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BACKGROUND: Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment by harnessing the immune system but ICI can induce life-threatening immune-related adverse events (irAE) affecting every organ. METHODS: We extracted irAE from VigiBase, the international pharmacovigilance database, first reported in 2008 until 01/2023 to characterize irAE reporting trends, clinical features, risk factors and outcomes. FINDINGS: We distinguished 25 types of irAE (n = 50,347cases, single irAE/case in 84.9%). Cases mainly involved anti-PD1 (programmed-death-1) monotherapy (62.4%) in male (61.7%) aged 64.3 ± 12.6 years. After 2020 vs. prior to 2016, proportion of anti-CTLA4 (Cytotoxic-T-Lymphocyte-Antigen-4) monotherapy prescription almost vanished (1.6% vs. 47%, respectively) contrasting with increased use of anti-PDL1 (PD1-ligand) monotherapy (18% vs. 0.9%) and anti-CTLA4+anti-PD(L)1 combination (20% vs. 8.9%). Anti-LAG3 (Lymphocyte-Activation-Gene-3) prescription was limited (5) were presence of thymic cancer for ICI-myotoxicities or hepatitis; presence of melanoma for vitiligo, uveitis or sarcoidosis; specific types of ICI regimen (anti-LAG3 for meningitis, anti-CTLA4 for hypophysitis); and specific reporting regions (eastern Asia for cholangitis). Median time-to-onset ranged from 31 to 273 days, being shortest for myotoxicities and most delayed for skin-bullous auto-immune reactions. Overall fatality was highest for myocarditis = 27.6%, myasthenia = 23.1%, severe cutaneous adverse reactions (SCAR) = 22.1%, myositis = 21.9%, pneumonitis = 21%, and encephalomyelitis = 18%; generally decreasing after 2020, except for myasthenia and SCAR. When reported, irAE recurrence rate after rechallenge was 28.9% (n = 275/951). INTERPRETATION: This up-to-date comprehensive worldwide pharmacovigilance study defines the spectrum, characteristics, and evolution of irAE reporting summarizing over a decade of use. Multiple risk factors and clinical peculiarities for specific irAE have been identified as signals to guide clinical practice and future research. FUNDING: Paul Gougis was supported by the academic program: Contrats ED: Programme blanc Institut Curie PSL for the conduct of his PhD. Baptiste Abbar was supported by the Fondation ARC Pour le Rechercher Sur le Cancer. The RT2L research group (Institut Curie) was supported by the academic program SHS INCa, Sanofi iTech award, and by Monoprix∗.

Enzymatic biocatalysis typically generates less waste, uses less water, and minimizes energy consumption compared to traditional chemical methods. Efficient, cell-free biosynthesis relies on the reuse of its valuable biocatalysts. Immobilization of enzymes on solid supports, such as enzyme carrier resins (ECRs), offers a reliable and widely deployed approach to maximize enzyme turnover in cell-free biosynthesis. We focus on two major bottlenecks associated with optimizing cell-free biocatalysis. First, we apply our lab's 3D-printed labware to screen ECRs in 96-well mini-reactors to optimize enzyme immobilization conditions. Second, we introduce inline infrared spectroscopy to monitor bioreactor output and maximize enzyme productivity. Urease provides a model system for examining immobilization conditions and continuous assessment of biocatalyst performance. As required for the high substrate concentrations to improve process efficiency and minimize waste, urease was studied in unusually high concentrations of its substrate – molar concentrations of urea. The optimized reactor processed 3.24 L of 4.00 M urea at an average volumetric productivity of 13 g ⋅ L−1 ⋅ h−1 over 18 h and achieved an estimated productivity number of >17.4 kg urea processed per g of immobilized urease Type-IX. This workflow can be generalized to most biocatalytic processes and could accelerate adoption of cell-free biosynthesis for greater chemical sustainability.

Abstract Aims Tafamidis improves clinical outcomes in transthyretin amyloid cardiomyopathy (ATTR‐CM), yet how tafamidis affects cardiac structure and function remains poorly described. This study prospectively analysed the effect of tafamidis on 12‐month longitudinal changes in cardiac structure and function by cardiac magnetic resonance (CMR) compared with the natural course of disease in an untreated historic control cohort. Methods and results ATTR‐CM patients underwent CMR at tafamidis initiation and at 12 months. Untreated patients with serial CMRs served as reference to compare biventricular function, global longitudinal strain (GLS), LV mass and extracellular volume fraction (ECV). Thirty‐six tafamidis‐treated (n = 35; 97.1% male) and 15 untreated patients (n = 14; 93.3% male) with a mean age of 78.3 ± 6.5 and 76.9 ± 6.5, respectively, and comparable baseline characteristics were included. Tafamidis was associated with preserving biventricular function (LVEF (%): 50.5 ± 12 to 50.7 ± 11.5, P = 0.87; RVEF (%): 48.2 ± 10.4 to 48.2 ± 9.4, P = 0.99) and LV‐GLS (−9.6 ± 3.2 to −9.9 ± 2.4%; P = 0.595) at 12 months, while a significantly reduced RV‐function (50.8 ± 7.3 to 44.2 ± 11.6%, P = 0.028; P (change over time between groups) = 0.032) and numerically worsening LVGLS (−10.9 ± 3.3 to −9.1 ± 2.9%, P = 0.097; P (change over time between groups) = 0.048) was observed without treatment. LV mass significantly declined with tafamidis (184.7 ± 47.7 to 176.5 ± 44.3 g; P = 0.011), yet remained unchanged in untreated patients (163.8 ± 47.5 to 171.2 ± 39.7 g P = 0.356, P (change over time between groups) = 0.027). Irrespective of tafamidis, ECV and native T1‐mapping did not change significantly from baseline to 12‐month follow‐up (P > 0.05). Conclusions Compared with untreated ATTR‐CM patients, initiation of tafamidis preserved CMR‐measured biventricular function and reduced LV mass at 12 months. ECV and native T1‐mapping did not change significantly comparable to baseline in both groups.

Abstract Background We assessed the prognostic value of serological humoral markers measured one month after the last dose of the primary COVID-19 vaccine course for predicting the risk of severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 infection over the following six months in specific populations. Methods ANRS0001SCOV-POPART is a French nationwide multicenter prospective observational cohort study assessing the immune response to Covid-19 vaccines routinely administered to 11 subgroups of patients with chronic disease and a control group. Participants from the ANRS0001S COV-POPART were included if they received at least two doses of Covid-19 vaccine for the primary vaccine course, had measurements of anti-Spike, anti-receptor binding domain (RBD) IgG-specific or neutralizing antibodies one month after the end of the primary vaccine course, without being infected by SARS-CoV-2 before the measurement. SARS-CoV-2 infections defined by a positive PCR/antigenic test or seroconversion to detectable anti nucleocapsid antibodies were evaluated until the first COVID-19 booster injection. Cox proportional hazards models taking into account interval-censored data were implemented to estimate the association between each antibody level and the risk of SARS-CoV-2 infection. Predictive performances were evaluated by the area under the receiving operating characteristic curve (AUROC). Results Two thousand five hundred seventy adults from a specific population and 1,123 from the control group were included. The cumulative probabilities of SARS-CoV-2 infections at five months after serological measurement were 6.0% 95% confidence interval: [5.0; 7.9] and 10.1% 95% confidence interval: [8.3; 11.9], respectively. Higher levels of anti-Spike IgG antibody were associated with a lower risk of SARS-CoV-2 infections in the control group, but not in the specific populations. Among the specific populations, AUROC were 74.5%, 74.9%, and 72.4% for anti-Spike IgG, anti-RBD IgG, and neutralizing antibodies, respectively. AUROC were superior in the specific populations, 82.0%, 81.2%, and 81.4% for anti-Spike IgG, anti-RBD IgG, and neutralizing antibodies, respectively. Conclusions Vaccine-induced antibody response after the primary course of Covid-19 infection only moderately discriminated between participants developing a SARS-CoV-2 infection during the Omicron wave. Trial registration NCT04824651 (first posted: 2021-04-01).

Abstract Background Toxoplasma gondii is a zoonotic protozoan parasite with a heteroxenus life cycle that involves felids as the definitive hosts and any warm-blooded animal, including humans, as intermediate hosts. Cats are key players in parasite transmission as they are capable of shedding high numbers of oocysts in their feces that contaminate the environment. Methods The study was performed on 31 domestic cats (31.23 ± 27.18 months old) originating from rural and urban areas (5.17:1) in the center and north-west Romania. Feces (n = 31), blood (n = 28), and heart samples (n = 27) were collected. Fecal samples were analyzed by flotation technique, and PCR (529 bp repetitive element). Fecal samples with T. gondii oocysts were bioassayed in mice. Serum samples were analyzed by modified agglutination test and ImmunoComb for the detection of specific anti-T. gondii IgG antibodies. Heart samples were bioassayed in mice, and analyzed by PCR. Toxoplasma gondii positive samples were genotyped by nPCR-RFLP targeting eleven genetic loci (SAG1, SAG2, alt-SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico). Results Toxoplasma gondii oocysts were found in 2 out of 31 fecal samples collected from a 3-months old stray kitten, and a 4-years old female. In total, 17 out of 27 sera were positive for T. gondii IgG antibodies. The antibody titers in MAT ranged from 1:6 to 1:384. Toxoplasma gondii DNA was detected in 7 out of 27 heart samples, and four of them were positive also by bioassay. Six T. gondii DNA samples from bioassayed mice could be assigned to ToxoDB PCR-RFLP genotype #1 or #3 (Type II) and one T. gondii DNA from heart digest to genotype #2 (Type III). Both of these genotypes are common in Europe. Conclusions Our results revealed that the infection with T. gondii is still high in cats from Romania. The oocysts shedded by these cats represent an important source of infection for intermediate hosts, including humans. Further studies on a wider range of cases are necessary for a more exhaustive definition of the T. gondii genotypes circulating in Romania.

Abstract Background The C-terminal-binding protein 1/brefeldin A ADP-ribosylation substrate (CtBP1/BARS) acts both as an oncogenic transcriptional co-repressor and as a fission inducing protein required for membrane trafficking and Golgi complex partitioning during mitosis, hence for mitotic entry. CtBP1/BARS overexpression, in multiple cancers, has pro-tumorigenic functions regulating gene networks associated with “cancer hallmarks” and malignant behavior including: increased cell survival, proliferation, migration/invasion, epithelial-mesenchymal transition (EMT). Structurally, CtBP1/BARS belongs to the hydroxyacid-dehydrogenase family and possesses a NAD(H)-binding Rossmann fold, which, depending on ligands bound, controls the oligomerization of CtBP1/BARS and, in turn, its cellular functions. Here, we proposed to target the CtBP1/BARS Rossmann fold with small molecules as selective inhibitors of mitotic entry and pro-tumoral transcriptional activities. Methods Structured-based screening of drug databases at different development stages was applied to discover novel ligands targeting the Rossmann fold. Among these identified ligands, N-(3,4-dichlorophenyl)-4-{[(4-nitrophenyl)carbamoyl]amino}benzenesulfonamide, called Comp.11, was selected for further analysis. Fluorescence spectroscopy, isothermal calorimetry, computational modelling and site-directed mutagenesis were employed to define the binding of Comp.11 to the Rossmann fold. Effects of Comp.11 on the oligomerization state, protein partners binding and pro-tumoral activities were evaluated by size-exclusion chromatography, pull-down, membrane transport and mitotic entry assays, Flow cytometry, quantitative real-time PCR, motility/invasion, and colony assays in A375MM and B16F10 melanoma cell lines. Effects of Comp.11 on tumor growth in vivo were analyzed in mouse tumor model. Results We identify Comp.11 as a new, potent and selective inhibitor of CtBP1/BARS (but not CtBP2). Comp.11 directly binds to the CtBP1/BARS Rossmann fold affecting the oligomerization state of the protein (unlike other known CtBPs inhibitors), which, in turn, hinders interactions with relevant partners, resulting in the inhibition of both CtBP1/BARS cellular functions: i) membrane fission, with block of mitotic entry and cellular secretion; and ii) transcriptional pro-tumoral effects with significantly hampered proliferation, EMT, migration/invasion, and colony-forming capabilities. The combination of these effects impairs melanoma tumor growth in mouse models. Conclusions This study identifies a potent and selective inhibitor of CtBP1/BARS active in cellular and melanoma animal models revealing new opportunities to study the role of CtBP1/BARS in tumor biology and to develop novel melanoma treatments.

Background Immune checkpoint inhibitors (ICIs) have been a major advance in cancer management. However, we still lack prospective real-world data regarding their usage in people with HIV infection (PWH).Methods The ANRS CO24 OncoVIHAC study (NCT03354936) is an ongoing prospective observational cohort study in France of PWH with cancer treated with ICI. We assessed the incidence of grade ≥3 immune-related adverse events (irAEs). All grade ≥3 irAEs were reviewed by an event review.Results Between January 17, 2018, and December 05, 2023, 150 participants were recruited from 33 sites and 140 were included in this analysis. At the data cut-off date of December 05, 2023, the median follow-up was 9.2 months (IQR: 3.9–18.3), with a total of 126.2 person-years.Median age was 59 years (IQR: 54–64) and 111 (79.3%) were men. Median time since HIV diagnosis was 25 years (12–31), the median duration on antiretroviral (ARV) was 19.5 years (7.7–25.4), and the CD4 nadir was 117/µL (51–240). ICI regimens comprised anti-programmed cell death protein-1 (PD-1) for 111 (79.3%) participants, anti-programmed death-ligand 1 for 25 (17.9%), a combination of anti-PD-1 and anti-cytotoxic T-lymphocyte associated protein 4 for 3 (2.1%), and anti-PD-1 along with anti-vascular endothelial growth factor receptor for 1 (0.7%). The most frequent cancers were lung (n=65), head/neck (n=15), melanoma (n=12), liver (n=11) and Hodgkin’s lymphoma (n=9).During follow-up, a total of 34 grade ≥3 irAEs occurred in 20 participants, leading to an incidence rate of 26.9 per 100 person-years. The Kaplan-Meier estimates of the proportion of participants with at least one episode of grade ≥3 irAEs were 13.8% at 6 months, 15.0% at 12 months and 18.7% at 18 months. One treatment-related death due to myocarditis was reported (0.7%). Multivariable analysis of cumulative incidence showed that participants with time since HIV diagnosis >17 years (incidence rate ratio (IRR)=4.66, p=0.002), with CD4

Significant changes in the quality and metabolic profile of fresh turkey sperm as a result of both cryopreservation and reproductive age have already been individually confirmed in our previous studies. This new dataset adds a relevant piece to the tangled puzzle of changes in metabolite levels affecting cryopreserved turkey sperm quality, taking into consideration two different reproductive period ages. Fresh semen samples were collected at 44 and 56 weeks of age and exposed to the cryopreservation process. All fresh and frozen-thawed samples were subjected to analysis of mobility, viability and osmotic tolerance as parameters for evaluating the sperm quality, while NMR spectroscopy was used to assess the quantitative changes in water and lipid-soluble metabolites. Our results showed that the cryopreservation process significantly affected all of the measured qualitative parameters both at 44 and 56 weeks. Concerning the metabolic profile, a greater number of quantitative changes for both water and lipid-soluble components were found in frozen semen at 56 weeks than at 44 weeks of age. These data could contribute to identifying new strategies aimed at improving freezing procedures even as reproductive age increases.

Abstract Risk behaviours are common in adolescent and persist into adulthood, people who engage in more risk behaviours are more likely to have lower educational attainment. We applied genetic causal inference methods to explore the causal relationship between adolescent risk behaviours and educational achievement. Risk behaviours were phenotypically associated with educational achievement at age 16 after adjusting for confounders (−0.11, 95%CI: −0.11, −0.09). Genomic-based restricted maximum likelihood (GREML) results indicated that both traits were heritable and have a shared genetic architecture (Risk $${{{{{{\boldsymbol{h}}}}}}}^{{{{{{\boldsymbol{2}}}}}}}$$ h 2 = 0.18, 95% CI: −0.11,0.47; education $${{{{{{\boldsymbol{h}}}}}}}^{{{{{{\boldsymbol{2}}}}}}}$$ h 2 = 0.60, 95%CI: 0.50,0.70). Consistent with the phenotypic results, genetic variation associated with risk behaviour was negatively associated with education ( $${{{{{{\boldsymbol{r}}}}}}}_{{{{{{\boldsymbol{g}}}}}}}$$ r g = −0.51, 95%CI: −1.04,0.02). Lastly, the bidirectional MR results indicate that educational achievement or a closely related trait is likely to affect risk behaviours PGI (β=−1.04, 95% CI: −1.41, −0.67), but we found little evidence that the genetic variation associated with risk behaviours affected educational achievement (β=0.00, 95% CI: −0.24,0.24). The results suggest engagement in risk behaviour may be partly driven by educational achievement or a closely related trait.

Abstract CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.

Abstract Bipolar disorder (BD) has been associated with premature cellular aging with shortened telomere length (TL) as compared to the general population. We recently identified a subgroup of young individuals with prematurely shortened TL. The aims of the present study were to replicate this observation in a larger sample and analyze the expression levels of genes associated with age or TL in a subsample of these individuals. TL was measured on peripheral blood DNA using quantitative polymerase chain reaction in a sample of 542 individuals with BD and clustering analyses were performed. Gene expression level of 29 genes, associated with aging or with telomere maintenance, was analyzed in RNA samples from a subsample of 129 individuals. Clustering analyses identified a group of young individuals (mean age 29.64 years), with shorter TL. None of the tested clinical variables were significantly associated with this subgroup. Gene expression level analyses showed significant downregulation of MYC, POT1, and CD27 in the prematurely aged young individuals compared to the young individuals with longer TL. After adjustment only POT1 remained significantly differentially expressed between the two groups of young individuals. This study confirms the existence of a subgroup of young individuals with BD with shortened TL. The observed decrease of POT1 expression level suggests a newly described cellular mechanism in individuals with BD, that may contribute to telomere shortening.

Abstract Glioblastoma (GBM) remains a deadly tumor. Treatment with chemo-radiotherapy and corticosteroids is known to impair the functionality of lymphocytes, potentially compromising the development of autologous CAR T cell therapies. We here generated pre-clinical investigations of autologous anti-GD2 CAR T cells tested against 2D and 3D models of GBM primary cells. We detected a robust antitumor effect, highlighting the feasibility of developing an autologous anti-GD2 CAR T cell-based therapy for GBM patients.

Clean pump oil is critical to the performance and longevity of oil-sealed vacuum pumps. Cold traps charged with cryogens can protect pump oil from solvent contamination but are subject to operator error. Notably, cold traps with evaporated or warmed cryogens do not protect the vacuum pump. Here, we report an open source device to automatically protect oil-sealed vacuum pumps from cold trap warming and facilitate the daily maintenance of cold traps.

During the sampling of a stratigraphic section along the shore of the Fiastra Lake (Carg Project - Sheet 313 “Camerino” of the Geological Map of Italy at 1:50 000 scale), a small rock boulder with partially exposed bony material was discovered at the base of a small cliff at the northern termination of the Sibillini Mts. In this area, the classical facies of Umbria-Marche stratigraphic succession are well exposed. The Oligocene-Miocene portion of the succession is represented by the ~200 m-thick Scaglia Cinerea Formation, passing upwards to the ~100 m-thick Bisciaro Formation. The microfossil assemblage has allowed the specimen to be constrained to the lower Burdigalian. The skeletal remains were examined using a CT-SCAN, a non-invasive method that has proven to be highly performing. The analysis revealed some articulated vertebrae, deformed by lithostatic compaction, which are attributed to a shark of the Order Lamniformes. Subsequently, the vertebrae were digitally isolated, extracted from the surrounding matrix, and rendered into three-dimensional prints. Through digital retro-deformation, the body length of the lamniform shark was estimated to be approximately 4 metres. Further considerations on the vertebrae allowed us to infer that the studied shark had similarities to either Isurus oxyrinchus Rafinesque, 1810 or Carcharodon carcharias Linnaeus, 1758. The development of a dead-fall microbial community likely facilitated the preservation of the vertebrae. The studied specimen represents the first occurrence of a lamniform shark in the Lower Miocene of the Umbria-Marche Domain and represents one of the very rare recorded occurrences of lamniforms from the Lower Miocene of Italy.

Non-Hodgkin lymphomas (NHL) commonly occur in immune-deficient (ID) patients, both HIV-infected and transplanted, and are often EBV-driven with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 ID (34 posttransplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were Large B Cells Lymphoma (LBCL) and 25% were primary central-nervous-system lymphoma (PCNSL) while 40% were EBV-positive. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden (TMB), tumor landscape and microenvironment (TME) and prediction of tumor neoepitopes. Both TMB (2.2 vs 3.4/Mb, p=0.001) and neoepitopes numbers (40 vs 200, p=0.00019) were lower in EBVpositive than in EBV-negative NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations exclusively observed in EBV-positive and ID NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV-negative cases but in only half EBV-positive ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The TME analysis showed higher CD8 T cell infiltrates in EBVpositive vs EBV-negative NHL, together with a more tolerogenic profile composed of Tregs, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV-negative patients, offering potential opportunities for future T cell-based immune therapies.

Hardware implementations represent the major challenges when digital signal processors for ultra-wideband (UWB) signals must be developed. Due to the limitation of the maximum clock rate in digital devices, systems with high sampling rates (above GHz) cannot easily be implemented. In the literature, several works propose parallel architectures for the implementation of UWB. They are implemented on Field-Programmable Gate Arrays (FPGAs) and Application-Specific Integrated Circuits (ASICs) and try to overcome the limitation on the maximum clock frequency. In this work, a novel parallel architecture for digital UWB equalizer and an optimized version of the Least Mean Square Block (LMS) based on the Fast FIR Algorithms (FFA) are presented. Circuit simulations show that the proposed equalizer can process a UWB signal with a bandwidth reaching several GHz, using the typical clock frequencies available in FPGAs. The proposed version of the Block LMS is compared with the Fast Block LMS in terms of computational complexity. It exhibits better results and greater hardware design flexibility. Finally, the hardware implementation based on a Xilinx Kintex Ultrascale to process a UWB signal sampled at 1.6 GHz is described.

This paper proposes a Design Space Exploration for Edge machine learning through the utilization of the novel MathWorks FPGA Deep Learning Processor IP, featured in the HDL Deep Learning toolbox. With the ever-increasing demand for real-time machine learning applications, there is a critical need for efficient and low-latency hardware solutions that can operate at the edge of the network, in close proximity to the data source. The HDL Deep Learning toolbox provides a flexible and customizable platform for deploying deep learning models on FPGAs, enabling effective inference acceleration for embedded IoT applications. In this study, our primary focus lies in investigating the impact of parallel processing elements on the performance and resource utilization of the FPGA-based processor. By analyzing the trade-offs between accuracy, speed, energy efficiency, and hardware resource utilization, we aim to gain valuable insights into making optimal design choices for FPGA-based implementations. Our evaluation is conducted on the AMD-Xilinx ZC706 development board, which serves as the target device for our experiments. We consider all the compatible Convolutional Neural Networks available within the HDL Deep Learning toolbox to comprehensively assess the performances.

Kingdon’s Multiple Streams Approach (MSA) and Jones and Baumgartner’s Punctuated Equilibrium Theory (PET) are public policy frameworks that have existed for many years. Given their long-term popularity, it is important for readers to have a strong working knowledge on how said frameworks function, and be able to compare and contrast them. It has also been put forth that PET only serves as an updated version of MSA, but this paper argues that said assertion is inaccurate, as PET is a useful framework in its own right. By inspecting this paper, readers will learn about MSA, PET, how they are similar and different, how they can be operationalized or used in real life circumstances, how they have been tested, and it is ultimately concluded that PET is not just a reworking of MSA.

Abstract Background The practice of self-medication is common but not without risk, especially for vulnerable populations such as the pediatric population. Community pharmacists have an important role of vigilance in dispensing drugs available without a medical prescription, with the possibility of carrying out a Pharmaceutical Intervention (PI) if necessary. The aim of our study was to characterize the Pediatric Pharmaceutical Interventions (PPIs) in self-medication carried out during a spontaneous request for a drug at the community pharmacy. Methods We conducted a descriptive study in 139 pharmacies in the Auvergne-Rhône-Alpes region (France). Data were collected from students under the supervision of internship masters in the pharmacy, using the validated GIPAMED (GrId for PhArmaceutical Self-MEDication interventions) notification grid, the first week of each month, from February to May for five years (2017 to 2021). Collected data were entered on a secure university platform. Results Of the 3,552 PIs collected, 8,3% (n = 286) were PPIs. Of these PPIs, 35% (n = 100) was generated by requests for optional prescription drugs contraindicated by the pathophysiological condition, 28.3% for drugs requiring a prescription and 20.6% for over the counter drugs not indicated by the symptomatology. Finally, 10% of requests required a referral for a medical consultation. Four Anatomical Therapeutic Chemical (ATC) classes accounted for more than 90% of the requests: respiratory system (39.5%), alimentary tract and metabolism (19.2%), nervous system (11.5%), and musculoskeletal system (10.8%). The most common drugs generating PPIs were: ibuprofen, oxomemazine and combination camphor/essential oils, mainly due to age-related or weight-related contraindication. Paracetamol also generated PPIs frequently, mainly due to problems with drug compliance and more precise infra-therapeutic doses. When these PPIs were dispensed, the pharmacist’s proposed solutions were accepted in 94.8% (n = 271) of the cases. Conclusions The community pharmacist has an important role in providing information about medicines and their correct use to patients. Our research shows that this attention benefits vulnerable populations, such as children, even for drugs that are widely used (e.g. paracetamol and non-steroidal anti-inflammatory drugs) or active substances for which there are age-related or weight-related contraindications (e.g. antitussives, camphor combinations).

Neurodegenerative disorders are the main cause of cognitive and physical disabilities, affect millions of people worldwide, and their incidence is on the rise. Emerging evidence pinpoints a disturbance of the communication of the gut–brain axis, and in particular to gut microbial dysbiosis, as one of the contributors to the pathogenesis of these diseases. In fact, dysbiosis has been associated with neuro-inflammatory processes, hyperactivation of the neuronal immune system, impaired cognitive functions, aging, depression, sleeping disorders, and anxiety. With the rapid advance in metagenomics, metabolomics, and big data analysis, together with a multidisciplinary approach, a new horizon has just emerged in the fields of translational neurodegenerative disease. In fact, recent studies focusing on taxonomic profiling and leaky gut in the pathogenesis of neurodegenerative disorders are not only shedding light on an overlooked field but are also creating opportunities for biomarker discovery and development of new therapeutic and adjuvant strategies to treat these disorders. Lactiplantibacillus plantarum (LBP) strains are emerging as promising psychobiotics for the treatment of these diseases. In fact, LBP strains are able to promote eubiosis, increase the enrichment of bacteria producing beneficial metabolites such as short-chain fatty acids, boost the production of neurotransmitters, and support the homeostasis of the gut–brain axis. In this review, we summarize the current knowledge on the role of the gut microbiota in the pathogenesis of neurodegenerative disorders with a particular focus on the benefits of LBP strains in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, autism, anxiety, and depression.

Purpose: This study assesses the efficacy and safety of self-expandable (SE) versus balloon-expandable (BE) stent grafts for managing visceral artery aneurysms (VAAs), focusing on procedural success and complication rates. Materials and Methods: We conducted a retrospective analysis of VAA patients treated at our institution from April 2006 to September 2021. The study reviewed patient demographics, aneurysm characteristics, treatment details, and outcomes, including endoleaks. Results: Among the 23 patients analyzed, splenic artery aneurysms represented 44% of cases. Fifteen patients were treated with balloon-expandable stent grafts (BE SGs), and eight patients were treated with self-expandable stent grafts (SE SGs). For saccular aneurysms, the average neck size was 10.10 ± 8.70 mm in the BE group versus 18.50 ± 3.40 mm in the SE group (p = 0.23), with an average sac size of 20.10 ± 18.9 mm in the BE group versus 15.60 ± 12.7 mm in the SE group (p = 0.16). The average sac-to-neck ratio was 1.69 ± 2.23 in the BE group versus 1.38 ± 0.33 in the SE group (p = 0.63). The BE group exhibited a significantly higher endoleak rate (60%) compared to the SE group (12.5%; p = 0.03). Conclusions: While further investigation is needed to fully assess the outcomes of stent graft treatment for VAAs, initial data show a significantly higher endoleak rate with BE SGs compared to SE SGs. The SE SGs may offer better outcomes due to their superior ability to conform to tortuous and mobile visceral arteries.

Introduction A 10-15 years decrease in life expectancy has been observed in individuals with bipolar disorder (BD) and has been associated with premature cellular aging, but mechanisms involved remain unclear. Our team recently identified a subgroup of young individuals with prematurely shortened telomere length (TL). Objectives The aims of the present study were to replicate this observation in a larger sample and to analyze the expression levels of genes associated with age or TL in a subsample of these individuals. Methods TL was measured by qPCR using peripheral blood DNA from 542 individuals with BD. Clustering analyzes were performed with age and TL as classification variables to identify similar groups. Gene expression of 29 genes, including 20 associated with age and 9 with TL, was analyzed by RT-qPCR using peripheral blood RNA in a subgroup of 129 individuals. Gene expressions were compared between groups obtained from the previous clustering analyzes by Kruskal-Wallis and Mann-Whitney tests. Results Clustering analyzes identified 3 subgroups and replicated the clustering previously described: a subgroup of aged individuals with a low TL (mean age : 51.73 years ; mean TL : 2), a subgroup of young individuals with a high TL (mean age : 29.02 years ; mean TL : 4.36) and a subgroup of young individuals but with a low TL (mean age : 29.64 years ; mean TL : 1.96). None of the tested clinical variables were significantly associated with this subgroup. Furthermore, gene expression level analyzes showed that only POT1 expression was different between the two subgroups of young individuals, with a downregulation of POT1 expression in the subgroup with a lower TL level. POT1 is a protein involved in the maintenance of TL. POT1 binds to another protein TPP1 allowing the recruitment of telomerase, the enzyme which extends TL. Our hypothesis is that in the subgroup presenting a lower POT1 expression, the POT1-TPP1 complex cannot form and thus prevents telomerase recruitment and TL elongation. Conclusions This study confirms, on a larger sample, the existence of a subgroup of young individuals with BD presenting accelerated cellular aging. The observed decrease of POT1 expression level suggests a newly described cellular mechanism in individuals with BD, that may contribute to telomere shortening. Disclosure of Interest None Declared

The thought of P.A. Florensky is a peculiar expression of Russian philosophy and, more generally, of Russian cultural identity. At the same time, it can nevertheless be regarded as a legitimate heir to the cultural tradition which from its powerful Ionian roots unfolds through the peaks and abysses of Western philosophy stricto sensu, up to the ultimate crises of contemporary thought...