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The optimal timing of anticoagulation for patients with acute ischaemic stoke with atrial fibrillation is uncertain. We investigated the efficacy and safety of early compared with delayed initiation of direct oral anticoagulants (DOACs) in patients with acute ischaemic stroke associated with atrial fibrillation.

We conducted a prespecified examination of the efficacy and safety of allopurinol and febuxostat administered using a treat-to-target strategy in trial participants with chronic kidney disease (CKD).

Although the reactivity of five-coordinate end-on superoxocopper(II) complexes, CuII(η1-O2•–), is dominated by hydrogen atom transfer, the majority of four-coordinate CuII(η1-O2•–) complexes published thus far display nucleophilic reactivity. To investigate the origin of this difference, we have developed a four-coordinate end-on superoxocopper(II) complex supported by a sterically encumbered bis(2-pyridylmethyl)amine ligand, dpb2-MeBPA (1), and compared its substrate reactivity with that of a five-coordinate end-on superoxocopper(II) complex ligated by a similarly substituted tris(2-pyridylmethyl)amine, dpb3-TMPA (2). Kinetic isotope effect (KIE) measurements and correlation of second-order rate constants (k2’s) versus oxidation potentials (Eox) for a range of phenols indicates that the complex [CuII(η1-O2•–)(1)]+reacts with phenols via a similar hydrogen atom transfer (HAT) mechanism to [CuII(η1-O2•–)(2)]+. However, [CuII(η1-O2•–)(1)]+performs HAT much more quickly, with its k2for reaction with 2,6-di-tert-butyl-4-methoxyphenol (MeO-ArOH) being >100 times greater. Furthermore, [CuII(η1-O2•–)(1)]+can oxidize C–H bond substrates possessing stronger bonds than [CuII(η1-O2•–)(2)]+is able to, and it reacts with N-methyl-9,10-dihydroacridine (MeAcrH2) approximately 200 times faster. The much greater facility for substrate oxidation displayed by [CuII(η1-O2•–)(1)]+is attributed to it possessing higher inherent electrophilicity than [CuII(η1-O2•–)(2)]+, which is a direct consequence of its lower coordination number. These observations are of relevance to enzymes in which four-coordinate end-on superoxocopper(II) intermediates, rather than their five-coordinate congeners, are routinely invoked as the active oxidants responsible for substrate oxidation.

Ion mobility mass spectrometry (IM-MS) measures the mass, size, and shape of ions in the same experiment, and structural information is provided via collision cross-section (CCS) values. The majority of commercially available IM-MS instrumentation relies on the use of CCS calibrants, and here, we present data from a family of poly(l-lysine) dendrimers and explore their suitability for this purpose. In order to test these compounds, we employed three different IM-MS platforms (Agilent 6560 IM-QToF, Waters Synapt G2, and a home-built variable temperature drift tube IM-MS) and used them to investigate six different generations of dendrimers in two buffer gases (helium and nitrogen). Each molecule gives a highly discrete CCS distribution suggestive of single conformers for each m/zvalue. The DTCCSN2values of this series of molecules (molecular weight: 330–16,214 Da) range from 182 to 2941 Å2, which spans the CCS range that would be found by many synthetic molecules including supramolecular compounds and many biopolymers. The CCS values for each charge state were highly reproducible in day-to-day analysis on each instrument, although we found small variations in the absolute CCS values between instruments. The rigidity of each dendrimer was probed using collisionally activated and high-temperature IM-MS experiments, where no evidence for a significant CCS change ensued. Taken together, this data indicates that these polymers are candidates for CCS calibration and could also help to reconcile differences found in CCS measurements on different instrument geometries.

Solving the puzzle of preterm birth has been challenging and will require novel integrative solutions as preterm birth likely arises from many etiologies. It has been demonstrated that many sociodemographic and psychological determinants of preterm birth relate to its complex biology. It is this understanding that has enabled the development of a novel preventative strategy, which integrates the omics profile (genome, epigenome, transcriptome, proteome, metabolome, microbiome) with sociodemographic, environmental, and psychological determinants of individual pregnant people to solve the puzzle of preterm birth.

It remains unknown whether frailty status portends an increased risk of adverse outcomes in patients with rheumatoid arthritis (RA) initiating biologic or targeted‐synthetic (b/ts) disease‐modifying antirheumatic drugs (DMARDs). The objective of our study was to evaluate the association between frailty and serious infections in a younger population of patients (<65 years old) with RA who initiated b/tsDMARDs. Using MarketScan data, we identified new users of tumor necrosis factor inhibitors (TNFi), non‐TNFi biologic DMARDs, or Janus kinase inhibitors (JAKi) between 2008 and 2019 among those with RA. Patients’ baseline frailty risk score was calculated using a Claims‐Based Frailty Index (≥0.2 defined as frail) 12 months prior to drug initiation. The primary outcome was time to serious infection; secondarily, we examined time‐to‐any infection and all‐cause hospitalizations. We used Cox proportional hazards to estimate adjusted hazard ratios and 95% confidence intervals (95% CIs) and assessed the significance of interaction terms between frailty status and drug class. A total of 57,980 patients, mean (±SD) age 48.1 ± 10.1 were included; 48,139 (83%) started TNFi, 8,111 (14%) non‐TNFi biologics, and 1,730 (3%) JAKi. Among these, 3,560 (6%) were categorized as frail. Frailty was associated with a 50% increased risk of serious infections (adjusted hazard ratio [95% CI] 1.5, 1.2–1.9) and 40% higher risk of inpatient admissions (1.4 [1.3–1.6]) compared with nonfrail patients among those who initiated TNFi. Frailty was also associated with a higher risk of any infection relative to nonfrail patients among those on TNFi (1.2 [1.1–1.3]) or non‐TNFi (1.2 [1.0–1.4]) or JAKi (1.4 [1.0–2.0]). Frailty is an important predictor for the risk of adverse outcomes among patients with RA treated with biologic or targeted‐synthetic DMARDs.

The large-conductance, voltage-gated, calcium (Ca2+)-activated potassium channel (BKCa) is one of the most abundant potassium channels in the myometrium. Previous work conducted by our group has identified a link between inflammation, BKCachannels and excitability of myometrial smooth muscle cells. Here, we investigate the role of BKCachannels in spontaneous and lipopolysaccharide (LPS)-stimulated uterine contraction to gain a better understanding of the relationship between the BKCachannel and uterine contraction in basal and inflammatory states. Uteri of C57BL/6 J mice on gestational day 18.5 (GD18.5) were obtained and either fixed in formalin or used immediately for tension recording or isolation of primary myocytes for patch-clamp. Paraffin sections were used for immunofluorescenctdetection of BKCaand Toll-like receptor (TLR4). For tension recordings, LPS was administered to determine its effect on uterine contractions. Paxilline, a BKCainhibitor, was used to dissect the role of BKCain uterine contraction in basal and inflammatory states. Finally, patch-clamp recordings were performed to investigate the relationship between LPS, the BKCachannel and membrane currents in mouse myometrial smooth muscle cells (mMSMCs). We confirmed the expression of BKCaand TLR4 in the myometrium of GD18.5 mice and found that inhibiting BKCachannels with paxilline suppressed both spontaneous and LPS-stimulated uterine contractions. Furthermore, application of BKCainhibitors (paxilline or iberiotoxin) after LPS inhibited BKCachannel activity in mMSMCs. Moreover, pretreatment with BKCainhibitor or the TLR4 inhibitor suppressed LPS-activated BKCacurrents. Our study demonstrates that BKCachannels are involved in both basal and LPS-stimulated uterine contraction in pregnant mice.LPS stimulates uterine contraction in part, by activating BKCamembrane currents in mMSMCs.Graphical Abstract

The objective of this study was to determine the proportion of new medication prescriptions observed in electronic health records (EHR) that represent true incident medication use, accounting for undocumented previous prescriptions (prevalent medication use) and failure to initiate treatment (primary nonadherence) with linked administrative claims data as the reference standard. Using single‐specialty rheumatology EHR data from more than 700 community practices in the United States linked to administrative claims data, we identified first (index) EHR prescriptions and assessed the positive predictive value (PPV) of different EHR‐derived new user definitions to identify true incident use (no prior claims). We then assessed how often index EHR prescriptions that met a definition of new use resulted in primary nonadherence (no subsequent claims). Overall, 12,405 index EHR prescriptions were identified with PPVs of 0.59 to 0.67 for true incident use. PPVs increased to 0.76 to 0.85 by excluding medications listed during the EHR medication reconciliation process and further increased to 0.87 to 0.93 by requiring ≥12 elapsed months since the first rheumatology office visit. Primary nonadherence at three months was observed in 33% to 38% overall and varied substantially by medication class, ranging from 15% to 23% for conventional synthetic disease‐modifying antirheumatic drugs (DMARDs) to 54% to 64% for targeted synthetic DMARDs. New DMARD use was accurately distinguished from prevalent use with EHR prescriptions and simple new user definitions that include current medications collected during medication reconciliation. Primary nonadherence was frequent and varied by DMARD class. This has important implications for epidemiologic studies using EHR data and for optimal delivery of clinical care.

The objective of this study was to determine the impact of emerging safety data on practice patterns by describing the characteristics of patients initiating and discontinuing advanced therapies for rheumatoid arthritis (RA) before and after January 2021. This cohort study evaluated US veterans with RA between April 2019 and September 2022. This period was divided into two 664‐day periods before and after January 2021. Eligible patients had ≥1 diagnosis code for RA and initiated a tumor necrosis factor inhibitor (TNFi), non‐TNFi biologic, or JAK inhibitor (JAKi). We tested for interaction within regression models to determine whether changes in patient characteristics for tofacitinib recipients were different from changes observed for other therapies. We also evaluated factors associated with therapy discontinuation in Cox models adjusted for age, sex, and duration on therapy, including assessment for effect modification. When comparing patients with RA initiating tofacitinib before (n = 2,111) with those initiating tofacitinib after (n = 1,664) January 2021, there was a decrease in mean age (64.1 vs 63.0 years) and in the proportion with cardiovascular comorbidities (all P< 0.01). These changes were significantly different from those observed for patients initiating TNFi or non‐TNFi biologics. Among active advanced therapy recipients, the likelihood of discontinuation was higher for tofacitinib than TNFi (hazard ratio 1.18, 95% confidence interval 1.10–1.26, P< 0.001). The higher rate of tofacitinib discontinuation was more pronounced in the presence of cardiovascular comorbidities (P< 0.05). Recent safety data significantly affected prescribing practices for advanced therapies, with a reduction in JAKi initiation and an increase in JAKi discontinuation among older patients and those at high cardiovascular risk.

The study objective was to update a method to identify comorbid conditions using only medication information in circumstances in which diagnosis codes may be undercaptured, such as in single‐specialty electronic health records (EHRs), and to compare the distribution of comorbidities across Rx‐Risk versus other traditional comorbidity indices. Using First Databank, RxNorm, and its web‐based clients, RxNav and RxClass, we mapped Drug Concept Unique Identifiers (RxCUIs), National Drug Codes (NDCs), and Anatomical Therapeutic Chemical (ATC) codes to Rx‐Risk, a medication‐focused comorbidity index. In established rheumatoid arthritis (RA) and osteoarthritis (OA) cohorts within the Rheumatology Informatics System for Effectiveness registry, we then compared Rx‐Risk with other comorbidity indices, including the Charlson Comorbidity Index, Rheumatic Disease Comorbidity Index (RDCI), and Elixhauser. We identified 965 unique ingredient RxCUIs representing the 46 Rx‐Risk comorbidity categories. After excluding dosage form and ingredient related RxCUIs, 80,911 unique associated RxCUIs were mapped to the index. Additionally, 187,024 unique NDCs and 354 ATC codes were obtained and mapped to the index categories. When compared to traditional comorbidity indices in the RA cohort, the median score for Rx‐Risk (median 6.00 [25th percentile 2, 75th percentile 9]) was much greater than for Charlson (median 0 [25th percentile 0, 75th percentile 0]), RDCI (median 0 [25th percentile 0, 75th percentile 0]), and Elixhauser (median 1 [25th percentile 1, 75th percentile 1]). Analyses of the OA cohort yielded similar results. For patients with a Charlson score of 0 (85% of total), both the RDCI and Elixhauser were close to 1, but the Rx‐Risk score ranged from 0 to 16 or more. The misclassification and under‐ascertainment of comorbidities in single‐specialty EHRs can largely be overcome by using a medication‐focused comorbidity index.

Long before X-men, X-Factor, Apple OS X, Netflix, Xbox, and SpaceX, the letter X was already a fascinating and potent character. It primarily represents the unknown, a trait it shares with photography. From cameras (Pentax) and film (Tri-X) to x-rays, xerography, crossing out and thus rejecting undesirable images, posing for photographs with our legs crossed, and more. It even refers to Generation X (of which I am part), a phrase coined by none other than Robert Capa, famed photojournalist and founder of Magnum Photos.This project focuses on the complex relationships between the letter X, artists’ bodies, frames, and processes involved in making art using photographs and/or tools of photography. In a nod to the roman numeral X, I chose ten works from the collection of the Archives of American Art that feature literal or conceptual X’s. I created new X-forms through collaboration, elimination, and transformation. These are hybrid works, unspecified things, objects that one need not give a specific name. They are artistic pseudonyms for ‘things’ that wish to remain unknown.

Myeloproliferative neoplasms (MPNs) are a group of chronic hematologic malignancies that lead to morbidity and early mortality due to thrombotic complications and progression to acute leukemia. Clinical and mutational risk factors have been demonstrated to predict outcomes in patients with MPNs and are used commonly to guide therapeutic decisions, including allogenic stem cell transplant, in myelofibrosis. Adolescents and young adults (AYA, age ≤45 years) comprise less than 10% of all MPN patients and have unique clinical and therapeutic considerations. The prevalence and clinical impact of somatic mutations implicated in myeloid disease has not been extensively examined in this population. We conducted a retrospective review of patients evaluated at eight Canadian centers for MPN patients diagnosed at ≤45 years of age. In total, 609 patients were included in the study, with median overall survival of 36.8 years. Diagnosis of prefibrotic or overt PMF is associated with the lowest OS and highest risk of AP/BP transformation. Thrombotic complications (24%), including splanchnic circulation thrombosis (9%), were frequent in the cohort. Mutations in addition to those in JAK2/MPL/CALRare uncommon in the initial disease phase in our AYA population (12%); but our data indicate they may be predictive of transformation to post-ET/PV myelofibrosis.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTNgene. The co-occurrence of predicted deleterious SRPK3/TTNvariants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3and ttn.1in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.

Differences in patient size often provide challenges for radiographers, particularly when choosing the optimum acquisition parameters to obtain radiographs with acceptable image quality (IQ) for diagnosis. This study aimed to assess the effect of body part thickness on IQ in terms of low‐contrast detail (LCD) detection and radiation dose when undertaking adult chest radiography (CXR). This investigation made use of a contrast detail (CD) phantom. Polymethyl methacrylate (PMMA) was utilised to approximate varied body part thicknesses (9, 11, 15 and 17 cm) simulating underweight, standard, overweight and obese patients, respectively. Different tube potentials were tested against a fixed 180 cm source to image distance (SID) and automatic exposure control (AEC). IQ was analysed using bespoke software thus providing an image quality figure inverse (IQFinv) value which represents LCD detectability. Dose area product (DAP) was utilised to represent the radiation dose. IQFinvvalues decreased statistically (P= 0.0001) with increasing phantom size across all tube potentials studied. The highest IQFinvvalues were obtained at 80 kVp for all phantom thicknesses (2.29, 2.02, 1.8 and 1.65, respectively). Radiation dose increased statistically (P= 0.0001) again with increasing phantom thicknesses. Our findings demonstrate that lower tube potentials provide the highest IQFinvscores for various body part thicknesses. This is not consistent with professional practice because radiographers frequently raise the tube potential with increased part thickness. Higher tube potentials did result in radiation dose reductions. Establishing a balance between dose and IQ, which must be acceptable for diagnosis, can prevent the patient from receiving unnecessary additional radiation dose. This study aimed to assess the effect of body part thickness on image quality in terms of low‐contrast detail detection and radiation dose when undertaking adult chest radiography. Findings of our study show that image quality decreased significantly with increasing body part thickness and the highest values of image quality were observed at lower tube potentials (80 and 85 kVp). Higher kVp settings did result in dose reductions.

This paper feeds into scholarly interest on place-based creative industrial development. It considers the creative-led economic development of two UK cities, Dundee and Chatham as emerging through a series of interdependent relationships between locally based higher education institutions (HEIs) and cultural and creative industries (CCIs) that are connected as part of a cultural and creative ecosystem (CCE). The discussion reflects on how interconnecting collaborations foster platforms and networks that support a sustainable CCE. Based on the research findings from qualitative investigations within each city, the paper applies the capability approach as a methodological tool to investigate how resources can be converted into tangible, accessible opportunities for local communities. The approach illustrates the need to focus on the resources that connect HEIs to CCIs within a geographical location for sustainable development. It concludes with a series of policy recommendations aimed at local governments to develop more integrated, ecological leadership models and policies to support sustainable CCEs.

Trauma bonds between sex trafficking survivors and their traffickers or other perpetrators are one of the most complex and least understood concerns facing survivors. This community-based participatory research phenomenological study sought to understand how survivors have experienced trauma bonding. The sample consisted of 19 female survivors who were all participants in or graduates of a human trafficking specialty docket. Two themes emerged from the data. The first theme is the source of the trauma bond, namely who survivors had trauma bonds with. The second theme is features of trauma bonds, which included three subthemes: survivors have experienced trauma bonds (a) as involuntary, (b) as having lingering power, and (c) as consisting of both love and hate. These findings contain significant implications for practice, policy, and future research.

Race is commonly used as a proxy for multiple features including socioeconomic status. It is critical to dissociate these factors, to identify mechanisms that affect infant outcomes, such as birth weight, gestational age, and brain development, and to direct appropriate interventions and shape public policy.

AbstractA circular lead tank was discovered in 2020 by metal detector users near Rudston, East Yorkshire, within the area of cropmarks of a ladder settlement complex. Emergency excavation revealed the tank to be associated with Roman potsherds and quern fragments and a possible flue. The tank had been nailed to a wooden vessel as an external basal lining which was damaged by heating from below. The subsequent decay of the wooden vessel promoted collapse of its setting. The finds and archive are deposited with the East Riding of Yorkshire Museum Service.

JTE-607 is an anticancer and anti-inflammatory compound and its active form, compound 2, directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-messenger RNA (pre-mRNA) 3′ processing. Surprisingly, compound 2-mediated inhibition of pre-mRNA cleavage is sequence specific and the drug sensitivity is predominantly determined by sequences flanking the cleavage site (CS). Using massively parallel in vitro assays, we identified key sequence features that determine drug sensitivity. We trained a machine learning model that can predict poly(A) site (PAS) relative sensitivity to compound 2 and provide the molecular basis for understanding the impact of JTE-607 on PAS selection and transcription termination genome wide. We propose that CPSF73 and associated factors bind to the CS region in a sequence-dependent manner and the interaction affinity determines compound 2 sensitivity. These results have not only elucidated the mechanism of action of JTE-607, but also unveiled an evolutionarily conserved sequence specificity of the mRNA 3′ processing machinery.