Isolation of a NHC-stabilized heavier nitrile and its conversion into an isonitrile analogue.

Nitriles (R-C≡N) have been investigated since the late eighteenth century and are ubiquitous encounters in organic and inorganic syntheses. In contrast, heavier nitriles, which contain the heavier analogues of carbon and nitrogen, are sparsely investigated species. Here we report the synthesis and isolation of a phosphino-silylene featuring an N-heterocyclic carbene-phosphinidene and a highly sterically demanding silyl group as substituents. Due to its unique structural motif, it can be regarded as a Lewis base-stabilized heavier nitrile. The Si-P bond displays multiple bond character and a bent R-Si-P geometry, the latter indicating fundamental differences between heavier and classical nitriles. In solution, a quantitative unusual rearrangement to a phosphasilenylidene occurs. This rearrangement is consistent with theoretical predictions of rearrangements from heavier nitriles to heavier isonitriles. Our preliminary reactivity studies revealed that both isomers exhibit highly nucleophilic silicon centres capable of oxidative addition and coordination to iron tetracarbonyl.

The third symposium on treatment-induced neuroendocrine prostate cancer: insights and future directions.

Neuroendocrine prostate cancer (NEPC) is a rare and aggressive subtype of prostate cancer (PCa), emerging from advanced treatments and characterized by loss of androgen receptor (AR) signaling and neuroendocrine features, leading to rapid progression and treatment resistance. The third symposium on treatment-induced NEPC, held from 21 to 23 June 2024, at Harrison Hot Springs Resort, BC, Canada, united leading global researchers and clinicians. Sponsored by the Vancouver Prostate Centre (VPC), Canadian Institute of Health Research, Prostate Cancer Foundation Canada and Pharma Planter Inc, the event focused on the latest NEPC research and innovative treatment strategies. Co-chaired by Drs. Yuzhuo Wang and Martin Gleave, the symposium featured sessions on NEPC's historical context, molecular pathways, epigenetic regulation and the role of the tumor microenvironment and metabolism in its progression. Keynotes from experts like Dr. Himisha Beltran and Dr. Martin Gleave highlighted the complexity of NEPC. The Emerging Talent session showcased new research, pointing to the future of NEPC treatment. The symposium concluded with a consensus on the need for early detection, targeted therapies and personalized medicine to effectively combat NEPC, emphasizing the importance of global collaboration in advancing NEPC understanding and treatment.

Orthopoxvirus-specific antibodies wane to undetectable levels 1 year after MVA-BN vaccination of at-risk individuals, the Netherlands, 2022 to 2023.

In response to the mpox outbreak in 2022 and 2023, widespread vaccination with modified vaccinia Ankara-Bavarian Nordic (MVA-BN, also known as JYNNEOS or Imvanex) was initiated. Here, we demonstrate that orthopoxvirus-specific binding and MVA-neutralising antibodies waned to undetectable levels 1 year post vaccination in at-risk individuals who received two doses of MVA-BN administered subcutaneously with an interval of 4 weeks, without prior smallpox or mpox vaccination. Continuous surveillance is essential to understand the impact of declining antibody levels.

Altering glycopeptide antibiotic biosynthesis through mutasynthesis allows incorporation of fluorinated phenylglycine residues.

Glycopeptide antibiotics (GPAs) are peptide natural products used as last resort treatments for antibiotic resistant bacterial infections. They are produced by the sequential activities of a linear nonribosomal peptide synthetase (NRPS), which assembles the heptapeptide core of GPAs, and cytochrome P450 (Oxy) enzymes, which perform a cascade of cyclisation reactions. The GPAs contain proteinogenic and nonproteinogenic amino acids, including phenylglycine residues such as 4-hydroxyphenylglycine (Hpg). The ability to incorporate non-proteinogenic amino acids in such peptides is a distinctive feature of the modular architecture of NRPSs, with each module selecting and incorporating a desired amino acid. Here, we have exploited this ability to produce and characterise GPA derivatives containing fluorinated phenylglycine (F-Phg) residues through a combination of mutasynthesis, biochemical, structural and bioactivity assays. Our data indicate that the incorporation of F-Phg residues is limited by poor acceptance by the NRPS machinery, and that the phenol moiety normally present on Hpg residues is essential to ensure both acceptance by the NRPS and the sequential cyclisation activity of Oxy enzymes. The principles learnt here may prove useful for the future production of GPA derivatives with more favourable properties through mixed feeding mutasynthesis approaches.

Recent trends and disparities in 24-hour movement behaviors among US youth with mental, behavioral and neurodevelopmental conditions.

BACKGROUND: Meeting 24-h movement behaviors (24-HMB: physical activity [PA], screen time [ST], and sleep [SL]) recommendations may be associated with positive health outcomes among youth with specific mental, behavioral, and neurodevelopmental (MBD) conditions. However, temporal trends and disparities in meeting 24-HMB guidelines in these higher-risk groups have not been investigated, hampering the development of evidence-based clinical and public health interventions. METHODS: Serial, cross-sectional analyses of nationally National Survey of Children's Health (NSCH) data (including U.S. youth aged 6-17 years with MBD conditions) were conducted. The time-trends survey data was conducted between 2016 and 2021. The prevalence of 24-HMB adherence estimates were reported for the overall sample and for various sociodemographic subgroups. The subgroups analyzed included: age group (children[aged 6 to 13 years], adolescents[aged 14 to 17 years]), sex, socioeconomic status, and ethnicity. RESULTS: Data on 52,634 individuals (mean age, 12.0 years [SD,3.5]; 28,829 [58.0 %] boys) were analyzed. From 2016 to 2021 the estimated trend in meeting PA + ST + SL guidelines declined (-0.8 % [95%CI, -1.0 % to -0.5 %], P for trend <0.001), whereas meeting none of 24-HMB guidelines increased (2.2 % [1.8 % to 2.6 %], P for trend <0.001). White participants, children, and boys reported higher estimated prevalence of meeting full integrated (PA + ST + SL) guidelines. DISCUSSION: The temporal trends observed in this study highlight the importance of consistently monitoring movement behavior among MBD youth and identifying variations by sociodemographic groups in meeting 24-HMB guidelines for health promotion within these vulnerable groups.

The chicken or the egg? Mycoplasma pneumoniae complicated by left ventricle thrombus and anterior myocardial infarction: a case report.

Background: Mycoplasma pneumoniae can be associated with extrapulmonary manifestations, including vasculitis, myocarditis, and thrombosis. In rare cases, it has also been implicated in intracardiac thrombus formation. Case Summary: A previously healthy 25-year-old male presented with worsening abdominal pain, an episode of acute chest pain, new lightheadedness, and gait instability in the setting of M. pneumoniae. Initial blood tests were notable for mild coagulopathy, thrombocytosis, transaminitis, and elevated high-sensitivity troponin. Further, workup revealed systematic emboli to the cerebellum, kidneys, spleen, anterior myocardial infarction, and a left ventricular multilobular mural mass. Due to the unknown composition of the mass with concern for further embolic events, the patient underwent successful surgical excision with the mass ultimately defined as a thrombus. Hypercoagulable workup was notably inconclusive and intraoperative myocardial biopsies revealed organizing infarction without inflammation or healed myocarditis. Post-operative course was complicated by left ventricular dysfunction and acute kidney injury, both with eventual improvement. Patient has remained on guideline-directed medical therapy and prophylactic anticoagulation. Discussion: We presume that the formation of the ventricular thrombus in this case was a result of transient thrombophilia in the setting of M. pneumonia resulting in coronary obstruction and subsequent myocardial injury. This case underscores the challenge of determining the pathophysiological sequence of events in patients with mycoplasma who develop systemic embolism and the management of a large residual thrombus, particularly in regard to surgical consideration.

Prescription and switching patterns of direct oral anticoagulants in patients with atrial fibrillation.

Background: The patterns of direct oral anticoagulant (DOAC) selection and switching to a different oral anticoagulant (OAC) in patients with atrial fibrillation (AF) are unknown. Objectives: To describe temporal patterns in first DOAC prescriptions, estimate the incidence, and identify predictors of switching to a different OAC within 1 year in OAC-naive AF patients. Methods: In this retrospective cohort study, using a near-nationwide prescription registry (IQVIA, the Netherlands), we determined the number of patients per month initiated on each DOAC and identified predictors of switching within 1 year with robust Poisson regression. Results: We included 94,874 patients. From November 2015 to November 2019, the monthly use of apixaban (n = 366 to n = 1066, +191%), rivaroxaban (n = 379 to n = 868, +129%), and edoxaban (n = 2 to n = 305, +15,150%) increased, whereas that of dabigatran decreased (n = 317 to n = 179, -44%). In the 66,090 patients with ≥1 year of available calendar time, 7% switched to a different OAC within 1 year. Strong predictors of switching to a different DOAC were using dabigatran (adjusted risk ratio [aRR], 3.33; 95% CI, 3.02-3.66) or edoxaban (aRR, 1.56; 95% CI, 1.34-1.82) rather than apixaban and using a standard DOAC dose (aRR, 2.54; 95% CI, 2.23-2.88). Strong predictors of switching to a vitamin K antagonist were using rivaroxaban (aRR, 1.36; 95% CI, 1.19-1.54 vs apixaban) and using a standard DOAC dose (aRR, 1.49; 95% CI, 1.26-1.77). Conclusion: In the Netherlands, factor Xa inhibitors are increasingly being selected for OAC-naive AF patients. Seven percent of patients switch to a different OAC within 1 year, and the initial DOAC type and dose are strong predictors of switching.

Phosphorylation of CRYAB Induces a Condensatopathy to Worsen Post-Myocardial Infarction Left Ventricular Remodeling.

Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart failure syndromes remains mechanistically unexamined. We observed mis-localization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by R120G mutation in the cognate chaperone protein, CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine-59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phospho-mimetic mutation of serine-59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity, and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knock-in was sufficient to induce desmin mis-localization and myocardial protein aggregates, while S59A CRYAB knock-in rescued left ventricular systolic dysfunction post-myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine-59 phosphorylation and rescued post-myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.

Tumor-derived GLI1 promotes remodeling of the immune tumor microenvironment in melanoma.

BACKGROUND: Melanoma progression is based on a close interaction between cancer cells and immune cells in the tumor microenvironment (TME). Thus, a better understanding of the mechanisms controlling TME dynamics and composition will help improve the management of this dismal disease. Work from our and other groups has reported the requirement of an active Hedgehog-GLI (HH-GLI) signaling for melanoma growth and stemness. However, the role of the downstream GLI1 transcription factor in melanoma TME remains largely unexplored. METHODS: The immune-modulatory activity of GLI1 was evaluated in a syngeneic B16F10 melanoma mouse model assessing immune populations by flow cytometry. Murine polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were differentiated from bone marrow cells and their immunosuppressive ability was assessed by inhibition of T cells. Conditioned media (CM) from GLI1-overexpressing mouse melanoma cells was used to culture PMN-MDSCs, and the effects of CM were evaluated by Transwell invasion assay and T cell inhibition. Cytokine array analysis, qPCR and chromatin immunoprecipitation were performed to explore the regulation of CX3CL1 expression by GLI1. Human monocyte-derived dendritic cells (moDCs) were cultured in CM from GLI1-silenced patient-derived melanoma cells to assess their activation and recruitment. Blocking antibodies anti-CX3CL1, anti-CCL7 and anti-CXCL8 were used for in vitro functional assays. RESULTS: Melanoma cell-intrinsic activation of GLI1 promotes changes in the infiltration of immune cells, leading to accumulation of immunosuppressive PMN-MDSCs and regulatory T cells, and to decreased infiltration of dendric cells (DCs), CD8 + and CD4 + T cells in the TME. In addition, we show that ectopic expression of GLI1 in melanoma cells enables PMN-MDSC expansion and recruitment, and increases their ability to inhibit T cells. The chemokine CX3CL1, a direct transcriptional target of GLI1, contributes to PMN-MDSC expansion and recruitment. Finally, silencing of GLI1 in patient-derived melanoma cells promotes the activation of human monocyte-derived dendritic cells (moDCs), increasing cytoskeleton remodeling and invasion ability. This phenotype is partially prevented by blocking the chemokine CCL7, but not CXCL8. CONCLUSION: Our findings highlight the relevance of tumor-derived GLI1 in promoting an immune-suppressive TME, which allows melanoma cells to evade the immune system, and pave the way for the design of new combination treatments targeting GLI1.

Bayesian spatial analysis of incomplete vaccination among children aged 12-23 months in Nigeria.

High childhood disease prevalence and under-five mortality rates have been consistently reported in Nigeria. Vaccination is a cost-effective preventive strategy against childhood diseases. Therefore, this study aimed to identify the determinants of Incomplete Vaccination (IV) among children aged 12-23 months in Nigeria. This cross-sectional design study utilized the 2018 Nigeria Demographic and Health Survey (NDHS) dataset. A two-stage cluster sampling technique was used to select women of reproductive age who have children (n = 5475) aged 12-23 months. The outcome variable was IV of children against childhood diseases. Data were analyzed using Integrated Nested Laplace Approximation and Bayesian binary regression models (α0.05). Visualization of incomplete vaccination was produced using the ArcGIS software. Children's mean age was 15.1 ± 3.2 months and the median number of vaccines received was four. Northern regions contributed largely to the IV. The likelihood of IV was lower among women aged 25-34 years (aOR = 0.67, 95% CI = 0.54-0.82, p < 0.05) and 35-49 years (aOR = 0.59, 95%CI = 0.46-0.77, p < 0.05) compared to younger women in the age group 15-24 years. An increasing level of education reduces the risk of odds of IV. Other predictors of IV were delivery at the health facility (aOR = 0.64, 95% CI = 053-0.76, p < 0.05), and media exposure (aOR = 0.63, 95%CI = 0.54-0.79, p < 0.05). Mothers' characteristics explained most of the variability in the IV, relatively to smaller overall contributions from the community and state-level factors (p < 0.05). The level of IV against childhood diseases was high in Nigeria. However, disparities exist across the regions and other socioeconomic segments of the population. More efforts are required to improve vaccination sensitization programs and campaigns in Nigeria.

Knowledge and Perceptions about Diagnosis, Clinical Management, and Prevention of Dengue Fever among Physicians during the 2023 Outbreak: A Cross-Sectional Study in Peru.

The objective of this study was to evaluate the knowledge level and perception of dengue fever management among Peruvian physicians and to determine the factors associated with higher knowledge. We conducted an analytical cross-sectional study based on an online survey. To evaluate the factors associated with a high level of knowledge (≥70% of correct answers), we used crude (cPR) and adjusted (aPR) prevalence ratios by the Poisson regression model. Of 359 respondents (median age: 33 years; male: 56.5%), 78.8% achieved a high level of knowledge. Multivariable analysis showed an independent association with having read the Peruvian clinical practice guidelines for dengue management (aPR: 1.29; 95% CI: 1.12-1.49), having experience in treating patients (aPR: 1.32; 95% CI: 1.03-1.68), and having treated cases frequently (aPR: 1.22; 95% CI: 1.02-1.46). Residing in the eastern macroregion (aPR: 0.83; 95% CI: 0.71-0.97) was associated with a low level of knowledge. In conclusion, Peruvian physicians had a high level of knowledge about dengue fever. This was associated with having clinical experience in dengue management. However, given the low level of knowledge in the eastern macroregion, educational campaigns are necessary in this area.

Community assessment of methods to deconvolve cellular composition from bulk gene expression.

We evaluate deconvolution methods, which infer levels of immune infiltration from bulk expression of tumor samples, through a community-wide DREAM Challenge. We assess six published and 22 community-contributed methods using in vitro and in silico transcriptional profiles of admixed cancer and healthy immune cells. Several published methods predict most cell types well, though they either were not trained to evaluate all functional CD8+ T cell states or do so with low accuracy. Several community-contributed methods address this gap, including a deep learning-based approach, whose strong performance establishes the applicability of this paradigm to deconvolution. Despite being developed largely using immune cells from healthy tissues, deconvolution methods predict levels of tumor-derived immune cells well. Our admixed and purified transcriptional profiles will be a valuable resource for developing deconvolution methods, including in response to common challenges we observe across methods, such as sensitive identification of functional CD4+ T cell states.

The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Ritlecitinib, a Janus Kinase 3 and Tyrosine-Protein Kinase Family Inhibitor, in Humans.

Ritlecitinib is an oral once-daily irreversible inhibitor of Janus kinase 3 and tyrosine-protein kinase family being developed for the treatment of moderate-to-severe alopecia areata. This study examined the disposition of ritlecitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite profiles. The results indicated ritlecitinib had a systemic clearance of 43.7 L/h, a steady state volume of distribution of 73.8 L, extent of absorption of 89%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 64%. An observed long terminal half-life of total radioactivity was primarily attributed to ritlecitinib binding to plasma albumin. Ritlecitinib was the main circulating drug species in plasma (∼30%), with one major pharmacologically inactive cysteine conjugated metabolite (M2) at >10%. Oxidative metabolism (fractional clearance 0.47) and glutathione-related conjugation (fractional clearance 0.24) were the primary routes of elimination for ritlecitinib with the greatest disposition of radioactivity shown in the urine (∼71%). In vitro phenotyping indicated ritlecitinib cytochrome P450 (CYP) fraction of metabolism assignments of 0.29 for CYP3A, 0.09 for CYP2C8, 0.07 for CYP1A2, and 0.02 for CYP2C9. In vitro phenotyping in recombinant human glutathione S-transferases indicated ritlecitinib was turned over by a number of cytosolic and microsomal enzyme isoforms. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of ritlecitinib, a JAK3 and TEC family kinase inhibitor for alopecia areata in humans, as well as characterization of clearance pathways and pharmacokinetics of ritlecitinib and its metabolites. As an AMS-based ADME study design, we have expanded on reporting the standard ADME endpoints, providing key pharmacokinetic parameters, such as clearance, volume of distribution, and bioavailability, allowing for a more comprehensive understanding of drug disposition.

Utility of Diffusion Tensor Imaging in Preterm Infants with Germinal Matrix Hemorrhage and Intraventricular Hemorrhage: A Systematic Review.

OBJECTIVE: Intraventricular hemorrhage (IVH) and germinal matrix hemorrhage (GMH) are the most common brain injuries in preterm infants. Neonates with these injuries are at greater risk of impaired neurodevelopmental outcome. Current guidelines recommend screening infants with cranial ultrasound (CUS); however, this is prone to missing subtle injury patterns, particularly within the posterior fossa. The present report sought to discuss the utility of diffusion tensor imaging (DTI) in preterm infants. METHODS: A systematic review of PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Included manuscripts were methodically scrutinized for quality, DTI use, and neurologic outcome. RESULTS: Twenty studies with 1574 infants who underwent DTI were included. There were 574 preterm infants with GMH-IVH on DTI. Twelve studies documented decreased fractional anisotropy, whereas 6 demonstrated structural segregation and asymmetrical white matter myelination in these infants. Seven studies documented concurrent CUS use with 2 studies comparing DTI findings with CUS findings. In both studies, DTI more accurately detected presence of GMH, especially within the cerebellum. Among GMH-IVH preterm infants, 58.5% demonstrated cognitive, intellectual, and language delays at follow-up (mean, 32.4 months). Additionally, lower fractional anisotropy values on initial DTI were associated with cognitive, language, and motor delays. CONCLUSIONS: Although DTI is more sensitive for picking up subtle injury patterns, CUS remains the standard of care when screening for injuries that would necessitate surgical intervention. DTI offers a refined understanding of the sequelae of GMH-IVH with microstructural changes found on DTI being associated with childhood motor and cognitive outcomes.

Combining Enhanced Resolving Power with Duty Cycle Improvements on a Multi-Reflecting Time-of-Flight Mass Spectrometer.

The combination of enhanced resolving power and improved duty cycle on a multireflecting time-of-flight mass spectrometer is described. Resolving power increases are achieved by extending the effective ion path length from 47 m to greater than 200 m. Path length increases are achieved through containment of ions within the analyzer for up to N = 5 passes using a pulsed deflection electrode. Resolving power was shown to increase from 220,000 to 402,000 (fwhm) at m/z 785 for N = 1 and N = 4 analyzer passes, respectively. Due to the timing of the pulsed deflection electrode, the approach is particularly suited to high resolution analysis over a targeted m/z range. Duty cycle enhancements are achieved for ions of the targeted m/z range via accumulation prior to orthogonal acceleration, providing signal improvements of 2 orders of magnitude. Achieving such high resolving powers at fast scan rates (30 Hz) can yield additional information such as fine isotope structure; when combined with ppb mass measurement accuracy, high confidence in analyte identification can be achieved. The technique is applied for N = 2 analyzer passes, demonstrating fine isotope structure for a typical UHPLC metabolite identification experiment at a 10 Hz acquisition rate. Additionally, mass spectrometry imaging data is acquired using DESI, demonstrating the improved image clarity achieved at >300,000 (fwhm).

Epigenetic regulation of the tumor microenvironment: A leading force driving pancreatic cancer.

Dysregulation of the epigenomic landscape of tumor cells has been implicated in the pathogenesis of pancreatic cancer. However, these alterations are not only restricted to neoplastic cells. The behavior of other cell populations in the tumor stroma such as cancer-associated fibroblasts, immune cells, and others are mostly regulated by epigenetic pathways. Here, we present an overview of the main cellular and acellular components of the pancreatic cancer tumor microenvironment and discuss how the epigenetic mechanisms operate at different levels in the stroma to establish a differential gene expression to regulate distinct cellular phenotypes contributing to pancreatic tumorigenesis.

Direct Oral Anticoagulants in Older and Frail Patients with Atrial Fibrillation: A Decade of Experience.

INTRODUCTION: Both the prevalence of atrial fibrillation (AF) and its subsequent use of direct oral anticoagulants (DOACs) are rapidly increasing in patients of older age. In the absence of contra-indications, guidelines advocate anticoagulation based on the CHA2DS2-VASc score for all AF patients aged 75 and above. However, some practitioners are hesitant to prescribe anticoagulants to older and frail patients due to perceived elevated bleeding risks. This review delves into the comparative treatment outcomes of DOACs versus vitamin K antagonists (VKAs) in older patients with AF, particularly focusing on those of advanced age, frailty, increased risk of falling, chronic kidney disease (CKD), or with a history of major bleeding. Additionally, considerations on the use of off-label DOAC doses, the role of left atrial appendage (LAA) closure and future developments in factor XIa-inhibitors will be discussed. RESULTS: While strong evidence supports the use of DOACs in the vital older patients with nonvalvular AF, it remains scant in frail patient groups. There is some evidence from non-randomized studies suggesting that the effect of DOACs compared with VKAs is consistent between frail and nonfrail patients. However, recent findings from a single randomized trial showed increased bleeding risks but comparable thromboembolic outcomes in frail individuals switching from VKAs to DOACs. In patients with an increased risk of falling, data suggest no relevant interaction of increased risk of falling on the effectiveness and safety of DOACs compared with warfarin. Resuming oral anticoagulants in patients with Af after major bleeding seems to be beneficial. Off-label low-dose DOAC is often prescribed to patients who were underrepresented in larger randomized trails because of an elevated risk of bleeding or overexposure to DOACs, but its effect on clinical outcomes remains uncertain. CONCLUSIONS: DOACs are the recommended oral anticoagulant for vital older patients with AF. The scarcity of data backing DOAC use in frail individuals, those with renal impairments, or significant bleeding history underscores the necessity for further investigation. However, existing evidence suggests at least similar effectiveness and safety and potential benefits for DOACs in these patient subsets. Therefore, there is no reason to suggest these patients should be treated differently than the established guidelines regarding anticoagulation.

A worldwide study of white matter microstructural alterations in people living with Parkinson's disease.

The progression of Parkinson's disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20-89 years; 33% female) and 885 controls (age: 19-84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen's d effect sizes reached d = -1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

Cryo-EM structure of the CDK2-cyclin A-CDC25A complex.

The cell division cycle 25 phosphatases CDC25A, B and C regulate cell cycle transitions by dephosphorylating residues in the conserved glycine-rich loop of CDKs to activate their activity. Here, we present the cryo-EM structure of CDK2-cyclin A in complex with CDC25A at 2.7 Å resolution, providing a detailed structural analysis of the overall complex architecture and key protein-protein interactions that underpin this 86 kDa complex. We further identify a CDC25A C-terminal helix that is critical for complex formation. Sequence conservation analysis suggests CDK1/2-cyclin A, CDK1-cyclin B and CDK2/3-cyclin E are suitable binding partners for CDC25A, whilst CDK4/6-cyclin D complexes appear unlikely substrates. A comparative structural analysis of CDK-containing complexes also confirms the functional importance of the conserved CDK1/2 GDSEID motif. This structure improves our understanding of the roles of CDC25 phosphatases in CDK regulation and may inform the development of CDC25-targeting anticancer strategies.