Dissecting the molecular determinants of GABAA receptors current rundown, a hallmark of refractory human epilepsy

GABAA receptors-(Rs) are fundamental for the maintenance of an efficient inhibitory function in the central nervous system (CNS). Their dysfunction is associated with a wide range of CNS disorders, many of which characterized by seizures and epilepsy. Recently, an increased use-dependent desensitization due to a repetitive GABA stimulation (GABAA current rundown) of GABAARs has been associated with drug-resistant temporal lobe epilepsy (TLE). Here, we aimed to investigate the molecular determinants of GABAA current rundown with two different heterologous expression systems (Xenopus oocytes and human embryonic kidney cells; HEK) which allowed us to manipulate receptor stoichiometry and to study the GABAA current rundown on different GABAAR configurations. To this purpose, we performed electrophysiology experiments using two-electrode voltage clamp in oocytes and confirming part of our results in HEK. We found that different degrees of GABAA current rundown can be associated with the expression of different GABAAR beta-subunits reaching the maximum current decrease when functional alpha1beta2 receptors are expressed. Furthermore, the blockade of phosphatases can prevent the current rundown observed in alpha1beta2 GABAARs. Since GABAAR represents one important therapeutic target in the treatment of human epilepsy, our results could open new perspectives on the therapeutic management of drug-resistant patients showing a GABAergic impairment

Improving the performance of printable carbon electrodes by femtosecond laser treatment

Low-cost carbon-conductive films were screen-printed on a Plexiglas® substrate, and then, after a standard annealing procedure, subjected to femtosecond (fs) laser treatments at different values of total accumulated laser fluence ΦA. Four-point probe measurements showed that, if ΦA > 0.3 kJ/cm2, the sheet resistance of laser-treated films can be reduced down to about 15 Ω/sq, which is a value more than 20% lower than that measured on as-annealed untreated films. Furthermore, as pointed out by a comprehensive Raman spectroscopy analysis, it was found that sheet resistance decreases linearly with ΦA, due to a progressively higher degree of crystallinity and stacking order of the graphitic phase. Results therefore highlight that fs-laser treatment can be profitably used as an additional process for improving the performance of printable carbon electrodes, which have been recently proposed as a valid alternative to metal electrodes for stable and up-scalable perovskite solar cells

Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton–proton collisions at the LHC

This paper presents the method and performance of primary vertex reconstruction in proton–proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of √s=8 TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about 30μm is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than 20μm and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

BNT162B2 mRNA COVID-19 vaccine in heart and lung transplanted young adults: is an alternative SARS-CoV-2 immune response surveillance needed?

[no abstract available

Baseline Ultrasound Assessment Improves the Response to Apremilast in Patients with Psoriatic Arthritis: Results from a Multicentre Study

ound: Psoriatic arthritis (PsA) phenotypes show different responses to the many available drugs. For a tailored medicine, it is important to choose the most effective treatment according to patients’ characteristics. Apremilast is recommended in PsA with moderate activity. In clinical practice, the most suitable PsA patients for apremilast are those affected by the peripheral oligoarticular arthritis. However, it is not so straightforward to definitely identify this phenotype. Musculoskeletal ultrasound (MUS) is a good tool for detecting the joints actually involved by PsA. The aim of this study is to verify if MUS assessment is useful in selecting the best PsA responders to apremilast. Methods: The following data of all consecutive PsA patients from 15 centres were recorded: anamnestic data, disease activity, PsA phenotype, apremilast treatment duration and reason of suspension. MUS assessment before apremilast treatment was the criteria which clustered patients in two groups. Apremilast retention rate estimate the drug’s effectiveness. The Cox analysis revealed the risk factors associated with treatment persistence. Mann-Whitney U and Chi-squared tests assessed the intergroup differences. Results: Only 40% of 356 patients (M:F: 152/204; median age 60 yrs) received MUS examination. In MUS group the moderate disease (median DAPSA 22.9 vs 26.9; p=0.0006) and the oligo-articular phenotype (63.6% vs 36.1%, p&lt;0.0001) were more common. The retention rate was higher in MUS group (HR 0.55 IC95% 0.32-0.94; p=0.03). Conclusion: In apremilast treated PsA patients, baseline MUS assessment is related to an increased retention rate. MUS may identify patients’ characteristics favourable to apremilast response

Predictors of DAPSA Response in Psoriatic Arthritis Patients Treated with Apremilast in a Retrospective Observational Multi-Centric Study (2023-02-07)

Background: To date, only a few real-world-setting studies evaluated apremilast effectiveness in psoriatic arthritis (PsA). The aims of this retrospective observational study are to report long-term Disease Activity Index for Psoriatic Arthritis (DAPSA) response of apremilast in PsA patients and to analyze the predictors of clinical response. Methods: All PsA consecutive patients treated with apremilast in fifteen Italian rheumatological referral centers were enrolled. Anamnestic data, treatment history, and PsA disease activity (DAPSA) at baseline, 6 months, and 12 months were recorded. The Mann–Whitney test and chi-squared tests assessed the differences between independent groups, whereas the Wilcoxon matched pairs signed-rank test assessed the differences between dependent samples. Logistic regressions verified if there were factors associated with achievement of DAPSA low disease activity or remission at 6 and 12 months. Results: DAPSA low disease activity or remission rates at 6 and 12 months were observed, respectively, in 42.7% (n = 125) and 54.9% (n = 161) patients. Baseline DAPSA was inversely associated with the odds of achieving low disease activity or remission at 6 months (odds ratio (OR) 0.841, 95% confidence interval (CI) 0.804–0.879; p &lt; 0.01) and at 12 months (OR 0.911, 95% CI 0.883–0.939; p &lt; 0.01). Conclusions: Almost half of the PsA patients receiving apremilast achieved DAPSA low disease activity or remission at 6 and 12 months. The only factor associated with achievement of low disease activity or remission at both 6 and 12 months was baseline DAPSA

Ixekizumab Retention Rate and Predictors of Treatment Persistence in Psoriatic Arthritis: Results of an Italian Multicenter Study

XE (Ixekizumab) is a monoclonal antibody targeting interleukin-17A (IL17A) which has demonstrated significant efficacy and safety in the management of psoriatic arthritis (PsA) in randomized controlled trials (RCTs). However, available data on long-term persistence of therapy are scarce. Methods: This multi-center study aimed to evaluate the drug retention rate (DRR) of IXE in a real-world setting and to identify key factors influencing treatment persistence. 195 patients with PsA treated with IXE between 2018 and 2024 were included. The primary outcome was DRR, calculated at 360, 720, and 1080 days after treatment initiation. Clinical and demographic factors were analyzed as potential predictors of IXE treatment permanency. Results: IXE retention rates were 66% at 360 days, 49% at 720 days, and 39% at 1080 days. Low baseline disease activity was a strong predictor of higher retention (HR 0.24, 95% CI: 0.09-0.62, p = 0.003), while younger age was significantly associated with improved persistence (HR 0.98, 95% CI: 0.96-1.00, p = 0.045). Conversely, patients with both axial and peripheral joint involvement were more likely to discontinue therapy (HR 1.78, 95% CI: 1.04-3.06, p = 0.036), as were those receiving IXE as a second- or third-line therapy (HR 1.17, 95% CI: 1.02-1.33, p = 0.021). Conclusions: This multicenter real-world study confirms the long-term retention rate of IXE in PsA. The findings highlight key factors influencing treatment persistence and provide valuable insights to optimize patient management. Further real-world research is needed to better understand the therapeutic performance of IXE in different patient populations. Keywords: biologic treatment; comparative effectiveness; interleukin 17 inhibitor; ixekizumab; psoriasis; psoriatic arthritis