Periodontitis is a highly prevalent chronic inflammatory disease characterized by irreversible destruction of the tooth-supporting tissues. Although classically interpreted as the consequence of excessive inflammation that drives microbial dysbiosis, accumulating experimental and clinical evidence indicates that periodontitis can be more precisely described as a disorder of failed inflammatory resolution. In periodontal tissues-constantly exposed to microbial challenge-resolution is not a terminal event but a constitutive biological requirement essential for maintaining tissue homeostasis. This chapter examines the molecular and cellular mechanisms through which pro-resolving pathways become dysregulated in periodontitis, with particular emphasis on imbalances in lipid mediator networks, defective biosynthetic class switching, impaired receptor-mediated signaling, altered leukocyte fate decisions, and disruption of osteoimmune coupling. We further discuss how these resolution defects are functionally expressed across immune, stromal, and bone compartments, and how they reshape the inflammatory microenvironment and host-microbiome interactions. Finally, we evaluate the implications of these mechanisms for resolution pharmacology, highlighting how restoration of endogenous termination and repair programs-rather than suppression of inflammatory initiation-offers a biologically grounded therapeutic paradigm. Collectively, this chapter positions periodontitis as both a disease-specific manifestation of resolution failure and a tractable translational model for advancing resolution-based therapeutic strategies with potential relevance beyond oral tissues.
Introduction. Acinetobacter baumannii is an opportunistic pathogen responsible for severe hospital-acquired infections, including bloodstream infections (BSIs). Although major epidemic clones and resistance mechanisms have been described, integrated analyses combining clinical features, patient outcomes and genomic characteristics of BSI isolates remain limited, particularly in China.Gap Statement. Comprehensive analyses integrating clinical outcomes, high-resolution genotyping, capsule locus diversity and their associations with mortality are still lacking.Aim. This study aimed to characterize the clinical characteristics and outcomes of patients with A. baumannii BSIs, as well as the phenotypic and genomic characteristics of the causative isolates. Specifically, we sought to identify high-risk clones and their association with 30-day mortality to improve diagnostic and therapeutic strategies.Methodology. A retrospective cohort study was conducted on 151 cases of A. baumannii BSIs in a tertiary hospital in China. Isolates were analysed using whole-genome sequencing to determine sequence types (STs), capsule loci and resistance and virulence gene profiles.Results. The 151 isolates were classified into 11 different STs using the Pasteur MLST scheme, with ST2Pasteur predominating (88.1%). One isolate represented a novel Pasteur ST (ST2831Pasteur). Using the Oxford MLST scheme, 22 STs were identified, with ST195Oxford, ST208Oxford and ST540Oxford being the most common. Four novel Oxford STs (ST2457Oxford, ST2458Oxford, ST2459Oxford and ST2460Oxford) were identified. Twenty-three capsule locus (KL) types were detected, with KL3 being the most prevalent. Phylogenetic analysis showed clear clustering according to STs and KL types. The ST2Pasteur lineage was characterized by the presence of the OXA-23 gene and carbapenem resistance, as well as an expanded virulence gene repertoire, suggesting enhanced pathogenic potential. The overall 30-day mortality rate was 35.1%. Patients in the death group had shorter hospital stays, fewer surgical interventions and higher rates of complications, invasive procedures and intensive care unit admission. Certain clone combinations, including ST369Oxford-KL9, ST938Oxford-KL210 and ST195Oxford-KL3, were associated with higher mortality rates.Conclusion. ST369Oxford-KL9, ST938Oxford-KL210 and ST195Oxford-KL3 represent high-risk clones associated with A. baumannii BSIs. Early identification of ST and capsule type, alongside clinical risk stratification, may improve diagnosis and guide treatment strategies.
Extended-spectrum cephalosporinases (ESCs) confer resistance to a range of beta-lactam compounds, including many cephalosporins and have grown in prevalence since the early 2000s. ESCs are often disseminated via plasmids, which can also encode other genes that confer bacterial fitness. Until recently, detailed characterization of plasmids encoding antimicrobial resistance genes was limited by the technical ability to close plasmid genomes. Recent advances in long-read technology have simplified this problem, facilitating the characterization of the genetic structure of plasmids and their component genes. This study examined the genetic mechanisms that underpin the stability of the most common cefotaximase-encoding plasmids in Escherichia coli recovered from UK livestock between 2013 and 2020. The most common plasmid replicon types were IncF, IncI1 and IncX, and the predominant cefotaximases were bla CTX-M-1, blaCTX-M-14, bla CTX-M-15 and bla CTX-M-55; in this study, we focused on IncI1 plasmids only which were most commonly associated with the cefotaximases in our dataset. Comparison of circularized plasmid genomes revealed that IncI1/bla CTX-M-1 plasmids showed a high degree of genetic similarity to one another in the time period examined, as did IncI1/bla CTX-M-14 plasmids, indicating stability of these plasmid genomes. Overall, our results indicate that IncI1/bla CTX-M-1 plasmids carry genes promoting their maintenance in host E. coli and encode several genes that may enhance their fitness. Therefore, these plasmids may play an important role in the persistence of ESC resistance in E. coli isolated from One-Health compartments, despite nationwide reductions in cephalosporin usage in both humans and livestock.
Asciminib (ASC) is a novel BCR::ABL1 tyrosine kinase inhibitor that binds to the ABL myristoyl pocket. Although dose adjustments for renal impairment are generally considered unnecessary, pharmacokinetic data for patients with end-stage renal disease or those on dialysis are limited. A 72-year-old man with chronic phase chronic myeloid leukemia undergoing maintenance hemodialysis for chronic renal failure was treated with ASC. Owing to cardiovascular risk, treatment was initiated at a reduced dose of 40 mg once daily. A major molecular response was achieved within 3 months without adverse events. Pharmacokinetic analysis revealed a delayed apparent Tmax (> 4 h), suggesting prolonged absorption. ASC concentrations did not decrease during dialysis sessions compared with non-dialysis days. The median trough concentration was 89.0 ng/mL, with a coefficient of variation of 30.9%. ASC demonstrated negligible dialyzability, likely because of its high plasma protein binding (97.3%). However, the study revealed a significantly delayed apparent Tmax and high intra-individual variability in plasma concentrations. These findings suggest that clinicians should prioritize monitoring for delayed gastrointestinal absorption and potentially reduced bioavailability in patients undergoing maintenance hemodialysis, rather than focusing on drug removal by dialysis.
Cardiac complications rank among the leading contributors to poor outcomes in ischemic stroke patients along with the neurological impairment, while the risk stratification and prognostic significance of post-stroke acute heart failure (PSHF) remain poorly characterized. This study aimed to investigate the incidence, predictors, and impacts of PSHF in patients with large vessel occlusion stroke (LVO) undergoing endovascular treatment (EVT). Given that cardioembolic stroke inherently involves underlying cardiac pathology, a secondary aim was to test whether the effect of stroke severity on PSHF was modified by cardioembolic etiology and whether PSHF mediated the effect of stroke severity on functional outcome in these patients. In a pooled analysis of individual patient data from four multicenter prospective studies conducted in China between January 2014 and June 2023, we included 3,415 patients with LVO who underwent EVT. The primary outcome was very poor functional outcome, defined as 90-day modified Rankin Scale (mRS) 5-6. Multivariable regression models, interaction testing, and mediation analysis were used, with adjustment for clinically relevant covariates including demographic characteristics, vascular risk factors, baseline stroke severity, imaging characteristics, and treatment-related factors. PSHF developed in 278 patients (8.14%), with its incidence reaching peak at 1 day after stroke onset. PSHF was significantly associated with a higher rate of very poor outcome (62.23% versus 31.08%, adjusted odds ratio (aOR) 3.09, 95% confidence interval (CI) [2.25, 4.24]). A significant interaction was observed between cardioembolism and the baseline National Institutes of Health Stroke Scale (NIHSS) score (p for interaction = 0.016). Moderate-to-severe stroke significantly increased the risk of PSHF in patients with cardioembolic stroke (aOR 1.91, 95% CI [1.28, 2.87]), but not in those with non-cardioembolic stroke (aOR 0.97, 95% CI [0.81, 1.82]). Mediation analysis showed that PSHF mediated 7.70% (95% CI [2.40, 12.40]) of the effect of moderate‑to‑severe stroke on very poor outcome among cardioembolic patients. The main methodological limitations were the pooled design using studies with different protocols and the potential for residual unmeasured confounding. PSHF was significantly associated with very poor outcome in LVO patients undergoing EVT. Moderate-to-severe cardioembolic LVO substantially elevated the risk of PSHF, with PSHF partially mediating the adverse prognostic impact of stroke severity. Early risk assessment and monitoring for PSHF may optimize management in this high-risk population.
Parkinson's disease (PD) is a progressive neurodegenerative disease characterised by disruption of brain homeostasis and degeneration of dopaminergic neurons in the substantia nigra. PD is characterised by motor symptoms, like tremor, rigidity, bradykinesia, and postural instability, as well as non-motor symptoms like cognitive impairment, mood disorders, sleep disturbances, and autonomic abnormalities that significantly affect quality of life. The molecular pathogenesis of PD involves Oxidative stress, neuroinflammation, mitochondrial dysfunction, α-synuclein (α-syn) misfolding and aggregation, insufficient autophagy-lysosomal clearance, and synaptic degeneration, leading to progressive neuronal loss. Transthyretin (TTR), a tetrameric transport protein that is primarily produced in the liver and choroid plexus, is well-known for carrying thyroxine and retinol-binding protein. Experimental studies have shown that TTR can protect neurons by binding misfolded proteins, such as α-syn, decreasing toxic aggregation, regulating oxidative stress responses, and affecting selective autophagic degradation. PD-related changes in TTR expression in brain tissue and cerebrospinal fluid provide strong evidence of TTR's significance as a molecular biomarker and a physiological regulator in the pathogenesis of the disease. This review highlights TTR involvement in neuroinflammation, oxidative stress, and α-syn aggregation, and discusses emerging evidence supporting TTR stabilizers as potential biomarkers and therapeutic targets for modulating disease progression in PD.
Colorectal cancer (CRC) represents one of the most prevalent and lethal malignancies worldwide, with rapidly increasing global incidence and mortality. Current clinical therapies for CRC are severely compromised by tumor metastasis, intrinsic and acquired drug resistance, and unsatisfactory prognosis for advanced patients, highlighting an urgent demand for novel and effective therapeutic candidates. As privileged multifunctional scaffolds, indole hybrids integrate diverse pharmacophores to achieve simultaneous modulation of multiple CRC-associated oncogenic signaling pathways and mutant proteins, enabling them to overcome the limitations of traditional single-target drugs, reduce systemic toxicity, and optimize pharmacokinetic performance. This review comprehensively summarizes the research progress of novel indole hybrids for anti-CRC therapy reported since 2021, excluding indole-pyrimidine and indole-pyridine hybrids covered in previous studies. Notably, among all summarized subclasses, indole-chalcone/chromene, indole-hydroxamic acid/benzamide, and indole-azole hybrids, show the most prominent and promising therapeutic outcomes. These three dominant hybrid categories display potent antiproliferative activity against both drug-sensitive and drug-resistant CRC cell lines, exert robust in vivo tumor growth inhibition in xenograft models, and possess favorable safety profiles with low cytotoxicity to normal cells. We systematically elaborate their key structure-activity relationships, core anti-CRC molecular mechanisms, including cell cycle arrest, apoptosis induction, and targeted pathway regulation, as well as superior preclinical pharmacological characteristics. Furthermore, the current challenges and future research directions for indole hybrid-based anti-CRC drug development are discussed.
Despite established sex differences in cardiovascular-kidney-metabolic (CKM) syndrome, sex-based treatment approaches remain lacking, partly due to limited appropriate female animal models. This study characterized sex differences in cardiorenal phenotype associated with high fat diet (HFD) intervention in mice, and additionally assessed the impact of the sodium glucose co-transporter 2 inhibitor (SGLT2i), dapagliflozin, a therapy previously shown to improve cardiorenal outcomes in patients. Chow or HFD (60% kJ lipids) commenced at 6 weeks of age in male and female C57BL/6J mice. At 18 weeks of age, HFD mice were randomized to 8 weeks of dapagliflozin (2.5 mg/kg/day) or vehicle (20% Trappsol®) treatment via s.c. osmotic mini-pumps. Metabolic phenotype and cardiac function were assessed pre-treatment and at endpoint, with cardiac and renal pathophysiology measured using tissue collected at study end. HFD-induced elevations in percentage fat mass were more pronounced in female mice, accompanied by modest impairments in left ventricular systolic function, and alterations in the cardiac lipidome and metabolome. In the kidney, sex differences were also apparent, in renal structure and remodeling, mitochondrial function and markers of oxidative stress, incretin receptors, and sodium solute carriers (at the transcriptomic level). Plasma concentrations of dapagliflozin did not reach target levels in either sex; low-dose treatment improved glucose tolerance and circulating creatinine levels only in male HFD mice. In conclusion, although only modest impact of HFD and dapagliflozin were observed, sex differences in the early development of CKM syndrome were apparent in male and female mice.
A series of thirteen novel β-carboline and chloroquine (CQ) hybrids was designed and synthesized. The compounds were evaluated for in vitro antiplasmodial activity against Plasmodium falciparum strains 3D7 (CQ-sensitive) and Dd2 (multidrug-resistant). All compounds exhibited potent activity, with IC 50 values in the nanomolar to low micromolar range, while retaining potency against the resistant strain (1.0 to 365.5 nmol L-1 for 3D7 and from 2.2 to 2415.3 nmol L-1 for Dd2 strain). Several compounds were more active against Dd2, then against 3D7 strain with resistance index (RI) lower than 1. Moreover, nearly all compounds showed lower RI values compared to CQ which additionally underscores their outstanding activity. At the highest tested concentration (250 μmol L-1), no cytotoxicity was observed in HepG2 cells, resulting in favourable selectivity indices expressed as lower limits. Overall, the obtained results confirm strong antiplasmodial activity of the β-carboline and chloroquine hybrids as promising antiplasmodial candidates, particularly due to their activity against resistant strains and improved selectivity.
Urinary incontinence (UI), a prevalent quality-of-life-limiting condition, frequently coexists with hip osteoarthritis, potentially through pelvic floor dysfunction related to obturator internus muscle involvement. Several reports suggest improvement after total hip arthroplasty (THA), although postoperative time-course changes remain unclear. This study aimed to clarify the temporal trends in UI after THA and examine association of postoperative UI trajectories with functional recovery. This retrospective study included 118 female patients who underwent THA for hip osteoarthritis between October 2021 and March 2024. UI, assessed using the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), was defined as ICIQ-SF ≥ 1 preoperatively and at 3, 6, 9, and 12 months postoperatively, and classified as stress (SUI), urge (UUI), or mixed (MUI). Hip-related patient-reported outcomes were evaluated using the Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ). Associations with BMI, age, surgical approach (direct lateral/Bauer vs. modified Watson-Jones/OCM), and UI type were tested using Mann-Whitney U, chi-squared, and repeated-measures ANOVA tests. Of 118 patients (mean age at surgery, 67 years; mean BMI, 24.3 kg/m2) preoperatively, 73 (61.9%) reported UI (mean ICIQ-SF 7.88), including SUI (n = 20), UUI (n = 26), and MUI (n = 27), with a higher baseline severity in MUI than in UUI. The mean ICIQ-SF improved markedly by 3 months (3.88) with a significant time effect (p < 0.001, η2 = 0.39), but then plateaued through 12 months. Although most patients improved, 45/73 (61.6%) had persistent UI at 12 months. These patients had higher preoperative ICIQ-SF and significantly worse postoperative JHEQ (notably pain) across multiple time points, while BMI, approach, and UI type showed no significant group differences. UI symptoms improved significantly within the first 3 months following THA; however, subsequent recovery was limited. Persistent UI was associated with poorer functional recovery and higher pain levels.
Decreased dietary K+-intake stimulates the expression of Regulatory-Associated-Protein-of-mTOR (RAPTOR) in kidneys and increases mRNA of Raptor in aldosterone sensitive distal nephrons. The aim of the study is to explore the role of mTORc1 in stimulating Kir4.1/Kir5.1 and Na-Cl-cotransporter (NCC), and inhibiting renal-outer-medullary K+ channel (ROMK or Kir1.1) and epithelial-Na+-channel (ENaC) during overnight low-K+-intake (LK). Deletion of RAPTOR in kidneys inhibited basolateral Kir4.1/Kir5.1 of distal convoluted tubule (DCT) and decreased the expression of phosphor-NCC and total-NCC. Furthermore, ENaC and ROMK baseline activity in late-DCT/early connecting tubule (CNT) and cortical collecting duct (CCD) of kidney-tubule-specific-RAPTOR knockout mice (Ks-RAPTOR-KO) were higher than Raptorflox/flox mice. Consequently, Ks-RAPTOR-KO mice had higher baseline kidney K+ excretion and lower plasma K+ concentrations than Raptorflox/flox mice. Overnight-LK-intake stimulated Kir4.1/Kir5.1 activity of DCT and the expression of phosphor-NCC and total-NCC in Raptorflox/flox mice. In contrast, overnight-LK failed to stimulate Kir4.1/Kir5.1 of the DCT and did not increase the expression of phosphor-NCC and total-NCC in Ks-RAPTOR-KO mice. Moreover, overnight-LK inhibits ROMK and ENaC in late-DCT/early-CNT and CCD only in Raptorflox/flox mice but not in Ks-RAPTOR-KO mice. Thus, male/female Ks-RAPTOR-KO mice on overnight-LK had lower plasma K+ levels and higher kidney K+ excretion than Raptorflox/flox mice. We conclude that mTORc1 plays a key role in suppressing kidney K+ excretion during decreased dietary K+ intake.
Sousa and colleagues recently published a review of substance use in supportive oncology ostensibly addressing its impact on clinical outcomes. The paper is substantively a monitoring review; no clinical outcomes data are presented or analyzed. I identify 11 domains of concern: (1) the title's unmet promise of outcomes evidence; (2) the conflation of complex opioid dependence with addiction; (3) the absence of demonstrated benefit from opioid monitoring in cancer populations; (4) the poor diagnostic accuracy of risk screening instruments as quantified by likelihood ratio analysis; (5) regulatory and guideline prohibitions against opioid discontinuation or practice dismissal on the basis of aberrant urine drug screens; (6) the systematic inadequacy of clinician competence in urine drug screen interpretation; (7) an unfavorable cost-benefit ratio for universal surveillance in supportive oncology; (8) the stigmatizing effect of universal screening and its contribution to disparities in cancer pain management; (9) the failure to distinguish patients with advanced cancer from cancer survivors, populations with fundamentally different risk horizons and therapeutic priorities; (10) the risk that evidence-free monitoring recommendations will propagate into institutional policy and payer requirements, generating measurable financial toxicity without demonstrated clinical return; and (11) the absence of any management pathway for positive screening results - a logical incompleteness that renders the entire surveillance framework clinically inoperable, since neither dismissal from practice nor opioid discontinuation is appropriate in most circumstances, and an absent opioid on UDS does not constitute evidence of diversion in isolation. I argue that the dominant failure mode in oncology opioid management is undertreatment, not diversion, and that any framework proposing expanded surveillance must first demonstrate that it does not worsen this problem.
Catheter-related right atrial thrombosis is a rare, potentially fatal complication of central venous catheterization. While most reported cases involve thrombi attached to the catheter tip or mobile intracardiac masses, systemic sclerosis (SSc) is associated with endothelial injury and impaired vascular repair, presenting a unique risk profile characterized by increased susceptibility to thrombus formation. A 56-year-old woman on maintenance hemodialysis for 20 years for IgA nephropathy has had SSc for 10 years after developing digital ulcers. One year before presentation, she developed steal syndrome, causing the closure of her arteriovenous access. Consequently, a tunneled dialysis catheter was inserted via the right internal jugular vein. Transthoracic echocardiography performed 1 year later revealed a right atrial mass, prompting referral for further evaluation. Anticoagulation with warfarin was initiated for a suspected right atrial thrombus. However, the mass enlarged progressively, raising suspicion of a neoplastic lesion. Surgical resection identified a 20 × 20 mm mass attached to the posterior-inferior right atrial wall, which was confirmed as an organized thrombus on histopathological examination. Although the catheter tip was not adherent to the thrombus, repetitive contact between the catheter tip and the right atrial wall occurred during atrial motion. Thus, thrombus formation was attributed to chronic mechanical irritation from the catheter tip, exacerbated by systemic sclerosis-related endothelial vulnerability. This case highlights that chronic mechanical irritation from a deeply positioned dialysis catheter tip can cause a non-catheter-adherent mural right atrial thrombus. SSc-associated endothelial vulnerability may have contributed to impaired recovery from chronic endothelial injury.
Aging is a major risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). Targeting cellular senescence has therefore emerged as a promising therapeutic strategy. Resveratrol (RV), a natural polyphenolic compound, exhibits anti-aging properties through the regulation of autophagy and oxidative stress; however, its mechanisms in AD remain incompletely understood. In this study, we investigated the effects and underlying mechanisms of RV in an Aβ1-42-induced AD model. In vivo, RV administration significantly reduced the expression of aging-related markers and activated autophagy-associated signaling pathways. In vitro, RV treatment markedly attenuated Aβ1-42-induced cell viability loss and excessive reactive oxygen species (ROS) production. Further mechanistic analyses demonstrated that RV-induced autophagy activation was closely associated with the AMP-activated protein kinase/UNC-51-like kinase 1 (AMPK/ULK1) and silent information regulator 1/nuclear factor-kappaB (SIRT1/NF-κB) pathways. Collectively, these findings suggest that RV alleviates AD-related pathological processes by promoting autophagy and delaying cellular senescence, highlighting its potential as a therapeutic agent for age-related neurodegenerative diseases.
BackgroundMigraine is a common condition that causes a high burden of disability even at a young age, significantly affecting various aspects of quality of life. Despite this significant burden, the pharmacological treatment of migraine is still a subject of debate, with controversial results that do not provide sufficient evidence of its effectiveness. Furthermore, the safety profile in this inherently fragile population leaves some doubts about pharmacological prophylaxis use. This study aims to provide an overview of the safety profile of the main drugs used in populations of children and adolescents with migraine, analysing the type and frequency of the main side effects reported.MethodsPubMed and Scopus were systematically searched for papers reporting adverse events (AEs) of pharmacological prophylaxis of migraine in children and adolescents, and all eligible original articles were included. A meta-analysis was carried out to define the pooled proportion of the summary safety information (i.e. the number of subjects reporting at least one AE) with 95% confidence intervals for those compounds present in at least two samples, regardless of dosage.ResultsIn total, 40 studies were included, accounting for 62 subsamples and 2742 patients (55% females). The most used compounds were topiramate (22 subsamples), propranolol and sodium valproate (six subsamples). Overall, 30% of patients reported at least one AE. Erenumab showed the highest rate of AEs, most likely due to the higher-precision detection typical of a randomized controlled trial, and cinnarizine the lowest. In total, 53 different AEs were reported, most frequently drowsiness, anorexia, fatigue and paraesthesia.ConclusionsIn accordance with the results of this systematic review with a meta-analysis, clinicians should consider that 30% of the paediatric patients with migraine will report some AEs from prevention treatment. The information on the safety profile is essential for clinicians in evaluating the choice of a specific therapy, making a better risk/benefit ratio evaluation for each single patient, which is crucial in consideration of the inconsistent efficacy profiles of preventive medications, with the exception of topiramate, in this population.
Obesity is a chronic, relapsing, multisystem disease in which cardiometabolic risk arises from excess adiposity and progressive dysfunction of peripheral organs, ultimately disrupting endocrine and metabolic crosstalk among tissues. Within this network, sulphur-based biology, centred on hydrogen sulphide and related reactive sulphur species, has emerged as a key regulator of metabolic homeostasis, vascular tone, inflammatory response and mitochondrial function. Here, we review the chemical and mechanistic landscape of sulphaceutics (pharmacological sulphur-releasing agents) and sulphanutraceutics (diet-derived organosulphur compounds), focusing on their capacity to reprogramme peripheral dysfunctions in obesity. Evidence from experimental models, also supported by emerging human data, indicates that sulphur-based interventions can enhance skeletal muscle insulin signalling and performance, restore endothelial reactivity and reduce vascular inflammation, thereby modulating adipose expansion and inflammatory tone. These actions reflect the engagement of upstream redox-sensitive regulatory nodes rather than non-specific antioxidant effects, consistent with a system pharmacology mode of action.
Endovascular thrombectomy (EVT) has transformed the treatment of acute ischemic stroke (AIS). However, a substantial proportion of AIS patients experience poor outcomes despite successful recanalization, often due to severe neurological deterioration or life-threatening complications. Early identification of these high-risk patients remains a major unmet need. In this study, we developed and validated machine-learning (ML) models that integrate automated quantitative brain arterial morphology and collateral grading with demographic, clinical, laboratory, and imaging variables to predict major post-EVT complications and early neurological outcomes. Using a prospectively collected database of 727 AIS patients that underwent EVT, we developed ML models to incorporate patient-specific vascular morphometry with conventional clinical, laboratory, and imaging data to predict emergence of early neurological deterioration (END), symptomatic intracranial hemorrhage (sICH), malignant brain edema (MBE) requiring surgical decompression, and neurogenic respiratory failure and dysphagia requiring tracheostomy/gastrostomy (TC/PEG). Our analysis of morphological features, including increased tortuosity and reduced vessel diameter, showed strong associations with complications. Morphology-informed (MI) models consistently outperformed baseline-clinical (BC) models for patients with END (AUROC 0.81 for MI model vs. 0.73 for BC), sICH (AUROC 0.68 MI vs. 0.56 BC model), MBE (AUROC 0.67 MI model vs. 0.56 BC), or patients who underwent TC/PEG (AUROC 0.66MI vs. 0.58 BC model). Statistical testing confirmed significant AUROC improvements for END, sICH and mRS (p < 0.05), Finally, patient-specific calibrated probability profiles enabled individualized, multidimensional risk stratification, revealing distinct complication-specific risk patterns across patients. These findings demonstrate that cerebrovascular structure-an often overlooked yet physiologically fundamental determinant of ischemic injury and reperfusion dynamics-provides significant predictive information that is not captured by standard clinical or visual imaging assessments. Automated vascular segmentation and collateral grading techniques enable rapid and objective integration of cerebrovascular metrics into prognostic models, offering a scalable tool for precision risk stratification, supporting earlier intervention, targeted monitoring, and improved post-EVT management.
Temozolomide (TMZ) is an oral alkylating agent that represents a cornerstone therapy for glioblastoma and other high-grade gliomas. Although TMZ is generally well tolerated, hypersensitivity reactions (HSRs), including urticaria, have rarely been reported and may lead to treatment interruption. Rapid drug desensitization (RDD) offers a potential strategy to enable continuation of essential therapy; however, standardized protocols for TMZ are limited. Here, we present a 46-year-old woman with glioblastoma who developed widespread urticaria during maintenance TMZ therapy. The reaction developed within four hours of the last dose and completely resolved following treatment with corticosteroids and antihistamines within 24 h. Based on clinical history and lesion characteristics, an immediate HSR to TMZ was considered. As no alternative treatment options were available, an oral RDD protocol targeting a dose of 240 mg was prepared. The protocol included stepwise dose escalation using diluted oral solutions followed by capsule administration, with premedication using cetirizine and methylprednisolone. Desensitization was successfully completed without breakthrough reactions, and the protocol was repeated in two consecutive cycles without complications. Our protocol provides detailed information on drug preparation, dose increments, and administration intervals, supporting its reproducibility and feasibility. This case contributes to the limited literature by demonstrating that oral RDD can be safely and effectively performed in patients with TMZ-induced urticaria. The successful repetition of desensitization further supports the safety of this approach. This protocol may assist clinicians in maintaining first-line TMZ therapy in patients with HSRs, thereby preventing unnecessary treatment interruptions and improving clinical outcomes.
Our research uncovers a new role for ATR in responding to extracellular matrix (ECM) stiffness and promoting epithelial-to-mesenchymal transition (EMT) and metastasis. ATR, when deubiquitinated and upregulated by USP21 under enhanced ECM stiffness conditions, phosphorylates the nuclear protein SUN2 which promotes β-catenin nuclear translocation and EMT. ATM mediated EMT promotes polymorphonuclear myeloid-derived suppressor cell recruitment and inhibits CD103+ dendritic cells, fostering an immunosuppressive tumor milieu. ATR inhibition disrupts this malignant cascade by promoting mesenchymal to epithelial transition to enhance anti-tumor immunity and mitigate metastases. Consistently, circulating HLA-DR+ dendritic cells were also enhanced following treatment with the ATR inhibitor, Berzosertib, in patients with therapeutically resistant early-stage breast cancer. Our data suggest that ATR targeted therapy may be optimized by considering both DNA damage dependent and EMT inducing effects of ATR.
To evaluate serum lipoproteins and other metabolites and their potential associations with the development of postoperative delirium. Prospective observational cohort study. Single-site academic medical hospital. Patients age 60 years and older scheduled for major cardiac surgery with cardiopulmonary bypass (CPB). Delirium assessments were performed at baseline and twice daily up to postoperative day 3. The primary outcome evaluated serum collected before surgery, at the start and end of CPB, and on postoperative day 1. Sixty-five patients were recruited, with 18% of subjects developing postoperative delirium within 3 days of surgery (10 of 57 subjects with complete cognitive assessments). Metabolomic analysis of serum revealed an association between the abundance of cholesterol in large high-density lipoprotein (L-HDL-C%) at the start of CPB and the development of postoperative delirium (odds ratio per standard deviation increment in biomarker concentration, 0.23; 95% confidence interval [CI], 0.08-0.66). Serum neurofilament light chain was inversely correlated with L-HDL-C% levels at the same time point (Spearman ρ, -0.39; 95% CI, -0.59 to -0.15) and was significantly higher at the end of CPB in subjects who developed delirium compared to subjects who did not develop delirium (median, 20.4 [interquartile range (IQR),16.1-25.4] pg/mL vs 11.9 [IQR, 7.9-16.9] pg/mL). Circulating blood biomarkers during surgery may provide insight into postoperative cognitive outcomes and should be evaluated in larger cohorts.