS: CHEs play a considerable role in providing care in rural areas where they are active. The high density of informal drug shops and private clinics highlights the need for clarity on the de facto roles played by different providers in both the public and private sector to improve primary healthcare.

[Mechanism of acteoside in prevention and treatment of gouty arthritis based on liver metabolomics].

This study aims to reveal the effect of acteoside on gouty arthritis(GA) in rats based on liver metabolomics. The ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed to search for the potential biomarkers and metabolic pathways. SD rats were randomly assigned into blank, model, colchicine(0.3 mg·kg~(-1)), and high-, medium-, low-dose(200, 100, and 50 mg·kg~(-1), respectively) acteoside groups(n=7). The rats were administrated once a day for 7 continuous days. Monosodium urate(MSU) was used to induce GA model in rats during administration. The degree of joint swelling and pathological changes of synovial tissue in rats were observed, and the levels of interleukin(IL)-1ß, IL-18 and tumor necrosis factor(TNF)-α in the synovial tissue of rats were measured. UPLC-Q-TOF-MS was employed to collect rat liver data, and Progenesis QI and EZ info were used for data analysis. Human Metabolomics Database(HMDB) and Kyoto Encyclopedia of Genes and Genomes(KEGG) were employed to predict the potential biomarkers and metabolic pathways. The results showed that acteoside alleviated joint swelling, reduced synovial tissue damage, and lowered the levels of inflammatory cytokines in GA rats. A total of 19 common biomarkers were identified, 17 of which can be regulated by acteoside. Seven metabolic pathways were enriched, such as glycerophospholipid metabolism, linoleic acid metabolism, and taurine and hypotaurine metabolism, among which glycerophospholipid metabolism was strongly disturbed. The metabolomics analysis suggested that acteoside may down-regulate the expression of inflammatory cytokines and alleviate the symptoms of GA rats by regulating glycerophospholipid metabolism, linoleic acid metabolism, and taurine and hypotaurine metabolism. The findings provide a reference for future research and development of acteoside.

Involvement of GAT2/Slc6a13 in hypotaurine uptake at fetal-facing plasma membrane of syncytiotrophoblasts at mid-to-late gestation in rats and mice.

INTRODUCTION: Hypotaurine, a precursor to taurine, is known for its antioxidant properties and is prominently present in fetal plasma and the placenta. Our previous research revealed that ezrin-knockout mice experience fetal growth retardation, coinciding with reduced hypotaurine levels in fetal plasma. This study aims to elucidate the expression and role of hypotaurine transporters within the placenta. METHODS: We employed quantitative RT-PCR to measure mRNA expression of GAT transporter family members in the placenta during mid-to-late gestation. LC/MS/MS was used to analyze the distribution of hypotaurine in different placental subregions. Immunohistochemistry was utilized to examine the localization of GAT2 in mice. Placental hypotaurine uptake from fetal circulation was studied via umbilical perfusion in rats. RESULTS: Among hypotaurine transporters, GAT2 exhibited increased mRNA and protein expression in murine placenta during mid-to-late gestation. Notably, GAT2/Slc6a13 mRNA and hypotaurine were most concentrated in the labyrinth of murine placenta. In contrast, enzymes responsible for hypotaurine synthesis, such as cysteine dioxygenase, cysteine sulfinic acid decarboxylase, and 2-aminoethanethiol dioxygenase, showed minimal expression in the labyrinth. These findings suggest that GAT2 is a key determinant of hypotaurine levels in the placental labyrinth. Immunohistochemical examination unveiled that GAT2 was predominantly localized on the fetal-facing plasma membrane within syncytiotrophoblasts, which co-localized with ezrin. In rat umbilical perfusion experiments, the GAT2/3 and TauT inhibitor, SNAP-5114, significantly reduced hypotaurine extraction from fetal circulation to the placenta. DISCUSSION: The results suggest that GAT2 plays a pivotal role in the concentrative uptake of hypotaurine from fetal plasma within syncytiotrophoblasts of the placenta.

Serum Carbohydrate Antigen 19-9 and Metabolite Hypotaurine Are Predictive Markers for Early Recurrence of Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: A significant number of patients experience early recurrence after surgical resection for pancreatic ductal adenocarcinoma (PDAC), negating the benefit of surgery. The present study conducted clinicopathologic and metabolomic analyses to explore the factors associated with the early recurrence of PDAC. MATERIALS AND METHODS: Patients who underwent pancreatectomy for PDAC at Kagawa University Hospital between 2011 and 2020 were enrolled. Tissue samples of PDAC and nonneoplastic pancreas were collected and frozen immediately after resection. Charged metabolites were quantified by capillary electrophoresis-mass spectrometry. Patients who relapsed within 1 year were defined as the early recurrence group. RESULTS: Frozen tumor tissue and nonneoplastic pancreas were collected from 79 patients. The clinicopathologic analysis identified 11 predictive factors, including preoperative carbohydrate antigen 19-9 levels. The metabolomic analysis revealed that only hypotaurine was a significant risk factor for early recurrence. A multivariate analysis, including clinical and metabolic factors, showed that carbohydrate antigen 19-9 and hypotaurine were independent risk factors for early recurrence ( P = 0.045 and P = 0.049, respectively). The recurrence-free survival rate 1 year after surgery with both risk factors was only 25%. CONCLUSIONS: Our results suggested that tumor hypotaurine is a potential metabolite associated with early recurrence. Carbohydrate antigen 19-9 and hypotaurine showed a vital utility for predicting early recurrence.

Limited exposure to pancreatic ERCP during advanced endoscopy training impacts competence and performance in independent practice.

BACKGROUND/OBJECTIVES: The impact of competency-based training programs on pancreatic endoscopic retrograde cholangiopancreatography (ERCP) performance remains unclear. This study aimed to describe the learning curves of pancreatic ERCP and subsequent performance during independent practice. METHODS: This was a multicenter prospective cohort study involving advanced endoscopy trainees (AETs). In the 1st phase, trainees were assessed on every 5th ERCP using the ERCP and EUS Skills Assessment Tool (TEESAT). Cumulative sum (CUSUM) analysis of pancreatic ERCP evaluations was used to establish learning curves. During the 2nd phase (1st year of independent practice), now-graduated participants documented their performance on key ERCP quality indicators. RESULTS: A total of 24 AETs (20 training programs) received sufficient evaluations for CUSUM analysis. Pancreatic ERCP accounted for 14.6 % (196/1339) of all ERCPs evaluated with 45 % of pancreatic ERCPs carrying a Grade 3 level of complexity. A minority of AETs (16.7 %) performed enough pancreatic ERCPs to generate meaningful learning curves with no AETs achieving competence in pancreatic cannulation, sphincterotomy, or stone clearance during Phase 1. In Phase 2, a total of 3620 ERCPs were performed, of which 281 (7.8 %) were pancreatic ERCPs. While the overall pancreatic duct cannulation rate was 92.2 %, the native papilla pancreatic duct cannulation rate was 85.7 %, which was below the recommended 90 % threshold. CONCLUSIONS: Advanced endoscopy training offers a low level of exposure to pancreatic ERCP, which is mirrored in independent practice, highlighting the inadequate training in pancreatic ERCP. Given the complexity of pancreatic ERCP, novel strategies are warranted to improve training in pancreatic ERCP.

In vitro and in vivo Biological Evaluation of Newly Tacrine-Selegiline Hybrids as Multi-Target Inhibitors of Cholinesterases and Monoamine Oxidases for Alzheimer's Disease.

Purpose: Alzheimer's disease (AD) is the most common neurodegenerative disease, and its multifactorial nature increases the difficulty of medical research. To explore an effective treatment for AD, a series of novel tacrine-selegiline hybrids with ChEs and MAOs inhibitory activities were designed and synthesized as multifunctional drugs. Methods: All designed compounds were evaluated in vitro for their inhibition of cholinesterases (AChE/BuChE) and monoamine oxidases (MAO-A/B) along with their blood-brain barrier permeability. Then, further biological activities of the optimizing compound 7d were determined, including molecular model analysis, in vitro cytotoxicity, acute toxicity studies in vivo, and pharmacokinetic and pharmacodynamic property studies in vivo. Results: Most synthesized compounds demonstrated potent inhibitory activity against ChEs/MAOs. Particularly, compound 7d exhibited good and well-balanced activity against ChEs (hAChE: IC50 = 1.57 µM, hBuChE: IC50 = 0.43 µM) and MAOs (hMAO-A: IC50 = 2.30 µM, hMAO-B: IC50 = 4.75 µM). Molecular modeling analysis demonstrated that 7d could interact simultaneously with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE in a mixed-type manner and also exhibits binding affinity towards BuChE and MAO-B. Additionally, 7d displayed excellent permeability of the blood-brain barrier, and under the experimental conditions, it elicited low or no toxicity toward PC12 and BV-2 cells. Furthermore, 7d was not acutely toxic in mice at doses up to 2500 mg/kg and could improve the cognitive function of mice with scopolamine-induced memory impairment. Lastly, 7d possessed well pharmacokinetic characteristics. Conclusion: In light of these results, it is clear that 7d could potentially serve as a promising multi-functional drug for the treatment of AD.

The identification of a correlation between lipid content in the model diatom Phaeodactylum tricornutum and pH treatment strategies.

pH treatment promotes single-cell lipid accumulation and significantly affects microalgae growth. This study investigates the correlation between lipid content and environmental pH using the model diatom Phaeodactylum tricornutum (P. tricornutum). We compared three distinct pH treatment strategies-continuous, intermittent, and a two-phase culture-in P. tricornutum. Rigorous analysis of chlorophyll content, cell density, and lipid content indicated that ongoing pH treatment at pH 9.5 (CHES) emerged as the most effective approach for lipid accumulation in P. tricornutum. The CHES buffer treatment significantly boosted total lipid yield and led to a reduction in protein content. Carbohydrate content experienced a slight decline under CHES buffer treatment, but changes were observed in the activities of key enzymes. Specifically, [acyl-carrier-protein] S-malonyltransferase (MAT) activity decreased after 3 days in the control treatment, while no significant change was noted under the CHES buffer treatment. In contrast, diacylglycerol O-acyltransferase (DGAT) activity showed upregulation 2 and 3 days post-CHES buffer treatment. Moreover, the study identified differentially expressed genes enriched in Gene Ontology (GO) terms associated with protein biosynthesis, photosynthesis, nucleoside metabolism, and transferase activity. These outcomes underscore the pivotal role of CHES buffer in orchestrating primary metabolism, potentially steering carbon flux towards lipogenesis. As a result, the potential of microalgae as a sustainable source of biofuels contributes significantly to the transition towards a more environmentally friendly energy landscape.

Cost-effectiveness of taurolidine-citrate in a cohort of patients with intestinal failure receiving home parenteral nutrition.

BACKGROUND: Catheter-related bloodstream infections (CRBSIs) in patients receiving home parenteral nutrition (HPN) for chronic intestinal failure (CIF) are associated with significant morbidity and financial costs. Taurolidine is associated with a reduction in bloodstream infections, with limited information on the cost-effectiveness as the primary prevention. This study aimed to determine the cost-effectiveness of using taurolidine-citrate for the primary prevention of CRBSIs within a quaternary hospital. METHODS: All patients with CIF receiving HPN were identified between January 2015 and November 2022. Data were retrospectively collected regarding patient demographics, HPN use, CRBSI diagnosis, and use of taurolidine-citrate. The direct costs associated with CRBSI-associated admissions and taurolidine-citrate use were obtained from the coding department using a bottom-up approach. An incremental cost-effective analysis was performed, with a time horizon of 4 years, to compare the costs associated with primary and secondary prevention against the outcome of cost per infection avoided. RESULTS: Forty-four patients received HPN within this period. The CRBSI rates were 3.25 infections per 1000 catheter days before the use of taurolidine-citrate and 0.35 infections per 1000 catheter days after taurolidine-citrate use. The incremental cost-effectiveness ratio indicates primary prevention is the weakly dominant intervention, with the base case value of $27.04 per CRBSI avoided. This held with one-way sensitivity analysis. CONCLUSION: Taurolidine-citrate in the primary prevention of CRBSIs in patients with CIF receiving HPN is associated with reduced hospital costs and infection rates.

Use of 2% taurolidine lock solution for treatment and prevention of catheter-related bloodstream infections in neonates: a feasibility study.

BACKGROUND: Taurolidine lock, a technique used to prevent or treat catheter-related bloodstream infection (CRBSI), is effective in adult and paediatric patients but has been described rarely in neonates. The aim of this descriptive retrospective study, was to determine the feasibility and direct outcomes of prophylactic and therapeutic taurolidine locks in term and preterm neonates. METHODS: We implemented the use of therapeutic taurolidine lock in addition to antibiotic treatment with the aim of catheter salvage in critical neonates with difficult vascular access (group 1). In addition, we introduced taurolidine lock as a preventive measure in neonates with a central venous catheter (CVC) at high risk of developing CRBSI (group 2). Every 24 h (in the treatment group) a 2% taurolidine solution was injected and the catheter locked for at least 120 min, until infection clearance (group 1). In the preventive group, the catheter was locked for 30 min every 48 h until CVC removal (group 2). FINDINGS: Thirty-seven neonates who received taurolidine were included in this study. We did not observe any major adverse events. In group 1 (21 cases), clinical symptom disappearance and bacteraemia clearance were achieved without catheter removal in 18 cases (85.7%); in the other three neonates the catheter was removed shortly after the start of the locks as it was possible to replace the CVC. In group 2 (16 neonates), no CRBSI was observed during the duration of the catheter placement. CONCLUSIONS: In this retrospective study, taurolidine was successfully used in neonates both for prevention and treatment of CRBSI, without major undesired effects. A larger cohort and a randomized clinical trial is warranted in order to establish its efficacy and safety in neonates.

Adverse childhood experiences and global mental health: avenues to reduce the burden of child and adolescent mental disorders.

Mental disorders are one of the largest contributors to the burden of disease globally, this holds also for children and adolescents, especially in low- and middle-income countries. The prevalence and severity of these disorders are influenced by social determinants, including exposure to adversity. When occurring early in life, these latter events are referred to as adverse childhood experiences (ACEs).In this editorial, we provide an overview of the literature on the role of ACEs as social determinants of mental health through the lenses of global mental health. While the relation between ACEs and mental health has been extensively explored, most research was centred in higher income contexts. We argue that findings from the realm of global mental health should be integrated into that of ACEs, e.g. through preventative and responsive psychosocial interventions for children, adolescents and their caregivers. The field of global mental health should also undertake active efforts to better address ACEs in its initiatives, all with the goal of reducing the burden of mental disorders among children and adolescents globally.

Taurolidine-related adverse events in patients on home parenteral nutrition frequently indicate catheter-related problems.

BACKGROUND & AIMS: A catheter-related bloodstream infection (CRBSI) is a serious complication of home parenteral nutrition (HPN) treatment. Despite taurolidine's frequent use as catheter lock solution (CLS) to prevent CRBSIs and its presumed favourable safety profile, data on taurolidine-related adverse events (AEs) and the clinical implications thereof remain merely anecdotal. Aim of this study was to explore taurolidine-related AEs in our large cohort of HPN patients and to develop an algorithm on how to deal with these AEs in clinical practice. METHODS: This retrospective cohort study comprised all adult HPN patients who used taurolidine as a CLS between 2006 and 2021 at our national HPN referral centre. Primary outcome was to identify taurolidine-related AEs. Secondary outcomes were median time to a taurolidine-related AEs and development of a clinical algorithm. A taurolidine-related AE was defined as an event that occurred directly after instillation of taurolidine in the CVAD or at start of fluid/PN infusion. RESULTS: In total, 470 patients used taurolidine during 700.232 catheter days. In 89 (19%) patients, 103 mild- to severe AEs related to taurolidine were observed. Six patients developed an allergic reaction. Reported AEs compromised vascular access device-related problems (group A) or taurolidine-related problems (group B) in 53 (51%) and 50 (49%), patients, respectively. In groups A and B, 51 (85%) and 21 (18%) patients presented with taurolidine infusion-related pain. Upon rechallenge, 45 (85%) and 16 (32%) patients, respectively, successfully resumed taurolidine locking without residual symptoms. CONCLUSION: In this study, use of taurolidine as CLS was generally safe. Most reported AEs were vascular access device-related, and the majority of symptoms concerned pain. Upon rechallenge, a substantial number of patients, especially those in whom pain was the main symptom, could resume CLS locking after addressing the underlying catheter-related problem. Based on these results, we present a clinical algorithm for patients with possible taurolidine-related symptoms.

The Antiseptic and Antineoplastic Agent Taurolidine Modulates Key Leukocyte Functions.

BACKGROUND/AIM: Although taurolidine is known to exert a wide spectrum of biological actions, its effects on immune cells have not been characterized in detail. In this study, we investigated the ex vivo effects of taurolidine on relevant innate and adaptive immune cell functions. MATERIALS AND METHODS: Leukocyte functions in whole blood were assessed following treatment with various taurolidine concentrations. Viability of peripheral blood mononuclear cells (PBMCs) and granulocytes was measured using the WST-1 assay. PBMC function was assessed by measuring TNFα and IFNγ production after stimulation with lipopolysaccharide (LPS) or Candida, respectively. Reactive oxygen species (ROS) production by granulocytes was measured in whole blood using luminol-enhanced chemiluminescence. Granulocyte degranulation and activation were evaluated by membrane expression of degranulation (CD63, CD66B) and adhesion markers (CD62L, CD11b) using immunofluorescent staining followed by flow-cytometric analysis. RESULTS: Taurolidine decreased viability of PBMCs and granulocytes: after 2 h, IC50 concentrations were 500 and 520 µg/ml, respectively. Following prolonged exposure (≥24 h) of PBMCs, the IC50 concentrations declined to 40 µg/ml. PBMC cytokine production significantly decreased at taurolidine concentrations below the cytotoxic threshold, whereas no changes in ROS production were observed. The expression of all granulocyte adhesion and degranulation markers increased at concentrations higher than 500 µg/ml (the cytotoxic level of taurolidine). CONCLUSION: Taurolidine exhibits a dose- and time-dependent cytotoxicity toward PBMCs and granulocytes. The effects on PBMCs, as exemplified by a decrease in cytokine production, occurred below the toxic threshold, whereas granulocyte function (ROS production) remained unchanged at these taurolidine concentrations. Granulocyte activation and degranulation markers only increased at cytotoxic taurolidine concentrations.

Screening for adverse childhood experiences in antenatal care settings: A scoping review.

BACKGROUND: Adverse childhood experiences (ACEs) are associated with many health problems in women during pregnancy, including depression/anxiety, gestational diabetes and adverse birth outcomes. However, unlike other health risk factors, screening for ACEs has not been widely implemented in antenatal care settings. AIMS: The aim of the scoping review was to explore the challenges in screening for ACEs in antenatal care settings and to provide the lessons learnt and evidence that guide the practice of ACE screening for both healthcare providers and pregnant women. METHODS: A five-stage process for conducting the scoping review was utilised. Searches of four key databases (PubMed, PsycINFO, CINAHL and SCOPUS) and reference lists from relevant studies were conducted. RESULTS: Seven publications met the inclusion criteria. Challenges identified for healthcare providers in screening for ACEs include lack of knowledge and confidence in ACE tool and shortage of time and resources to undertake screening. Impediments for pregnant women include concerns about privacy. However, there were examples of effective practice for ACE screening in antenatal care settings that could apply widely. CONCLUSION: Addressing impediments to ACE screening is critical in implementing trauma-informed practices that can identify women at risk of adverse health outcomes during pregnancy. A study on screening for ACEs in antenatal care in both public and private settings is needed to examine its feasibility and acceptability in the Australian context before being included in the National Perinatal Data Collection.