Retinal degenerative diseases range from rare inherited forms to common multifactorial disorders such as age-related macular degeneration, which is the leading cause of blindness in developed countries. Recent evidence identifies impaired autophagy as a key pathogenetic mechanism. In the disease process alterations of the outer retina start from the retinal pigment epithelium (RPE), to progress downstream in the inner retina leading to widespread whole retinal degeneration. Recent studies indicate that among autophagy-related proteins Beclin1 plays a relevant effect in sustaining retinal integrity, since it is induced by light exposure and it is placed at the intersection between mitophagy, lipophagy, and glycophagy, which are involved during retinal degeneration. The present study was carried out by profiting of BECN1 heterozygous aged mice (BECN+/-), where RT-PCR and western blotting analysis confirmed the loss of both the primary transcript (BECN1) and protein (Beclin1) in the whole retina. Multiple converging techniques indicate a marked degeneration of RPE and photoreceptor layer, where a dismantling of proteins forming tight junction was documented. Inner retinal degeneration was extended within outer and inner nuclear layer. In the inner retina the expression of the detrimental protein alpha synuclein was increased concomitantly with a defect of autophagy markers. The study indicates a seminal role of Beclin1 in maintaining retinal integrity and it defines the vulnerability of various retinal layers in the spreading of Beclin1-dependent retinal degeneration. The potential of increasing the expression of Beclin1 through photobiomodulation is discussed, since it supports retinal integrity when amber/red light-induced stimulation occurs.
Perioperative management of chronic antithrombotic therapy in elderly patients undergoing elective anterior cervical discectomy and fusion (ACDF) remains poorly standardized. This study evaluated the safety and feasibility of an institutional protocol based on temporary substitution rather than interruption of preexisting antithrombotic regimens. We retrospectively analyzed 189 consecutive patients aged ≥ 65 years who underwent elective ACDF between 2019 and 2023. Patients were stratified according to their chronic antithrombotic regimen. Group A included patients with no prior antithrombotic therapy, who received standard postoperative prophylaxis with enoxaparin after drain removal. Group B comprised patients on primary prevention therapy, whose home regimen was discontinued 7 days before surgery and replaced with bridging low-molecular-weight heparin (enoxaparin 40 mg daily) until 15 days postoperatively. Group C included patients on secondary prevention therapy, who suspended their regimen 7 days preoperatively and received low-dose aspirin (100 mg daily) from the preoperative week through postoperative day 15 before resuming their chronic therapy. Primary outcomes were hemoglobin decrease, operative time, and length of stay, while secondary outcomes included complications (Clavien–Dindo classification) and early functional recovery (mJOA, ODI). Non-inferiority analyses using the TOST procedure evaluated whether perioperative outcomes remained within predefined a priori clinical margins across groups. Baseline characteristics and surgical parameters were comparable among groups. No major hemorrhagic or thromboembolic events occurred. Perioperative parameters and minor complications (Clavien–Dindo I–II) were similar across all groups. Functional improvement at 3 months was consistent (p > 0.3). This substitution-based perioperative protocol proved feasible and clinically safe in elderly ACDF patients. Although underpowered to detect rare events, these findings support prospective studies aimed at further investigating the adoption of standardized replacement strategies in this growing surgical population.
Glioblastoma (GBM) is the most common and malignant brain tumor in adult humans. Recent studies have demonstrated a link between the composition of the gut microbiota and glioma progression. Here, we describe that the growth of glioma in mice is inversely correlated with the relative abundance of the anaerobic bacterium Muribaculum intestinale in the feces. We found that M. intestinale administration: 1) induced an inflammatory environment in the gut; 2) reduced glioma growth; 3) increased the pro-inflammatory profile of tumor-associated microglial cells and the frequency of CD8+ T cells; and 4) increased the peripheral TNF-α levels. The effects induced by M. intestinale administration were significantly attenuated upon toll-like receptor 2 (TLR2) silencing using TLR2-targeting siRNA. As a pattern-recognition receptor, TLR2 detects microbial-associated molecular patterns and orchestrates host immune responses to infection. Collectively, these data demonstrate that M. intestinale induces a pro-inflammatory response in glioma bearing mice, inhibiting tumor growth via TLR2-dependent signaling.
Importance:Treatment decisions in drug-resistant focal epilepsy remain largely empirical, as direct comparative evidence among newer antiseizure medications (ASMs) is limited. Real-world data can complement randomized clinical trials by providing insights into long-term effectiveness and safety across diverse populations. Objective:To compare effectiveness and safety of brivaracetam, cenobamate, lacosamide, and perampanel as adjunctive therapies in adults with drug-resistant focal epilepsy. Design, Setting, and Participants:This was a multicenter pooled analysis of 4 previously conducted retrospective real-world medical record-review studies (January 2017-January 2024). Included were adult patients (aged ≥16 years) with drug-resistant focal epilepsy, as defined by the International League Against Epilepsy. Participants were recruited from 71 epilepsy centers. Exposures:Add-on treatment with brivaracetam, cenobamate, lacosamide, or perampanel. Main Outcomes and Measures:The primary outcome was the responder rate at 6 months, defined as greater than or equal to 50% seizure frequency reduction from baseline. Secondary outcomes included 12-month responder rate, seizure freedom (≥3 months at 6 months and ≥6 months at 12 months), and 12-month ASM retention. Safety was assessed by incidence of adverse effects. Generalized linear mixed models adjusted for demographic and clinical covariates were used to compare treatment outcomes, with cenobamate as reference ASM. Results:Of 2386 ASM prescriptions screened, 1993 prescriptions from 1949 patients (1036 of 1947 female [53.2%]; sex information was missing in 0.1% of prescriptions) with a median (IQR) age of 42 (29-55) years at ASM prescription, met inclusion criteria and were included in the pooled analysis. Brivaracetam accounted for 953 prescriptions (47.8%), followed by perampanel (607 [30.5%]), lacosamide (241 [12.1%]), and cenobamate (192 [9.6%]). After adjustment, cenobamate demonstrated significantly higher odds of 50% or greater response at 6 months compared with brivaracetam (odds ratio [OR], 0.18; 95% CI, 0.12-0.28; P < .001), perampanel (OR, 0.26; 95% CI, 0.16-0.42; P < .001), and lacosamide (OR, 0.29; 95% CI, 0.17-0.49; P < .001). Results were consistent for secondary effectiveness outcomes at 12 months, with cenobamate outperforming other ASMs in terms of 50% or greater response and seizure freedom. Cenobamate was associated with the highest rate of adverse effects during follow-up (111 [57.8%]), and lacosamide was associated with the lowest (35 [14.8%]). Cenobamate was associated with a higher likelihood of treatment retention at 12 months compared with brivaracetam (OR, 0.43; 95% CI, 0.26-0.69; P < .001) and perampanel (OR, 0.56; 95% CI, 0.32-0.99; P = .047), with no significant difference vs lacosamide (OR, 0.81; 95% CI, 0.41-1.59; P = .53). Conclusions and Relevance:These study findings suggest superior effectiveness of cenobamate over brivaracetam, lacosamide, and perampanel in adults with drug-resistant focal epilepsy in a large real-world setting.
Background Dysosmobacter welbionis is a recently discovered butyrate producer whose presence in stool correlates with improved metabolic health. Whether its abundance is reduced in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unknown. Mechanistic insight into its butyrate production from myo-inositol, a dietary compound from fruits, beans, grains and nuts with metabolic benefits, is also limited.Objective To assess population-level distribution, relative abundance and strain diversity of D. welbionis in humans, and to elucidate its metabolic capacity to ferment myo-inositol into butyrate.Design We analysed several human cohorts for associations with liver health and evaluated D. welbionis J115T supplementation in a diet-induced steatosis mouse model. An antibody-guided anaerobic cell-sorting strategy enabled isolation of distinct strains. We combined 13C-labelled inositol isotopes with NMR, mass spectrometry, genomics and proteomics.Results We found that D. welbionis and two related species (D. hominis and D. segnis) are prevalent gut bacteria in the human gut. D. welbionis abundance was reduced in MASLD across two cohorts and inversely correlated with fibrosis score in a third cohort. Treatment with D. welbionis J115T improved glycaemia and hepatic steatosis in high-fat diet fed mice. We identified a non-canonical myo-inositol-to-butyrate fermentation pathway. 19 human strains were isolated, comparative genomics of 23 strains revealed an open pangenome (about 2100 core genes) including the full myo-inositol fermentation pathway.Conclusion D. welbionis possesses a unique, conserved route to convert dietary myo-inositol into butyrate, distinguishing it from other commensals and supporting its potential as a next-generation probiotic for metabolic and liver health.
