Importance Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting. Objective To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW). Design, Setting, and Participants This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate. Exposure Association between NfL z scores and CDW. Main Outcome Measures CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively. Results A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years). Conclusions and Relevance This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

This study aims to evaluate two distinct approaches for fiber radius estimation using diffusion‐relaxation MRI data acquired in biomimetic microfiber phantoms that mimic hollow axons. The methods considered are the spherical mean power‐law approach and a T2‐based pore size estimation technique.

SAŽETAK Perfuzija se odnosi na isporuku kiseonika i hranljive materije u tkiva putem protok krvi i jedan je od najosnovnijih fiziološki parametri. Poremećaji perfuzije takođe čine većinu vodeći uzroci medicinskog invaliditeta i mortalitet. Dok mjerenja od perfuzije imaju direktnu dijagnostičku vrijednost u vaskularni poremećaji, mjerenja perfuzije takođe služe kao biomarkeri za a širi spektar fizioloških i patofizioloških funkcije. Bliska sprega između cerebralnog krvotoka i metabolizma omogućava regionalnu funkciju mozga biti procijenjen mjerenjima od cerebralnu perfuziju i povećanu vaskularnost neoplazmi omogućava perfuziju tumora da se koristi kao mjera tumora stepena i za praćenje odgovora na tumor terapija. U oblasti MRI, najviše ljudi povezuju pojam perfuzije snimanje s dinamičkim kontrastom osjetljivosti snimanje pomoću kontrasta za opuštanje agent. ASL Perfuzija je tehnika MR perfuzije koja ne zahtjeva intravensku primjenu kontrastnog sredstva ( za razliku od DSc I DCE perfuzije). Umjesto toga, koristi sposobnost MRI-a da magnetski označi arterijsku krv. Parametar koji se najčešče izvodi je cerebralni protok krvi (CBF). ASL je vrlo pogodna tehnika za upotrebu u pedijatriji, u kojoj upotreba radioaktivnih tragova moze biti ograničena. Također je sigurna metoda za primjenu kod pacijenata sa oštečenom bubrežnom funkcijom.

There is an increasing demand for green plant walls in indoor environments because of their multifaced benefits, such as aesthetic appeal, indoor air quality improvement, or psychological well-being. Mosses are believed to be excellent for these walls due to their easy application and maintenance. However, so far there is no evidence for their indoor survival. In this study, we tested the moss species Hypnum cupressiforme, Bryachythecium rutabulum, Eurrhynchium angustirete, Thuidium tamariscinum, Streblotrichum convolutum, Syntrichia ruralis, and Ceratodon purpureus for indoor use in living moss walls. We evaluated their vitality through the monitoring of leaf coloration over a twelve month period, subjecting them to varying temperature ranges (14–20 °C), humidity levels (60–100%), and diverse irrigation methods (drip and spray irrigation, 300–1500 mL per day) within controlled climate chambers. Depending on the combination of these variables, mosses survived up to six months. Hypnum cupressiforme and Ceratodon purpureus performed best. However, as the time span of survival was limited, the use of living mosses for indoor purposes at the current stage cannot be recommended. An additional problem is that the requisition of living material such as in the culturing of moss under horticultural conditions is difficult and harvesting from natural environments is detrimental to most habitats.

Background The absence of the susceptibility vessel sign (SVS) in patients treated with mechanical thrombectomy (MT) is associated with poor radiological and clinical outcomes after 3 months. Underlying conditions, such as cancer, are assumed to influence SVS status and could potentially impact the long-term outcome. We aimed to assess SVS status as an independent predictor of long-term outcomes in MT-treated patients. Methods SVS status was retrospectively determined in consecutive MT-treated patients at a comprehensive stroke center between 2010 and 2018. Predictors of long-term mortality and poor functional outcome (modified Rankin Scale (mRS) ≥3) up to 8 years were identified using multivariable Cox and logistic regression, respectively. Results Of the 558 patients included, SVS was absent in 13% (n=71) and present in 87% (n=487) on baseline imaging. Patients without SVS were more likely to have active cancer (P=0.003) and diabetes mellitus (P<0.001) at the time of stroke. The median long-term follow-up time was 1058 days (IQR 533–1671 days). After adjustment for active cancer and diabetes mellitus, among others, the absence of SVS was associated with long-term mortality (adjusted HR (aHR) 2.11, 95% CI 1.35 to 3.29) and poor functional outcome in the long term (adjusted OR (aOR) 2.90, 95% CI 1.29 to 6.55). Conclusion MT-treated patients without SVS have higher long-term mortality rates and poorer long-term functional outcome. It appears that this association cannot be explained by comorbidities alone, and further studies are warranted.

Clinical utility and diagnostic sensitivity of new‐generation flat‐panel computed tomography perfusion imaging (FPCTP) performed immediately after mechanical thrombectomy (MT) is unknown. We aimed to assess whether FPCTP obtained directly after MT could provide additional potentially relevant information on tissue reperfusion status. Qualitative, single‐center analysis of all consecutive acute stroke patients admitted between 06/2019 and 03/2021 who underwent MT and post‐interventional FPCTP (n=26). A core‐lab blinded to technical details and clinical data performed reperfusion grading on post‐interventional digital subtraction angiography (DSA) images and time‐sensitive FPCTP maps. All patients were classified according to agreement between DSA and FPCTP. In 10/26 patients FPCTP revealed new, potentially clinically relevant information. Core‐lab adjudicated dichotomized detection of hypoperfusion (present/absent) was concurring in 21/26 (81%) patients. Of these, reperfusion findings showed perfect agreement on location and size in 16 (62%) patients, while in 5 (19%) patients with incomplete reperfusion, FPCTP showed additional hypoperfused areas missed on DSA. Of the remaining five patients subject to disagreement regarding the presence or absence of hypoperfusion, three showed complete reperfusion on DSA but hypoperfusion was noted on FPCTP, whereas two showed incomplete reperfusion on DSA without detectable hypoperfusion on FPCTP. FPCTP findings could have avoided Thrombolysis in Cerebral Infarction (TICI) overestimation in all false‐positive operator‐rated TICI3 cases. In both core‐lab and real‐world operator assessment, FPCTP may provide additional clinically relevant information in a considerable percentage of patients undergoing MT. Hence, FPCTP may constitute a new standard for evaluating reperfusion efficacy and informed decision making in the angiography suite.

The benefit of additional reperfusion attempts in patients with partial angiographic reperfusion (TICI2b) is unknown. The PROCEED model predicts subsequent favorable occurrence of complete reperfusion (i.e. delayed reperfusion [DR]) at 24 hours after initial incomplete angiographic reperfusion at the conclusion of thrombectomy. This study aims to externally validate the PROCEED model using pooled data from multiple international trials that systematically performed follow‐up perfusion imaging. Individual patient data for external validation were obtained from the EXTEND‐IA, EXTEND‐IA TNK part 1 and 2 trials (clinicaltrials.gov, unique‐identifier: NCT01492725, NCT02388061 and NCT03340493). The model’s primary outcome of interest was the occurrence of DR, defined as the absence of any focal perfusion deficit on follow‐up CT or MRI perfusion imaging maps, despite initial incomplete angiographic reperfusion on the final thrombectomy angiography series. The updated model’s performance was evaluated with discrimination, calibration and clinical decision curves. We analyzed 267 patients for the external validation, with median age of 74 (IQR 64 – 80), 44.2% were female and 62% had DR. The externally validated model had good discrimination (C‐statistic 0.81, 95% CI 0.72 – 0.86) and was well calibrated (intercept 0.22, 95% CI 0.18‐0.33 and slope 0.96, 95% CI 0.81‐1.23). With threshold probability of R=12% (i.e. 88% chance of having DR), pursuing additional reperfusion attempts to pursue complete angiographic reperfusion in a patient with high‐likelihood of DR were seven times worse (Cost:Benefit Ratio 1:7, Figure 1) than no further endovascular maneuver. In terms of standardized net reduction, the PROCEED model could reduce one in five unnecessary interventions without missing an intervention for any patient who would eventually have DR. Across a wide range of threshold probabilities, the model outperformed the scenario of the typical decision‐making process in the angiography suite, based on the current treatment guidelines. The externally validated model had good predictive accuracy and discrimination. Depending on the acceptable risk threshold, the model may compliment clinical judgment of the treating physicians and inform on natural progression of untreated incomplete reperfusion.

Exclusive semileptonic b hadron decays (b → uℓν) serve as a sandbox for probing strong and electroweak interactions and for extracting the CKM element Vub. Instead, this work investigates their underexplored potential to reveal new short-distance physics. Utilizing SMEFT as a conduit to chart territory beyond the SM, we demonstrate that substantive new physics contributions in b → uℓν are necessarily linked to correlated effects in rare neutral-current b decays, neutral B meson mixing or high-mass Drell-Yan tails. We find that measurements of the latter processes strongly restrict the allowed deviations in the former. A complete set of tree-level mediators, originating from a perturbative ultraviolet model and matching at dimension 6, is thoroughly explored to support this assertion. As a showcase application, we examine the feasibility of a new physics interpretation of the recent tension in exclusive |Vub| extraction from B → Vℓν where V = (ρ, ω).

This systematic review assesses current molecular targeted therapies for glioblastoma multiforme (GBM), a challenging condition with limited treatment options. Using PRISMA methodology, 166 eligible studies, involving 2526 patients (61.49% male, 38.51% female, with a male-to-female ratio of 1.59/1), were analyzed. In laboratory studies, 52.52% primarily used human glioblastoma cell cultures (HCC), and 43.17% employed animal samples (mainly mice). Clinical participants ranged from 18 to 100 years, with 60.2% using combined therapies and 39.8% monotherapies. Mechanistic categories included Protein Kinase Phosphorylation (41.6%), Cell Cycle-Related Mechanisms (18.1%), Microenvironmental Targets (19.9%), Immunological Targets (4.2%), and Other Mechanisms (16.3%). Key molecular targets included Epidermal Growth Factor Receptor (EGFR) (10.8%), Mammalian Target of Rapamycin (mTOR) (7.2%), Vascular Endothelial Growth Factor (VEGF) (6.6%), and Mitogen-Activated Protein Kinase (MEK) (5.4%). This review provides a comprehensive assessment of molecular therapies for GBM, highlighting their varied efficacy in clinical and laboratory settings, ultimately impacting overall and progression-free survival in GBM management.

Thyroid cancer is the predominant endocrine-related malignancy. ST6 β-galactoside α2,6-sialyltransferase 1 (ST6GAL1) has been studied in various types of cancers; however, the expression and function of ST6GAL1 in thyroid cancer has not been investigated so far. Previously, we conducted two genome-wide association studies and have identified the association of the ST6GAL1 gene with plasma thyroglobulin (Tg) levels. Since Tg levels are altered in thyroid pathologies, in the current study, we wanted to evaluate the expression of ST6GAL1 in thyroid cancer tissues. We performed an immunohistochemical analysis using human thyroid tissue from 89 patients and analyzed ST6GAL1 protein expression in papillary thyroid cancer (including follicular variant and microcarcinoma) and follicular thyroid cancer in comparison to normal thyroid tissue. Additionally, ST6GAL1 mRNA levels from The Cancer Genome Atlas (TCGA, n = 572) and the Genotype-Tissue Expression (GTEx) project (n = 279) were examined. The immunohistochemical analysis revealed higher ST6GAL1 protein expression in all thyroid tumors compared to normal thyroid tissue. TCGA data revealed increased ST6GAL1 mRNA levels in both primary and metastatic tumors versus controls. Notably, the follicular variant of papillary thyroid cancer exhibited significantly higher ST6GAL1 mRNA levels than classic papillary thyroid cancer. High ST6GAL1 mRNA levels significantly correlated with lymph node metastasis status, clinical stage, and reduced survival rate. ST6GAL1 emerges as a potential cancer-associated glycosyltransferase in thyroid malignancies, offering valuable insights into its diagnostic and prognostic significance.

As the global population grows, we are witnessing rapid urbanization and the development of industry and agriculture. Novel, largely toxic substances are being used in agriculture to improve yields. All of this has led to the generation of large amounts of pollutants that need to be disposed of and treated. Irresponsible behavior and discharges into nature and river channels not clearly defined by law or sanctioned, certainly have an environmental impact. The Drina River Basin occupies parts of the territories of four countries. It is one of the most important drainage areas in the West Balkans. It calls for international cooperation in many areas, such as public water supply, irrigation, hydropower generation, and the like. However, in order to achieve such cooperation, all the countries that “steward” the resource need to commit to water quality conservation and protection. The DPSIR approach proposed by the Water Framework Directive of the European Union is followed to identify major pressures (pollution sources) in the Serbian part of the Drina River Basin. The pressures are grouped into several categories and described in detail.

Hypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of "vascular" GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ2 and α1-5 subunit proteins. To confirm the role of "vascular" GABAA receptors, we investigated the vascular effects of standard benzodiazepines, midazolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5β3γ2 over other αxβ3γ2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazolam, both of which at 100 µmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators.