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STAT3 SH2 Domain Aspartic Acid 661 Mutations Activate Immune Gene Programs
No full textThe conserved aspartic acid residue D661 within the STAT3 SH2 domain is a recurrent mutational hotspot in hematologic malignancies, including T-cell large granular lymphocytic leukaemia, myelodysplastic syndromes and acute lymphoblastic leukaemia. To define the functional consequences of distinct STAT3
variants, we integrated computational, structural and in vitro and in vivo genetic approaches. AlphaMissense and PolyPhen-2 classified all four STAT3
variants (D661Y, D661V, D661N and D661H) as pathogenic. ClinVar classified D661Y and D661V as variants of uncertain significance. AlphaFold 3-based modelling predicted that D661Y and D661V strongly promoted SH2-TAD-mediated dimerization, while D661N and D661H exerted weaker structural effects. Functional in vitro assays in Stat3-deficient T cells demonstrated a gain-of-function (GOF) hierarchy of the STAT3 variants (D661Y ≈ V > H > N) resulting in activation of canonical STAT3 target genes and immune transcriptional programs. In vivo, only STAT3
mice were viable, displaying reduced CD4
T cells, expansion of memory CD8
T cells and enhanced immune gene expression. Collectively, our findings define a gradient of STAT3 D661 GOF variants, consistent with in vitro and in vivo experiments. D661Y and D661V mutants exhibited stronger transcriptional activity in T cells with impaired viability of mice carrying these variants
CCDC 2515370: Experimental Crystal Structure Determination
No full textAn entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures
The global need for paediatric palliative care: the evolution of serious health-related suffering in children aged 0–19 years from 1990 to 2023: a modelling study
No full textUltrasonographic Thrombosis Rates Associated with Midline Catheters in Patients with Advanced Chronic Kidney Disease: A Prospective Cohort Study
No full textBackground: Preserving arm veins is important for arteriovenous fistula (AVF) creation in patients with advanced chronic kidney disease (CKD), as mature AVF is the preferred hemodialysis access. Midline catheters introduced into AVF candidate veins may cause thrombosis, hindering AVF formation. This study aims to determine ultrasonographic rates of midline-associated upper extremity deep venous thrombosis (UE-DVT) or superficial venous thrombosis (SVT) in patients with advanced CKD. Methods: We conducted a prospective study involving subjects with advanced CKD, who had a point-of-care ultrasound-guided midline placed in an arm vein. Within 35 days of midline insertion, participants underwent routine bilateral UE venous duplex ultrasound. The primary outcome was a composite occurrence of UE-DVT/SVT ipsilateral to the midline. Comparative analyses were performed based on patient demographics and device-specific variables. Results: 49 subjects with advanced CKD received midlines. The median midline catheter dwell time was <6 days for 15/49 patients (30.6%). The primary outcome occurred in 15/49 patients (30.6%), mostly asymptomatic thrombosis. No significant associations were found between outcomes and patient or device characteristics. Conclusions: Our study identified frequent use of midlines with short dwell times in subjects with advanced CKD which calls into question proper device selection. In this cohort, midline-associated arm clots were frequent
Employing Machine Learning for New Particle Formation Identification and Mechanistic Analysis: Insights From a Six-Year Observational Study in the Southern Great Plains
No full textWe present a supervised machine learning (ML) framework to automatically identify new particle formation (NPF) events and analyze key atmospheric factors associated with their occurrence and growth. We applied ML to detect NPF events using start time and particle concentrations across size ranges, while identifying atmospheric variables including ambient temperature, relative humidity, solar radiation intensity (SRI), wind speed, wind direction, boundary layer height, total organics, sulfate, nitrate, total surface area concentration, sulfur dioxide, and turbulent kinetic energy (TKE). We analyzed a 6-year data set from the Atmospheric Radiation Measurement at the Southern Great Plains (SGP) site in Oklahoma, USA. Using long-term ground-based measurements, we identified NPF events and applied Random Forest Classifiers, which achieved 90%-95% prediction accuracy. Feature importance analysis highlighted SRI, relative humidity, and ambient temperature as the most influential variables, contributing normalized importances of 28%, 17%, and 10%. Partial Dependence Plots (PDPs) indicated that higher SRI and lower relative humidity were critical in promoting NPF formation at SGP. Seasonally, NPF events were more frequent in winter (42.1%) and spring (35.5%), and least in summer (4.0%). Particle growth rates also exhibited a seasonal variation, with the lowest in winter (below 2 nm hr-1) and highest in late spring and early summer (exceeding 5 nm hr-1). Temperature, turbulent kinetic energy, and aerosol properties were the primary factors of growth rate variability. This study advances predictive modeling of NPF, offers insights for future campaign deployments, and demonstrates the effectiveness of ML in understanding the formation and growth of atmospheric aerosols
The Role of Obstructive Sleep Apnea and Diabetes Mellitus in the Development of Cerebrovascular Complications: A Narrative Review
No full textBackground: Cerebrovascular accidents (stroke) remain a leading global cause of death and disability, with its burden increasingly overlapping the rising prevalence of obstructive sleep apnea (OSA) and diabetes mellitus (DM). These highly prevalent cardiometabolic conditions frequently coexist and may jointly amplify cerebrovascular risk through shared and interacting pathophysiologic pathways. This narrative review synthesizes current evidence on the independent and combined contributions of OSA and DM to cerebrovascular complications, with emphasis on mechanisms, stroke outcomes and implications for screening and integrated management. Methods: A narrative review was conducted using PubMed, MEDLINE, and the Cochrane Library to identify English-language articles published between January 2000 and December 2024. Search terms combined OSA or sleep-disordered breathing with stroke or cerebrovascular disease and DM or hyperglycemia. Secondary searches targeted mechanistic domains including intermittent hypoxia, insulin resistance, metabolic syndrome, atrial fibrillation, hypercoagulability, and bariatric surgery. Priority was given to systematic reviews and meta-analyses, randomized controlled trials, and large prospective cohort studies, with smaller studies included when mechanistically informative. Findings were synthesized thematically across OSA-related mechanisms, DM-related mechanisms, bidirectional interactions, combined risk through metabolic syndrome, stroke outcomes, and clinical management considerations. Results: OSA is associated with increased cerebrovascular risk through intermittent hypoxemia-related oxidative stress and inflammation, sympathetic activation with blood pressure surges and sustained hypertension, endothelial dysfunction and atherosclerosis, impaired cerebral autoregulation, arrhythmogenesis, particularly atrial fibrillation and prothrombotic changes. DM increases stroke risk via accelerated atherosclerosis, cerebral small vessel disease, endothelial injury, hypercoagulability, glycemic variability, and cardioembolic mechanisms. Evidence indicates that coexisting OSA and DM are common and associated with greater vascular injury markers, higher rates of cerebrovascular events, and poorer post-stroke recovery. Conclusions: OSA and DM contribute to cerebrovascular complications through convergent mechanisms centered on metabolic syndrome, obesity, inflammation, vascular dysfunction, and thrombosis. These findings support proactive screening and coordinated management strategies to reduce cerebrovascular risk and improve outcomes
Effectiveness of Corticosteroid-Sparing Topical Treatments for Vernal Keratoconjunctivitis in Children: A Report by the American Academy of Ophthalmology
No full textTo review the published literature assessing the efficacy of corticosteroid-sparing topical treatments for vernal keratoconjunctivitis (VKC) in children 18 years of age and younger.
A literature search of the PubMed database was last conducted in August 2025 and limited to articles published in English without date restrictions. The search yielded 56 articles, which were reviewed by the primary author in abstract form; 24 were selected for full-text review. Fifteen articles met the inclusion criteria and were assigned a level of evidence rating by the panel methodologist.
Six studies were rated level I, and 9 studies were rated level III. Level I evidence evaluated the efficacy of cyclosporine (4/6), tacrolimus (4/6), interferon alpha-2b (1/6), and sodium cromoglycate (1/6) ophthalmic preparations. Most level III evidence studies (5/9) reported outcomes using tacrolimus drops or ointment. Regardless of the medication, concentration, dosing frequency, or treatment duration, level I and level III evidence included in the assessment demonstrated that signs and symptoms of VKC in children can be improved with intervention. Apart from application site discomfort, the studies reported no significant adverse events.
Level I and III evidence demonstrate that treatment with corticosteroid-sparing topical interventions such as cyclosporine, tacrolimus, sodium cromoglycate, and interferon alpha-2b can improve clinical signs and symptoms of VKC in children. Most of the level I evidence supports the use of the calcineurin inhibitors-cyclosporine and tacrolimus.
Proprietary or commercial disclosure may be found after the references
Characterizing UV-induced fluorescence dermatoscopy (UVFD) of warts and molluscum contagiosum and its utility for expert and novice dermatoscopists
No full textUltraviolet-induced fluorescence dermatoscopy (UVFD), an emerging dermatoscopy mode, has proven utility in guiding the diagnosis of skin conditions by identifying unique patterns. The primary aim of this study was to describe the dermatoscopic findings of warts and molluscum contagiosum (MC) using UVFD. The secondary objective was to determine the perceived diagnostic confidence of this technique across different levels of experience. We conducted a descriptive and observational study at a Tertiary Care Center. 30 warts and 55 MCs were included. Polarized dermoscopy and UVFD structures were evaluated. Diagnostic confidence (scored from 1 to 6) under UVFD was assessed for both conditions and tested across different levels of dermatoscopy expertise using an online-survey. Under UVFD, 96.7% of the warts had bluish-white fluorescence, while 43.6% of MC were hyporeflective and 100% had yellowish or bluish fluorescent rounded/oval structures. There was a statistically significant increase in the mean diagnostic confidence score when using UVFD compared to polarized light for the assessment of warts (5.52 ± 0.45 vs. 4.89 ± 0.75; p = 0.005) and MC (5.41 ± 0.43 vs. 5.05 ± 0.42; p = 0.012) in the ‘non-expert group’. In the ‘expert group’ this difference in confidence was not significant. UVFD revealed distinct fluorescence patterns in warts and MCs and was associated with higher perceived diagnostic confidence among non-experts. Limitations include the descriptive design, small sample size, and lesion heterogeneity. This study describes the potential of UVFD as a complementary tool to traditional dermatoscopy for identification of warts and MC. UVFD could be especially relevant among less experienced dermatoscopists
Therapeutic management of intracranial internal carotid artery blowout syndrome: an institutional case series and individual participant data meta-analysis
No full textCarotid blowout syndrome is a constellation of clinical presentations involving injury to the extracranial carotid system. It is frequently secondary to postradiation effects or direct invasion from head and neck cancers and is often managed via endovascular therapy (EVT). However, intracranial internal carotid artery blowout syndrome (ICABS) is a less described entity, has no predefined management algorithms, and can be difficult to manage due to the inherent anatomical limitations of the intracranial carotid. The aim of this study was to perform an individual participant data meta-analysis and present an institutional case series to describe the clinical course of ICABS, as well as to provide a treatment algorithm for this rare syndrome.
A search for all reported ICABS cases was performed using PubMed, Embase, Scopus, Web of Science, and Google Scholar until June 30, 2024. Additional cases from our institution were added. The primary outcomes were hemorrhagic control, postoperative complications, and all-cause mortality.
The database search yielded 31 studies, and with the addition of 8 patients from the study institution, 80 patients (median age was 55 years) with ICABS were analyzed. The most common injury type was acute blowout (53.8%) and the most commonly affected segment was the petrous internal carotid artery (43.8%). The most frequent underlying diagnosis was head and neck cancer (52.5%). Radiation therapy (37.5%) and surgery (37.4%) were the most common preceding interventions. Overall bleeding control after individualized therapy was attained in 81.2% of patients, with most requiring parent vessel sacrifice (41.2%). The overall postoperative complication rate was 35%. The overall mortality rate was 27.5%, with mortality occurring predominantly in the conservative treatment group (60%) compared with the EVT (27.6%) and surgery (17.6%) groups.
ICABS is rare and often fatal. It frequently occurs after radiation therapy for head and neck cancer or iatrogenically during transsphenoidal surgery. First-line treatment for acute ICABS is often EVT, as it offers a rapid means of halting further hemorrhage. Emerging technologies have allowed for more vessel-preserving strategies and warrant further investigation. Herein, an evidence-based algorithm is provided to help guide management. Systematic review registration no.: CRD42022385494 (www.crd.york.ac.uk/prospero/)
