PRMT5-mediated histone arginine methylation antagonizes transcriptional repression by polycomb complex PRC2.

Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks that are generally associated with transcriptional repression. However, we found that PRMT5 inhibition or depletion led to more genes being downregulated than upregulated, indicating that PRMT5 can also act as a transcriptional activator. Indeed, the global level of histone H3K27me3 increases in PRMT5 deficient cells. Although PRMT5 does not directly affect PRC2 enzymatic activity, methylation of histone H3 by PRMT5 abrogates its subsequent methylation by PRC2. Treating AML cells with an EZH2 inhibitor partially restored the expression of approximately 50% of the genes that are initially downregulated by PRMT5 inhibition, suggesting that the increased H3K27me3 could directly or indirectly contribute to the transcription repression of these genes. Indeed, ChIP-sequencing analysis confirmed an increase in the H3K27me3 level at the promoter region of a quarter of these genes in PRMT5-inhibited cells. Interestingly, the anti-proliferative effect of PRMT5 inhibition was also partially rescued by treatment with an EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects.

Involving Persons With Lived Experience to Improve Vocational Students' Stigmatizing Attitudes Toward Mental Disorders: A Quasi-Experimental Study.

BACKGROUND: Mental health problems are estimated to affect one in six individuals in the European Union. Fifty percent of mental disorders start in adolescence, around the age of 14. The stigma associated with having a mental health problem is one of the main barriers to seeking help for psychiatric and psychological disorders among adolescents and young adults. Interventions to reduce social stigma could contribute to increased help-seeking behavior in this population. AIMS: To assess the effectiveness of a direct contact intervention in the classroom by persons with lived experience to reduce vocational students' stigmatizing attitudes. METHOD: One person with lived experience and one first-degree relative implemented a classroom intervention lasting 90 min. Its effectiveness was measured using a quasi-experimental study with a pretest-posttest design and within-subject control. RESULTS: A total of 128 students from three different Vocational and Technical Schools from Spain participated in the study. After the intervention, statistically significant differences were observed in the scores of 11 of the 13 dimensions measured with the Spanish Mental Illness Stigma Attribution Questionnaire (AQ-27-E) and the Community Attitudes toward Mental Illness (CAMI) questionnaires. No differences associated with gender or familiarity with the mental disorder were observed. CONCLUSION: Vocational students' negative attitudes and emotions can be improved through a direct contact intervention in the classroom involving people who have experienced a mental disorder themselves. The age range for optimal results with this type of intervention appears to be 18 to 20 years.

Histone-binding of DPF2 mediates its repressive role in myeloid differentiation.

Double plant homeodomain finger 2 (DPF2) is a highly evolutionarily conserved member of the d4 protein family that is ubiquitously expressed in human tissues and was recently shown to inhibit the myeloid differentiation of hematopoietic stem/progenitor and acute myelogenous leukemia cells. Here, we present the crystal structure of the tandem plant homeodomain finger domain of human DPF2 at 1.6-Å resolution. We show that DPF2 interacts with the acetylated tails of both histones 3 and 4 via bipartite binding pockets on the DPF2 surface. Blocking these interactions through targeted mutagenesis of DPF2 abolishes its recruitment to target chromatin regions as well as its ability to prevent myeloid differentiation in vivo. Our findings suggest that the histone binding of DPF2 plays an important regulatory role in the transcriptional program that drives myeloid differentiation.

Operational Definition of Serious Mental Illness: Heterogeneity in a Review of the Research on Quality-of-Life Interventions.

BACKGROUND: An operational definition of serious mental illness (SMI) with well-defined inclusion criteria allows the identification of the most vulnerable individuals and secures resources to meet their needs and develop social programs for their treatment, rehabilitation, and recovery. In addition, the contents of a clinical construct such as SMI have an impact on both the development and the clinical application of the research results. However, currently, different ways of operationalizing the definition of SMI coexist. AIMS: The aim of this review was to explore whether unanimity exists in the operationalization of SMI definitions in quality-of-life interventions research. METHODS: A review of the literature based on searches of the MEDLINE and PsycINFO databases was conducted. Intervention studies were selected in which quality of life was the outcome variable and adults with SMI were the subject population. RESULTS: A wide range of definition of SMI is used in the scientific literature. CONCLUSIONS: There is a lack of unanimity in the variables considered necessary to identify SMI. The scientific literature uses different approaches to operationalize SMI, and these approaches vary considerably among studies. Caution is required when interpreting quality-of-life research that includes individuals labeled with SMI. It is necessary to reach a consensus on the criteria for applying the SMI label to ensure its content validity.

Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015-2019).

Sustained proliferative capacity and gene dysregulation are hallmarks of cancer. In mammalian cells, cyclin-dependent kinases (CDKs) control critical cell cycle checkpoints and key transcriptional events in response to extracellular and intracellular signals leading to proliferation. Significant clinical activity for the treatment of hormone receptor positive metastatic breast cancer has been demonstrated by palbociclib, ribociclib and abemaciclib, dual CDK4/6 inhibitors recently FDA-approved. SY-1365, a CDK7 inhibitor has shown initial encouraging data in phase I for solid tumors treatment. These results have rejuvenated the CDKs research field. This review provides an overview of relevant advances on CDK inhibitor research since 2015 to 2019, with special emphasis on transcriptional CDK inhibitors, new emerging strategies such as target protein degradation and compounds under clinical evaluation.

A subpopulation of itch-sensing neurons marked by Ret and somatostatin expression.

Itch, the unpleasant sensation that elicits a desire to scratch, is mediated by specific subtypes of cutaneous sensory neuron. Here, we identify a subpopulation of itch-sensing neurons based on their expression of the receptor tyrosine kinase Ret. We apply flow cytometry to isolate Ret-positive neurons from dorsal root ganglia and detected a distinct population marked by low levels of Ret and absence of isolectin B4 binding. We determine the transcriptional profile of these neurons and demonstrate that they express neuropeptides such as somatostatin (Sst), the NGF receptor TrkA, and multiple transcripts associated with itch. We validate the selective expression of Sst using an Sst-Cre driver line and ablated these neurons by generating mice in which the diphtheria toxin receptor is conditionally expressed from the sensory neuron-specific Avil locus. Sst-Cre::Avil(iDTR) mice display normal nociceptive responses to thermal and mechanical stimuli. However, scratching behavior evoked by interleukin-31 (IL-31) or agonist at the 5HT1F receptor is significantly reduced. Our data provide a molecular signature for a subpopulation of neurons activated by multiple pruritogens.

RBM5/Luca-15/H37 regulates Fas alternative splice site pairing after exon definition.

RBM5/Luca-15/H37 is a gene frequently inactivated in lung cancers and overexpressed in breast tumors. Its protein product has been detected in prespliceosomal complexes and modulates cell proliferation and Fas-mediated apoptosis. We report that RBM5 is a component of complexes involved in 3' splice site recognition and regulates alternative splicing of apoptosis-related genes, including the Fas receptor, switching between isoforms with antagonistic functions in programmed cell death. In contrast with classical mechanisms of splicing regulation, RBM5 does not affect early events of splice site recognition that lead to Fas exon 6 definition. Instead, RBM5 inhibits the transition between prespliceosomal complexes assembled around exon 6 to mature spliceosomes assembled on the flanking introns and promotes sequence-specific pairing of the distal splice sites. An OCRE domain important for RBM5 function contacts components of the U4/5/6 tri-snRNP, consistent with the idea that RBM5 modulates splice site pairing after prespliceosome assembly and exon definition.

Prevention of anti-tumor necrosis factor-associated tuberculosis: a 10-year longitudinal cohort study.

BACKGROUND: The extent to which anti-tumor necrosis factor (TNF)-associated tuberculosis can be prevented is unclear, and there is no established guidance on the optimal screening strategy for latent tuberculosis (LTBI) in patients about to start anti-TNF therapy. We aimed to determine the effectiveness of a comprehensive program for the prevention of anti-TNF-associated tuberculosis, and to evaluate 3 LTBI screening strategies and the need for retesting patients with negative results at baseline. METHODS: In total, 726 patients were screened prior to anti-TNF therapy using 1 of 3 diagnostic strategies over 3 consecutive periods: first, a 2-step tuberculin skin test (TST); second, a 2-step TST plus QuantiFERON-TB Gold In-Tube test (QFT-GIT) (2-step TST/QFT); and third, a single-step TST plus QFT-GIT (TST/QFT). Infected patients were offered preventive therapy. We assessed differences in the incidence of tuberculosis between anti-TNF exposed and nonexposed patients, and between the 3 study periods. RESULTS: Tuberculosis developed during the first year in 2.85 per 1000 exposed patient-years (3/1052 patient-years) and 1.77 per 1000 nonexposed patient-years (1/566 patient-years). No cases occurred beyond the first year of treatment. LTBI diagnoses decreased with the single-step TST/QFT (26.5%) compared with the 2-step TST (42.5%; P < .001) and 2-step TST/QFT (38.5%; P = .02); the incidence of tuberculosis among exposed patients did not change significantly across the 3 periods (2.63/1000, 3.91/1000, and 2.4/1000 patient-years, respectively). CONCLUSIONS: Although anti-TNF-associated tuberculosis can be reduced, some risk remains during the first year of therapy. Neither the 2-step TST nor systematic retesting after negative baseline testing is justified.

Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft.

Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. Targeting the CDK4/CDK6-cyclin D1-Rb-p16/ink4a pathway using a potent CDK4 and CDK6 kinase inhibitor has potential for treating primary central nervous system tumors such as glioblastoma and some peripheral tumors with high incidence of brain metastases. We compared central nervous system exposures of two orally bioavailable CDK4 and CDK6 inhibitors: abemaciclib, which is currently in advanced clinical development, and palbociclib (IBRANCE; Pfizer), which was recently approved by the U.S. Food and Drug Administration. Abemaciclib antitumor activity was assessed in subcutaneous and orthotopic glioma models alone and in combination with standard of care temozolomide (TMZ). Both inhibitors were substrates for xenobiotic efflux transporters P-glycoprotein and breast cancer resistant protein expressed at the blood-brain barrier. Brain Kp,uu values were less than 0.2 after an equimolar intravenous dose indicative of active efflux but were approximately 10-fold greater for abemaciclib than palbociclib. Kp,uu increased 2.8- and 21-fold, respectively, when similarly dosed in P-gp-deficient mice. Abemaciclib had brain area under the curve (0-24 hours) Kp,uu values of 0.03 in mice and 0.11 in rats after a 30 mg/kg p.o. dose. Orally dosed abemaciclib significantly increased survival in a rat orthotopic U87MG xenograft model compared with vehicle-treated animals, and efficacy coincided with a dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and CDK6 Ki values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats similar to TMZ, and the combination of abemaciclib and TMZ was additive or greater than additive. These data show that abemaciclib crosses the blood-brain barrier and confirm that both CDK4 and CDK6 inhibitors reach unbound brain levels in rodents that are expected to produce enzyme inhibition; however, abemaciclib brain levels are reached more efficiently at presumably lower doses than palbociclib and are potentially on target for a longer period of time.

Cyclin dependent kinase (CDK) inhibitors as anticancer drugs.

Sustained proliferative capacity is a hallmark of cancer. In mammalian cells proliferation is controlled by the cell cycle, where cyclin-dependent kinases (CDKs) regulate critical checkpoints. CDK4 and CDK6 are considered highly validated anticancer drug targets due to their essential role regulating cell cycle progression at the G1 restriction point. This review provides an overview of recent advances on cyclin dependent kinase inhibitors in general with special emphasis on CDK4 and CDK6 inhibitors and compounds under clinical evaluation. Chemical structures, structure activity relationships, and relevant preclinical properties will be described.

Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine.

The G1 restriction point is critical for regulating the cell cycle and is controlled by the Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This pathway is important because of its inactivation in a majority of human tumors. Transition through the restriction point requires phosphorylation of retinoblastoma protein (Rb) by CDK4/6, which are highly validated cancer drug targets. We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 hours after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different histologies in tumor-bearing mice. LY2835219 is effective and well tolerated when administered up to 56 days in immunodeficient mice without significant loss of body weight or tumor outgrowth. In calu-6 xenografts, LY2835219 in combination with gemcitabine enhanced in vivo antitumor activity without a G1 cell cycle arrest, but was associated with a reduction of ribonucleotide reductase expression. These results suggest LY2835219 may be used alone or in combination with standard-of-care cytotoxic therapy. In summary, we have identified a potent, orally active small-molecule inhibitor of CDK4/6 that is active in xenograft tumors. LY2835219 is currently in clinical development.

Mineral element contents in commercially valuable fish species in Spain.

The aim of this study was to measure selected metal concentrations in Trachurus trachurus, Trachurus picturatus, and Trachurus mediterraneus, which are widely consumed in Spain. Principal component analysis suggested that the variable Cr was the main responsible variable for the identification of T. trachurus, the variables As and Sn for T. mediterraneus, and the rest of variables for T. picturatus. This well-defined discrimination between fish species provided by mineral element allows us to distinguish them on the basis of their metal content. Based on the samples collected, and recognizing the inferential limitation of the sample size of this study, the metal concentrations found are below the proposed limit values for human consumption. However, it should be taken into consideration that there are other dietary sources of these metals. In conclusion, metal contents in the fish species analyzed are acceptable for human consumption from a nutritional and toxicity point of view.

Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity.

An important epigenetic component of tyrosine kinase signaling is the phosphorylation of histones, and epigenetic readers, writers, and erasers. Phosphorylation of protein arginine methyltransferases (PRMTs), have been shown to enhance and impair their enzymatic activity. In this study, we show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates tyrosine residues (Y149 and Y334) in coactivator-associated arginine methyltransferase 1 (CARM1), an important target in hematologic malignancies, increasing its methyltransferase activity and altering its target specificity. While non-phosphorylatable CARM1 methylates some established substrates (e.g. BAF155 and PABP1), only phospho-CARM1 methylates the RUNX1 transcription factor, on R223 and R319. Furthermore, cells expressing non-phosphorylatable CARM1 have impaired cell-cycle progression and increased apoptosis, compared to cells expressing phosphorylatable, wild-type CARM1, with reduced expression of genes associated with G2/M cell cycle progression and anti-apoptosis. The presence of the JAK2-V617F mutant kinase renders acute myeloid leukemia (AML) cells less sensitive to CARM1 inhibition, and we show that the dual targeting of JAK2 and CARM1 is more effective than monotherapy in AML cells expressing phospho-CARM1. Thus, the phosphorylation of CARM1 by hyperactivated JAK2 regulates its methyltransferase activity, helps select its substrates, and is required for the maximal proliferation of malignant myeloid cells.

Antidiabetic and Anti-Inflammatory Effect of Cinnamomum cassia Oil in Alloxan-Induced Diabetic Rats.

Diabetes mellitus presents a great diversity of treatments that cause adverse effects; therefore, plants are a source of compounds that may have fewer adverse effects; Cinnamomum cassia (C. cassia) has compounds with potential antidiabetic activity. The objective was to evaluate the antidiabetic effect of C. cassia oil (CCO) and its impact on oxidative stress in Wistar rats. Five groups were evaluated: (1) sham (SH), (2) 300 mg/kg CCO (CCO), (3) diabetic (D) induced with alloxan, (4) D + 300 mg/kg of CCO (D + CCO), and (5) D + 500 mg/kg of metformin (D + MET); all were treated for 5 days. CCO did not show alteration in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) vs. SH. D + CCO vs. D significantly reduced glucose (333 ± 109 vs. 458 ± 81 mg/dL), ALT (66 ± 15 vs. 160 ± 54 U/L), AST (119 ± 26 vs. 243 ± 104 U/L), and blood urea nitrogen (18.8 ± 2.3 vs. 29.2 ± 6.9 mg/dL). No significant changes were observed in D + CCO vs. D in malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD), whereas a significant reduction in MDA and GSH was achieved in D + MET, with an increase in SOD. There was a reduction in Rela and Gpx in D + CCO and D + MET vs. D. CCO has antidiabetic and anti-inflammatory effects and reduces ALT, AST, and BUN levels.

Targeted and untargeted serum NMR metabolomics to reveal initial kidney disease in diabetes mellitus.

Serum 1H NMR metabolomics has been used as a diagnostic tool for screening type 2 diabetes (T2D) with chronic kidney disease (CKD) as comorbidity. This work aimed to evaluate 1H NMR data to detect the initial kidney damage and CKD in T2D subjects, through multivariate statistical analysis. Clinical data and biochemical parameters were obtained for classifying five experimental groups using KDIGO guidelines: Control (healthy subjects), T2D, T2D-CKD-mild, T2D-CKD-moderate, and T2D-CKD-severe. Serum 1H NMR spectra were recorded to follow two strategies: one based on metabolite-to-creatinine (Met/Cr) ratios as targeted metabolomics, and the second one based on untargeted metabolomics from the 1H NMR profile. A prospective biomarkers panel of the early stage of T2D-CKD based in metabolite-to-creatinine ratio (ornithine/Cr, serine/Cr, mannose/Cr, acetate/Cr, acetoacetate/Cr, formate/Cr, and glutamate/Cr) was proposed. Later, a statistical model based on non-targeted metabolomics was used to predict initial CKD, and its metabolic pathway analysis allowed identifying the most affected pathways: phenylalanine, tyrosine, and tryptophan biosynthesis; valine, leucine, and isoleucine degradation; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; and histidine metabolism. Nonetheless, further studies with a larger cohort are advised to precise ranges in metabolite-to-creatinine ratios and evaluate the prediction pertinency to detect initial CKD in T2D patients in both statistical models proposed.

MicroRNA-204 Regulates Angiogenesis and Vasculogenic Mimicry in CD44+/CD24- Breast Cancer Stem-like Cells.

Tumors have high requirements in terms of nutrients and oxygen. Angiogenesis is the classical mechanism for vessel formation. Tumoral vascularization has the function of nourishing the cancer cells to support tumor growth. Vasculogenic mimicry, a novel intratumoral microcirculation system, alludes to the ability of cancer cells to organize in three-dimensional (3D) channel-like architectures. It also supplies the tumors with nutrients and oxygen. Both mechanisms operate in a coordinated way; however, their functions in breast cancer stem-like cells and their regulation by microRNAs remain elusive. In the present study, we investigated the functional role of microRNA-204 (miR-204) on angiogenesis and vasculogenic mimicry in breast cancer stem-like cells. Using flow cytometry assays, we found that 86.1% of MDA-MB-231 and 92% of Hs-578t breast cancer cells showed the CD44+/CD24- immunophenotype representative of cancer stem-like cells (CSCs). The MDA-MB-231 subpopulation of CSCs exhibited the ability to form mammospheres, as expected. Interestingly, we found that the restoration of miR-204 expression in CSCs significantly inhibited the number and size of the mammospheres. Moreover, we found that MDA-MB-231 and Hs-578t CSCs efficiently undergo angiogenesis and hypoxia-induced vasculogenic mimicry in vitro. The transfection of precursor miR-204 in both CSCs was able to impair the angiogenesis in the HUVEC cell model, which was observed as a diminution in the number of polygons and sprouting cells. Remarkably, miR-204 mimics also resulted in the inhibition of vasculogenic mimicry formation in MDA-MB-231 and Hs-578t CSCs, with a significant reduction in the number of channel-like structures and branch points. Mechanistically, the effects of miR-204 were associated with a diminution of pro-angiogenic VEGFA and ß-catenin protein levels. In conclusion, our findings indicated that miR-204 abrogates the angiogenesis and vasculogenic mimicry development in breast cancer stem-like cells, suggesting that it could be a potential tool for breast cancer intervention based on microRNA replacement therapies.

All I missed in the therapeutic relationship: The lived experience narrative of a mental health nurse receiving mental healthcare.

WHAT IS KNOWN ON THE SUBJECT?: The therapeutic relationship is crucial for mental health practice, especially to practice that is recovery-orientated. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: This lived experience suggests that mental health professionals can be a long way from knowing the service users' feelings and their precise needs. The narrative reveals how mental health professionals maintain stereotypes and prejudices against people with mental health conditions and how these are reflected in their practice through lack of respect and users' dignity. WHAT ARE THE IMPLICATIONS FOR MENTAL HEALTH NURSING?: This lived experience narrative highlights the need to humanize care. ABSTRACT: INTRODUCTION: The therapeutic relationship is not always functional in clinical practice due to various factors, such as lack of time, lack of job motivation, exhaustion and rejection towards the person cared for. AIM: The aim of this study is to illustrate to professionals the needs of the persons they care for and how they see the world. METHOD: The aim was achieved through the development of a lived experience narrative. RESULTS: This lived experience narrative describes the experience of a mental health nurse since her first psychotic symptoms and her perceptions of the therapeutic relationship with mental health staff in her trajectory from the first psychiatric appointment until her last contact with the community mental health services. DISCUSSION: This narrative suggests that mental health professionals are sometimes far from discovering what service users are feeling and their precise needs. This highlights the need to humanize mental healthcare.

The Promotion of Mental Health and Prevention of First-Episode Psychosis: A Pilot and Feasibility Non-Randomised Clinical Trial.

BACKGROUND: Mental-health-related stigma prevents active help seeking and therefore early therapeutic approaches and the recovery of functionality. National and international agencies recommend the implementation of prevention and mental health promotion programs that support the elimination of stigma in the classroom, since most mental health problems usually start in the adolescent stage. In view of the evidence that teachers present stigmatizing attitudes towards mental health, it has been considered as convenient to carry out an anti-stigma program with the main objective of evaluating the impact of an intervention based on the education and promotion of mental health, aimed at teachers and counsellors of a secondary school. The specific objectives were to get to know which were the most stigmatising attitudes that prevailed in the sample before and after the intervention; to evaluate the knowledge of the teaching staff and counsellors on psychosis before the intervention; to analyse correlations between clinically relevant variables; and assess whether this programme was beneficial and feasible for alphabetising counsellors/teachers of educational centres on stigma and FEP. METHODS: This was a non-randomised clinical trial in which a nursing intervention was performed. TOOLS: a psychosis test (pre), Stigma Attribution Questionnaire (AQ-27) (pre-post), and satisfaction survey (post) were used. The inferential analysis included the Wilcoxon and the Pearson Correlation Test. RESULTS: In the sample (n = 22), the predominant stigmatising attitude was "Help". The p-values obtained in the Wilcoxon Test were statistically significant, except for "Responsibility" and "Pity". The following constructs of interest were faced: "Fear"-"Age" and "Professional experience"; and "Help"-"Psychosis test". CONCLUSIONS: Despite the scores obtained in "Responsibility" and "Pity", the intervention was useful for reducing stigma in the sample. Implications for the profession: There are adolescents who have suffered stigma from their teachers, and consequently have minimized their symptoms and not asked for help. For this reason, we implemented a nursing intervention based on the education and promotion of mental health, with the aim of expanding knowledge and reducing stigma. In fact, this intervention, which we carried out on high school teachers, managed to reduce the majority of stigmatizing attitudes measured on the stigma attribution scale.

Non-tunneled catheter tip depth position in urgent hemodialysis: a randomized controlled trial.

BACKGROUND: The average accepted depth for non-tunneled catheters (NTC) insertion does not guarantee its correct position, so controversy exists. The aim of this study was to assess the effect of two NTC placement depths on the number of NTC complication episodes. METHODS: We designed a triple blind, parallel group, randomized controlled trial in a single Hemodialysis Center in Mexico (Registry: ACTRN12619000774123). We included patients in urgent need of hemodialysis via internal right jugular vein NTC. The length of the NTC tip placement depth was randomized to second intercostal space (2ICS) or fourth intercostal space (4ICS), using physical landmarks. The primary outcome was to compare the composite number of NTC dysfunction, repositioning, and relocation episodes for 48 hours post-procedure. RESULTS: One hundred and sixty-five patients were included, 86 and 79 patients to NTC placement in the 2ICS and 4ICS, respectively. All patients underwent intention-to-treat analysis. The incidence of the composite outcome was lower in the 2ICS group compared to the 4ICS group, 4 (4.6%) and 50 (63%) combined episodes, respectively (P<0.001). Compared to the 4ICS group, the 2ICS group presented a relative risk of 0.06 (CI: 0.02-0.21, P<0.001) and number needed to treat (NNT) of 2.1. No adverse events occurred, derived from the NTC placement. CONCLUSIONS: NTC tip placement in the 2ICS compared to 4ICS decreases the incidence of the combined number of dysfunctions, repositioning and relocation episodes, with a NNT of 2 for its prevention.