Cerebral amyloid angiopathy (CAA) is most commonly associated with β-amyloid deposition, but other amyloid proteins may accumulate in leptomeningeal and superficial cortical vessels. We report a man first evaluated neurologically at 44 years of age after approximately one year of recurrent upper-limb and perioral sensory symptoms with speech disturbance, retrospectively considered transient focal neurological episodes (TFNEs). During follow-up, he developed bilateral vitritis and progressive behavioral, psychiatric, and cognitive impairment. Brain computed tomography showed diffuse linear and serpiginous leptomeningeal hyperdensities, consistent with calcified amyloid deposits with focal cortical subarachnoid hemorrhagic lesions SAH); angiography showed no underlying vascular abnormality. Follow-up neuroimaging demonstrated persistent leptomeningeal abnormalities and hemorrhagic lesions. Leptomeningeal biopsy revealed Congo red- and thioflavin S-positive vascular and meningeal amyloid deposits, with negative β-amyloid and amyloid A immunohistochemistry. A subcutaneous adipose tissue biopsy supported systemic amyloid deposition, and genetic testing identified the heterozygous TTR c.265T > C, p.(Tyr89His) variant. Electroneurography showed no large-fiber peripheral neuropathy. An off-label trial of tolcapone produced no clinical benefit. The patient subsequently developed severe cognitive and functional disability and progressive hydrocephalus, and died at 55 years of age from acute respiratory failure. This case highlights TTR-related cerebral amyloid angiopathy (TTR-CAA) as an important non-β-amyloid cause of TFNEs, calcified leptomeningeal infiltration, focal superficial hemorrhage, and progressive neuropsychiatric decline.

Severe COVID-19 has been associated with hypercoagulability and platelet activation, which is known to result in excessive accumulation of serotonin. However, few studies have evaluated whether serotonergic blockade may improve clinical outcomes among those with COVID-19.

Does cyproheptadine, an antiserotonergic drug most commonly used to treat serotonin syndrome, improve time to clinical recovery in patients with severe COVID-19?

The Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis in COVID (I-SPY COVID) study is a phase 2, multicenter, adaptive, open-label randomized controlled trial designed to screen potential therapeutic agents rapidly to identify those with a high probability of improving outcomes for hospitalized critically ill patients with COVID-19. For this report, participants randomized to receive cyproheptadine 8 mg enterally every 8 hours for 10 days or until hospital discharge were compared with concurrently enrolled control patients who were treated with the standard of care regimen of dexamethasone and remdesivir and did not receive an investigational agent. Bayesian survival regression models were used to model the hazard functions for the 2 events of interest: (1) recovery (treating death as a competing event) and (2) overall death as a function of randomization arm and baseline COVID-19 level.

From September through December 2021, 35 participants were randomized and consented to receive cyproheptadine and 61 concurrent control patients were eligible for analysis. At that point, futility criteria were met and the data monitoring committee halted further enrollment into the cyproheptadine arm. The posterior probability that cyproheptadine would increase the rate of recovery was 0.1% and the posterior probability that cyproheptadine would improve survival was 16.3%.

In an open-label phase 2 trial of adults critically ill with severe COVID-19, cyproheptadine did not improve recovery or survival compared with the standard of care.

ClinicalTrials.gov; No.: NCT04488081; URL: www.clinicaltrials.gov.

Ischemic stroke (IS) management is challenged by low drug delivery efficiency and limitations in current imaging modalities. We aimed to assemble rapamycin (RAPA), indocyanine green (ICG), epigallocatechin-3-gallate (EGCG), and Gd³⁺ as neuroprotective drugs, near-infrared fluorescence (NIRF) imaging agents, biomimetic coatings, and MRI agents, respectively, into a carrier-free, dual-modal imaging-guided theranostic nanoplatform (IREGd NPs) for the integrated diagnosis and therapy of IS.

The physicochemical properties, cytotoxicity, drug release characteristics, and cellular uptake of IREGd NPs were characterized. Therapeutic efficacy was evaluated in vitro using oxygen-glucose deprivation/reoxygenation (OGD/R) models of cell injury and in vivo in a transient middle cerebral artery occlusion (tMCAO) rat model. Outcomes included sensorimotor function, cerebral infarct volume, brain edema, neuronal apoptosis, neuroinflammation, oxidative stress, and biodistribution. The bimodal imaging properties were verified in vitro and in vivo.

IREGd NPs demonstrated good dispersibility and stability, with a RAPA loading efficiency of 65.9 wt%, enabling enhanced MRI and NIRF imaging capabilities with a longitudinal relaxation rate of 40.18 mM^-1·s^-1 for precise visualization of the ischemic region and drug biodistribution. In vitro experiments confirmed effective cellular uptake and superior neuroprotective effects in OGD/R-treated cells compared with RAPA or EGCG alone. Finally, in vivo experiments in rats with tMCAO confirmed that IREGd NPs passively accumulated in the ischemic hemisphere, enabling accurate bimodal imaging and exerting neuroprotective effects, as evidenced by improved sensorimotor function, reduced cerebral infarct volume and brain edema, decreased neuronal apoptosis, and attenuated neuroinflammation and oxidative stress, outperforming individual RAPA or EGCG treatment. Histology revealed no systemic toxicity.

IREGd NPs efficiently deliver RAPA, and the neuroprotective effects are exerted by RAPA in combination with EGCG. Dual-modal imaging enables precise visualization of the ischemic region and drug biodistribution. These results suggest the translational potential of the biomimetic nanotheranostic platform for the treatment of IS.

In anesthesia and analgesia, opioids alone or in combination with local anesthetics (bupivacaine, lidocaine, and ropivacaine) have been investigated to prolong peripheral nerve blocks. Ultra-low-dose naloxone administration in local anesthetic solutions could lengthen sensory and motor blocks through enhanced opioid effects or direct antagonistic effects on the receptors. We aim to assess the role of ultra-low-dose naloxone as an additive in anesthesia duration, motor, and sensory block duration, visual analog scale (VAS) scores, opioid consumption, and the incidence of postoperative complications.

A systematic search was conducted in PubMed/Medline, Ovid Embase, and Web of Science up to November 23rd, 2023, and 840 records were retrieved and screened. Accordingly, seven randomized controlled trials met the eligibility criteria and were included for data extraction. The National Institute of Health's (NIH) Quality Assessment Tool for Clinical Trials was used for critical appraisal of the studies.

The effects of ultra-low-dose naloxone on intravenous regional anesthesia and various nerve blocks (including axillary and supraclavicular brachial plexus, peribulbar, femoral, and intercostal nerve block) were assessed. The administration of naloxone at doses of 100 and 50 ng as an additive to bupivacaine, lidocaine, and ropivacaine was associated with longer postoperative analgesia, prolonged motor and/or sensory block, lower postoperative opioid or analgesic consumption, and lower VAS pain scores in several included studies. Besides, in most studies, postoperative complications did not significantly differ between the groups.

The available evidence suggests that ultra-low-dose naloxone may be associated with prolonged postoperative analgesia and, in some studies, longer motor and/or sensory block duration and reduced postoperative opioid consumption. These findings should be interpreted as observations reported by individual studies rather than definitive treatment effects. Although no major safety concerns were identified, the available evidence is insufficient to establish the overall safety or efficacy of ultra-low-dose naloxone.

Observational studies have linked the gut microbiota and inflammatory proteins to atrial fibrillation (AF), but confounding, reverse causation, and instrument validity remain concerns.

We evaluated 473 microbial traits and 91 inflammatory proteins in relation to AF using two GWAS datasets. Sensitivity analyses included instruments selected at p < 5 × 10^-8, MR-RAPS, cis/trans-stratified protein MR, reverse MR, and FGF-5 colocalization. Participants were predominantly of European ancestry.

Under conventional IVW analysis, six associations were FDR-significant in the discovery analysis and remained FDR-significant when selectively evaluated in the second AF GWAS, with FDR correction applied across the six prioritized tests: Leptospirae (OR 0.605, 95% CI 0.457-0.800), Leptospirales (0.499, 0.371-0.673), leukemia inhibitory factor receptor (LIF-R; 0.905, 0.869-0.943), TWEAK (0.891, 0.856-0.927), FGF-5 (1.077, 1.051-1.103), and interleukin-6 (0.886, 0.834-0.942). At p < 5 × 10^-8, neither microbial trait had a harmonized instrument, whereas the protein estimates retained their directions. MR-RAPS supported LIF-R in both datasets, but support for the other signals varied. The prioritized proteins also differed in cis/trans genetic architecture. The FGF-5 cis-only estimates were based on two harmonized instruments and were therefore preliminary, while cis-region colocalization provided little evidence of a shared variant (PP.H4 = 0.0045).

The conventional IVW associations varied in robustness across alternative analyses. These findings prioritize hypotheses, not established causal pathways or clinical targets. Generalizability beyond predominantly European populations remains uncertain.

The ageing of the cirrhotic population, together with the epidemiological shift toward metabolic dysfunction-associated steatohepatitis, is redefining the profile of patients referred for transjugular intrahepatic portosystemic shunt (TIPS). Although TIPS remains a cornerstone in the management of complications of portal hypertension, its abrupt hemodynamic and metabolic effects challenge the physiological reserve of multiple organ systems. Age-related cardiovascular remodeling, cirrhotic cardiomyopathy, impaired renal function and autoregulation, and reduced neurocognitive reserve interact with the hyperdynamic circulatory state of cirrhosis increasing the susceptibility to heart failure, acute kidney injury (AKI), and hepatic encephalopathy following TIPS. This vulnerability is further amplified by metabolic comorbidities, obesity, sarcopenia, frailty, and age-related alterations of the gut microbiota and gut-liver axis, which collectively promote systemic inflammation, immune dysregulation, endothelial dysfunction, and reduced metabolic adaptability. Rather than independently, these factors shape an interconnected heart-liver-kidney-brain network in which dysfunction in one domain may rapidly propagate to others. This review summarizes how ageing influences the cardiovascular, renal, neurological, and metabolic response to TIPS, critically appraises current strategies for pre-procedural risk assessment, and discusses approaches to improve patient selection and peri-procedural management. Because chronological age alone inadequately reflects procedural risk and clinical outcomes, TIPS evaluation should incorporate a structured assessment of biological ageing, including cardiovascular and renal reserve, neurocognitive vulnerability, sarcopenia, frailty, body-composition phenotype, and metabolic burden. Integrating these domains into pre-procedural assessment may improve patient selection, inform shunt sizing, and ultimately optimize outcomes in this rapidly evolving patient population.

Stimuli-responsive nanotherapy (SRN) has emerged as a promising therapeutic strategy that employs nanosensitizers activated by external physical or chemical stimuli to generate reactive species for disease treatment. Among various nanosensitizers, metal nanoparticles (MNPs) have attracted considerable attention owing to their unique physicochemical properties, including tunable optical responses, catalytic activity, magnetic behavior, and high surface reactivity. These characteristics enable the construction of versatile nanoplatforms for multiple dynamic therapeutic modalities. In this review, we summarize the fundamental physicochemical properties of representative metal nanoparticles and their relevance to stimulus-responsive nanotherapies. We systematically review major therapeutic modalities, including photodynamic therapy (PDT), photothermal therapy (PTT), sonodynamic therapy (SDT), piezocatalytic therapy (PCT), magnetic hyperthermia therapy (MHT), chemodynamic therapy (CDT), and electrodynamic therapy (EDT), with emphasis on their underlying mechanisms, material design, and recent biomedical applications. We further discuss the advantages and limitations of these therapeutic strategies and highlight recent advances in multifunctional nanoplatforms that integrate multiple therapeutic mechanisms to achieve synergistic effects. The biomedical applications of these metal nanoparticle-based therapies in tumor treatment, infection control, neurological disorders, bone tissue regeneration, and cardiovascular diseases are highlighted. Finally, current challenges and future perspectives are addressed, with particular emphasis on biosafety, therapeutic efficiency, stimulus control, multimodal integration, and clinical translation. This review provides an integrated overview of metal nanoparticle-based stimuli-responsive nanotherapies and highlights opportunities for the rational design of multifunctional therapeutic platforms.

Cancer-associated cachexia (CAC) is increasingly recognized as a systemic metabolic disorder characterized by progressive skeletal muscle wasting, adipose tissue remodeling, chronic inflammation, and profound metabolic dysfunction, which collectively compromise therapeutic efficacy and patient survival. Although accumulating experimental studies have demonstrated that tumor-derived extracellular vesicles (EVs) contribute to CAC, current evidence is largely fragmented, with most studies focusing on individual EV cargoes or isolated signaling pathways rather than providing an integrated mechanistic perspective. This review evaluates representative experimental studies describing how tumor-derived EVs regulate skeletal muscle atrophy, adipose tissue remodeling, inflammatory responses, and metabolic reprogramming during cachexia progression. We further summarize recent advances in EV-based biomarkers and therapeutic strategies, while discussing current challenges and future directions for clinical translation. In particular, circulating EV-associated molecules, including glucose-regulated protein 75 (GRP75) and specific miRNAs, have shown promise as diagnostic and prognostic biomarkers. Unlike previous reviews that primarily focus on individual EV cargoes or signaling pathways, this review integrates representative experimental evidence spanning molecular mechanisms, biomarker discovery, and therapeutic intervention, thereby providing a comprehensive overview of the multifaceted roles of tumor-derived EVs in CAC and their translational potential as biomarkers and therapeutic targets.

Cerebral venous sinus thrombosis is a rare cerebrovascular disease of importance both during pregnancy and in the puerperium. However, the existing cohort literature relates to two distinct clinical populations: women with acute onset of pregnancy-/puerperium-associated cerebral venous thrombosis (CVST), and women with known previous CVST who were assessed in connection with a subsequent pregnancy. As these populations address distinct clinical questions and have distinct denominators and follow-up structures, this review has distinguished outcomes from the two populations and synthesized them separately.

A PRISMA-compliant systematic review was conducted searching six bibliographic databases for evidence on CVST/central venous thrombosis (CVT), pregnancy/puerperium, and follow-up cohorts. Cohort studies only have been eligible for inclusion, with the additional criterion of a follow-up period of ≥5 years or participant-level follow-up period of ≥5 years. This particular criterion was used mainly as an aid to interpreting data on recurrence or subsequent pregnancy, while for outcomes related to acute obstetric CVST, it was used simply as a measure of study period. Outcomes have been summarized as pooled proportions by random-effects meta-analysis with pre-specified stratification in follow-up cohorts (women with known CVST in the past) and study period cohorts (acute obstetric CVST).

Twelve studies were included. In follow-up cohorts assessing subsequent pregnancy following previous CVST, deliveries/livebirths pooled to 69.6% (95% CI 59.2 to 78.4%, I² = 51.7%), spontaneous miscarriage pooled to 19.4% (95% CI 13.8 to 26.5%, I² = 20.6%), and recurrence of cerebral venous sinus thrombosis during subsequent pregnancy/puerperium pooled to 3.17% (95% CI 1.43 to 6.89%, I² = 0%). In acute pregnancy/puerperium cerebral venous sinus thrombosis cohorts, maternal mortality pooled to 8.28% (95% CI 5.65 to 11.97%, I² = 0%), while acute-phase anticoagulation use pooled to 92.9% (95% CI 64.8 to 98.9%) with high heterogeneity (I² = 81.2%). These outcomes were thus interpreted within the context of their particular population and observation period.

Long-term follow-up cohorts indicated that subsequent pregnancy following previous cerebral venous sinus thrombosis was associated with good delivery outcomes and low recurrence in cases when CVST management included structured risk stratification and appropriate prophylaxis. Acute obstetric CVST cohorts, on the other hand, dealt with acute morbidity, mortality, and treatment, and not with future pregnancy safety, with significant maternal mortality burden.

PROSPERO registration number CRD420261328921.

This study aimed to determine the effects of dosage forms on the steady-state dose-corrected (C/D) concentrations of quetiapine and N-desalkylquetiapine in patients.

This was a retrospective cohort study that included 831 therapeutic drug monitoring samples derived from 512 patients. Multiple linear regression analysis was used to identify independent factors that affected the C/D values for quetiapine and N-desalkylquetiapine. Moreover, we compared the C/D values of quetiapine and N-desalkylquetiapine between the two groups and conducted subgroup analyses based on daily dose, sex, and age.

The C/D ratio of quetiapine in the extended-release (XR) group was 1.7-fold higher compared with that in the immediate-release (IR) group (P < 0.001); however, no statistically significant difference was observed in the C/D ratio of N-desalkylquetiapine between the two subgroups (P > 0.05). In the subgroups stratified by daily dose, sex, and age group, the C/D ratios of quetiapine in the XR group were 1.31-2.65-fold higher compared with that in the IR group (all P < 0.001). No significant differences were observed in the C/D ratio of N-desalkylquetiapine among the subgroups (P > 0.05).

Dosage form significantly affects the steady-state C/D ratio of quetiapine; however, it does not significantly affect the C/D ratio of N-desalkylquetiapine.