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Objectives: People experiencing trafficking often seek health care but are not identified. Although the Centers for Disease Control and Prevention added new International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes specific to human trafficking (hereinafter, HT ICD-10-CM codes) that could systematize the identification and documentation of human trafficking in US health care settings, the extent of their use is unknown. The objectives of this study were to investigate (1) the frequency of HT ICD-10-CM code use in US health care organizations (HCOs) and (2) demographic data associated with HT ICD-10-CM codes using a large clinical database. Methods: This retrospective study used deidentified data collected from October 1, 2018, through March 30, 2021, from a clinical database (N = 69 740 144 patients) network (TriNetX) of 48 collaborating US HCOs. Data included number of patients with ≥1 HT ICD-10-CM code, diagnoses, and demographic characteristics (age, sex, race, ethnicity, and region). Results: HT ICD-10-CM codes were associated with 298 patients in US HCOs, most of whom were young (mean [SD] age, 26 [16] y), White (53.0%; n = 158), and female (87.9%; n = 262). Thirty-seven of 48 (77.1%) participating HCOs used ≥1 HT ICD-10-CM code. The most frequently used HT ICD-10-CM codes were “forced sexual exploitation, suspected” (32.2%; n = 96) and “personal history of forced labor or sexual exploitation” (27.1%; n = 81). Labor trafficking codes were noted in approximately 3.7% of cases. Conclusions: HT ICD-10-CM codes are being used by health care professionals, as confirmed by large databases. Further research is needed to understand variation in code use and risk factors associated with human trafficking.

RNA molecules undergo a vast array of chemical post-transcriptional modifications (PTMs) that can affect their structure and interaction properties. In recent years, a growing number of PTMs have been successfully mapped to the transcriptome using experimental approaches relying on high-throughput sequencing. Oxford Nanopore direct-RNA sequencing has been shown to be sensitive to RNA modifications. We developed and validated Nanocompore, a robust analytical framework that identifies modifications from these data. Our strategy compares an RNA sample of interest against a non-modified control sample, not requiring a training set and allowing the use of replicates. We show that Nanocompore can detect different RNA modifications with position accuracy in vitro, and we apply it to profile m 6 A in vivo in yeast and human RNAs, as well as in targeted non-coding RNAs. We confirm our results with orthogonal methods and provide novel insights on the co-occurrence of multiple modified residues on individual RNA molecules. Nanopore direct RNA Sequencing data contain information about the presence of RNA modifications, but their detection poses substantial challenges. Here the authors introduce Nanocompore, a new methodology for modification detection from Nanopore data.

IntroductionA significant proportion of patients with asthma remain uncontrolled despite treatment with inhaled corticosteroids and bronchodilators. Multiple reasons exist for this. Suboptimal inhaler adherence, inadequate inhaler technique and continuous exposure to allergens are often found to contribute to poor asthma control. Additionally, symptoms from some comorbid conditions, such as obesity, GORD and deconditioning, may be perceived as arising from asthma. The first priority should always be to confirm if asthma is the cause of the patients’ current symptoms.Methods & analysisIn this protocol paper, we describe the design of a prospective cohort replicate study. We will test the hypothesis that digitally acquired data on lung function and medication use can better establish that asthma is the cause of symptoms, rather than guideline-recommended practice. Patients with clinician-diagnosed asthma who remain uncontrolled despite inhaled corticosteroid treatment will be enrolled. Over 26 weeks and five visits, lung function, markers of T2 inflammation and symptoms will be repeatedly assessed. The ‘ground truth’ diagnosis for each patient will be established using a multimodal template comprised of lung function, T2 inflammation data, response to treatment, assessment of alternative diagnoses and patient outcome over time.The primary aim of this study is to compare guideline-recommended methods to diagnose asthma with a novel metric derived from digitally measured lung function in combination with T2 inflammation, which has been developed in an independent cohort of patients with severe asthma and a healthy control group. In secondary analysis, we will assess the direct costs and cost-effectiveness of this approach.Ethics & disseminationThe trial was approved by the Beaumont Hospital’s Research & Ethics Committee, REC number 21/89. Participants completed an informed, written consent form. Data will be analysed, anonymised and reported in relevant peer-reviewed journals and at national and international conferences. Data will be anonymised prior to publication.Trial registration numberNCT05357274.

Tudor Interacting Repair Regulator (TIRR) is an RNA-binding protein (RBP) that interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. We utilized iCLIP to identify RNAs that directly bind to TIRR within cells, identifying the long non-coding RNA NEAT1 as the primary RNA partner. The high affinity of TIRR for NEAT1 is due to prevalent G-rich motifs in the short isoform (NEAT1_1) region of NEAT1. This interaction destabilizes the TIRR/53BP1 complex, promoting 53BP1’s function. NEAT1_1 is enriched during the G1 phase of the cell cycle, thereby ensuring that TIRR-dependent inhibition of 53BP1’s function is cell cycle-dependent. TDP-43, an RBP that is implicated in neurodegenerative diseases, modulates the TIRR/53BP1 complex by promoting the production of the NEAT1 short isoform, NEAT1_1. Together, we infer that NEAT1_1, and factors regulating NEAT1_1, may impact 53BP1-dependent DNA repair processes, with implications for a spectrum of diseases. TIRR interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. Here, the authors show that the lncRNA NEAT1, regulated by TDP-43, destabilizes the TIRR/53BP1 complex in G1, promoting 53BP1’s function in DSB repair and p53 transactivation.

l-Arginine is shown to protect hematopoietic progenitor (32D cl 3) cells from death due to exposure to γ radiation (137Cs). Some of the other intermediates in the urea cycle, namely ornithine and citrulline, plus urea itself, were not found to have any significant impact on cell survival after irradiation. Intriguingly, supplementation of irradiated cells with l-arginine results in decreased production of peroxynitrite, suggesting that suppression of superoxide generation by nitric oxide synthase in one or more microenvironments is an important factor in the observed radioprotection. The absence of any radioprotective effect of l-arginine in cells at 3% oxygen also confirms the involvement of one or more oxygen-derived species. Knockdown experiments with nitric oxide synthase (NOS) siRNAs in cells and NOS knockout animals confirm that the observed radioprotection is associated with nNOS (NOS-1). l-Arginine also ameliorates the transient inhibition of the electron-transport chain complex I that occurs within 30 min of completing the dose (10 Gy) and that appears to be a functional marker for postirradiation mitochondrial oxidant production.

Low-dose azathioprine with allopurinol (LDAA) has been proposed as a potent therapy in inflammatory bowel disease (IBD) with the benefit of overcoming side effects regularly associated with thiopurine monotherapy and poor responses. Concerns regarding safety remain, while a layer of complexity has been added by the trend toward treatment directed by red cell thioguanine nucleotide (TGN) profiling. We report on the clinical efficacy and safety of LDAA use in IBD undirected by metabolite profiling.MethodsObservational study of clinical practice from a single IBD center. Patient outcomes were defined clinically based on established activity scores and corticosteroid withdrawal. Red cell TGN was monitored only for suspected nonadherence.ResultsOverall, 113/164 (69%) patients with Crohn's disease and 83/136 (61%) patients with ulcerative/unclassified colitis had a clinical response by the end of follow-up (median 19 months), while 85 (52%) patients with Crohn's disease and 74 (54%) patients with ulcerative/unclassified colitis were in clinical remission. Clinical response was seen in 45/57 (79%) patients with Crohn's disease and 34/53 (64%) patients with ulcerative/unclassified colitis who were thiopurine naive, had active IBD, and received LDAA as the first line immunomodulator, while in 35 (61%) and 28 (53%), respectively, remission was achieved. LDAA was stopped in 20/300 (7%) patients because of side effects, all of which resolved on drug cessation.ConclusionsThis is the largest cohort supporting the favorable safety profile and high efficacy of LDAA in IBD. It presents 2 advances in therapy: prescribing LDAA for thiopurine-naive patients, and bypassing TGN monitoring in favor of clinical monitoring (blood counts, etc.), which will make it more accessible for clinics without access to TGN assays.

A significant proportion of patients with asthma remain uncontrolled despite treatment with inhaled corticosteroids and bronchodilators. Multiple reasons exist for this. Suboptimal inhaler adherence, inadequate inhaler technique and continuous exposure to allergens are often found to contribute to poor asthma control. Additionally, symptoms from some comorbid conditions, such as obesity, GORD and deconditioning, may be perceived as arising from asthma. The first priority should always be to confirm if asthma is the cause of the patients' current symptoms. In this protocol paper, we describe the design of a prospective cohort replicate study. We will test the hypothesis that digitally acquired data on lung function and medication use can better establish that asthma is the cause of symptoms, rather than guideline-recommended practice. Patients with clinician-diagnosed asthma who remain uncontrolled despite inhaled corticosteroid treatment will be enrolled. Over 26 weeks and five visits, lung function, markers of T2 inflammation and symptoms will be repeatedly assessed. The 'ground truth' diagnosis for each patient will be established using a multimodal template comprised of lung function, T2 inflammation data, response to treatment, assessment of alternative diagnoses and patient outcome over time.The primary aim of this study is to compare guideline-recommended methods to diagnose asthma with a novel metric derived from digitally measured lung function in combination with T2 inflammation, which has been developed in an independent cohort of patients with severe asthma and a healthy control group. In secondary analysis, we will assess the direct costs and cost-effectiveness of this approach. The trial was approved by the Beaumont Hospital's Research & Ethics Committee, REC number 21/89. Participants completed an informed, written consent form. Data will be analysed, anonymised and reported in relevant peer-reviewed journals and at national and international conferences. Data will be anonymised prior to publication. NCT05357274.

Although research on nonsuicidal self-injury (NSSI) is accumulating, there is as yet little data on psychopathological features associated with NSSI in nonclinical samples. College students may be particularly susceptible to engaging in NSSI and NSSI may be phenomenologically and etiologically different for males and females. This archival study examined differences between college student women with (n = 34) and without (n = 32) a history of NSSI in scores on the clinical scales and subscales of the Personality Assessment Inventory (PAI). Multivariate analyses revealed significantly higher levels of depression, anxiety, borderline personality features, suicidality, and certain psychotic features in self-injurers. Follow-up analysis identified four symptom themes associated with NSSI across diagnostic categories: emotional distress, physiological distress, cognitive distortion, and interpersonal difficulties. This study confirms previous findings of higher levels of affective symptoms in self-injurers. Unique findings of this study included significantly higher scores for self-injurers on the PAI Thought Disorder, Psychotic Experiences, and Hypervigilance subscales. This suggests a need to expand the conceptualization of the clinical correlates of NSSI to encompass a broader array of symptomatology. Implications for clinical practice are discussed.

This commentary discusses the major claims and arguments presented by Field and Hineline (2008) against the general use of dispositional causal explanations in science and psychology and in favor of an alternative account that applies to cases in which causes and behavioral effects are separated over time. We conclude that their central claims and arguments are weak or implausible, and that the dispositional explanatory strategy emerges unscathed.

RNA methylation is an important regulator of RNA metabolism. The most common form of internal mRNA methylation is N6-methyladenosine (m⁶A), which is deposited by the m6A methyltransferase complex (MTC). This occurs co-transcriptionally, meaning the MTC must interact with components within the broader chromatin environment, in order to rapidly and selectively access nascent RNA. My thesis is a step towards a better understanding of those interactions. In the first part of my thesis, I examine the cellular response to UV-C irradiation, which has recently been demonstrated to induce dynamic m6A deposition. Not only do I find limited evidence to support this model, I also show this discrepancy partly arises from the cross-reactivity of m6A antibodies with poly (ADP-ribose) (PAR), which confounds imaging data. I then identify a previously uncharacterised regulatory relationship between the core MTC protein, METTL3, and the synthesis of PAR (PARylation). In the second part of the thesis, I utilise a range of experimental techniques in an attempt to describe how PARylation is affected by the loss of METTL3. These experiments give no single answer, but indicate several contexts in which PARylation and METTL3 may be linked. In the third section, I present a study of how PARP-1 and PARylation is regulated by METTL3 during the exit from pluripotency, and in the context of MEK/ERK signalling. At the heart of this section is a proteomic dataset that measures changes to the PARP-1 chromatin-associated interactome, in the presence and absence of METTL3. This identifies several interesting candidate proteins, on which further research can be based. In summary, I have identified, and begun the characterisation of, a regulatory relationship between two important processes: the m⁶A modification of RNA and PARylation. This may have important consequences for understanding several aspects of cell homeostasis and disease.