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Left atrial appendage closure (LAAC) is a crucial intervention for stroke prevention in patients with non-valvular atrial fibrillation who are unsuitable for long-term anticoagulation. Amulet and Watchman are the most implanted devices worldwide for performing LAAC, and the aim of this review is to provide a comprehensive comparison focusing on their efficacy, safety, and short- and long-term outcomes. The Watchman device, the first to gain FDA approval, has been extensively studied and demonstrates significant reductions in stroke and systemic embolism rates. The Amulet device, a newer alternative, promises enhanced design features for more efficient appendage sealing. Current data highlight that both devices offer similar efficacy and safety for LAAC. While the two devices differ in terms of intraprocedural complication rates, they offer similar short- to long-term outcomes in terms of peri-device leaks, device-related thrombosis, and mortality. Both devices are indicated for patients who are unable to tolerate OAC, given their similar risk and safety profiles. Newer clinical studies are directed at establishing the efficacy of both devices as the primary method for stroke prevention in AF as an alternative to OAC.

This research examined the response of flax-fiber-reinforced composites (FFRCs) to simulated outdoor conditions involving repeated exposure to salt fog and drying. The study investigated the effect of cycles on the toughness of the FFRCs. To achieve this, the composites were exposed to humidity (salt fog) for 10 days, followed by 18 days of drying in cycles. A total of up to 3 cycles, each lasting 4 weeks, were conducted over a 12-week period. Throughout this process, changes in the material's weight, water absorption, and mechanical properties were monitored by water uptake and three-point bending tests. The findings revealed the significant impact of these humid-dry cycles on the mechanical response of the FFRCs. When exposed to humid environments without drying, the composite's toughness increased significantly, due to a weakening effect more pronounced for stiffness, with strength reductions of about 20%. However, subsequent drying partially restored the material's performance. After 18 days of drying, the composite regained most of its initial performance.

Competing Interests: Dr Barbanti is consultant for Medtronic, Edwards Lifescience and Boston Scientific. Dr Tamburino is consultant for Medtronic. Dr Grasso is proctor for Abbott, Boston Scientific and Eclipse Medical. Dr Di Salvo is proctor for Gore, Lifetech, Occlutech, and Innova Medical.

Muscle damage resulting from physical activities such as exercise triggers an immune response crucial for tissue repair and recovery. This study investigates the immune cell profiles in muscle biopsies of individuals engaged in resistance exercise (RE) and explores the impact of age and sex on the immune response following exercise-induced muscle damage. Microarray datasets from muscle biopsies of young and old subjects were analyzed, focusing on the gene expression patterns associated with immune cell activation. Genes were compared with immune cell signatures to reveal the cellular landscape during exercise. Results show that the most significant modulated gene after RE was Folliculin Interacting Protein 2 (FNIP2) a crucial regulator in cellular homeostasis. Moreover, the transcriptome was stratified based on the expression of FNIP2 and the 203 genes common to the groups obtained based on sex and age. Gene ontology analysis highlighted the FLCN-FNIP1-FNIP2 complex, which exerts as a negative feedback loop to Pi3k-Akt-mTORC1 pathway. Furthermore, we highlighted that the young females exhibit a distinct innate immune cell activation signature compared to males after a RE session. Specifically, young females demonstrate a notable overlap with dendritic cells (DCs), M1 macrophages, M2 macrophages, and neutrophils, while young males overlap with M1 macrophages, M2 macrophages, and motor neurons. Interestingly, in elderly subjects, both sexes display M1 macrophage activation signatures. Comparison of young and elderly signatures reveals an increased M1 macrophage percentage in young subjects. Additionally, common genes were identified in both sexes across different age groups, elucidating biological functions related to cell remodeling and immune activation. This study underscores the intricate interplay between sex, age, and the immune response in muscle tissue following RE, offering potential directions for future research. Nevertheless, there is a need for further studies to delve deeper and confirm the dynamics of immune cells in response to exercise-induced muscle damage., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Concomitant mitral transcatheter edge-to-edge repair (M-TEER) and left atrial appendage closure (LAAC) showed to be a feasible approach to optimize the treatment of patients eligible for both procedures, but mid-term outcomes are unclear., Methods: We retrospectively analyzed consecutive patients undergoing M-TEER and enrolled in the local prospective Getting Reduction of Mitral Insufficiency by Percutaneous Clip Implantation (GRASP) registry. We compared patients undergoing isolated M-TEER ( n = 58, 58.5%) with those undergoing concomitant M-TEER and LAAC ( n = 41, 41.5%) from January 2018 to December 2022. The primary endpoint was a composite of all-cause death, stroke or systemic embolism, hospitalization for heart failure, and bleeding at 1 year. The co-primary endpoint was procedural success., Results: The primary endpoint was similar between patients undergoing concomitant M-TEER+LAAC or isolated M-TEER (Kaplan Meier (KM) estimates 36.6% vs. 44.8%; p log-rank = 0.75). Procedural success was also similar (92.7% vs. 94.8%; p = 0.69). At 1- year, minor bleeds were lower in patients undergoing concomitant M-TEER and LAAC (KM estimates 0.0% vs. 18.9%; p log-rank < 0.01)., Conclusion: In patients with concomitant MR and AF and eligible for M-TEER and LAAC treatment, a combined approach of M-TEER and LAAC was as safe as an M-TEER-alone strategy and associated with lower minor bleeding at 1 year.

Despite natural fibers gaining significant attention in recent decades, their limited performance and poor durability under humid environments cannot allow them to fully replace their synthetic counterparts as reinforcement for structural composites. In such a context, this paper aims to investigate how exposure to a humid/dry cycle affects the mechanical response of epoxy laminates reinforced with flax and glass fibers. In particular, the main goal is to assess the performance evolution of a glass-flax hybridized stacking sequence in comparison with the full glass and flax fiber reinforced composites. To this end, the investigated composites were first exposed to salt-fog for 15 or 30 days and then to dry conditions (i.e., 50% R.H. and 23 °C) for up to 21 days. The presence of glass fibers in the stacking sequence significantly stabilizes the mechanical performance of composites during the humid/dry cycle. Indeed, hybridization of inner flax laminae with outer glass ones, acting as a protective shield, hinders the composite degradation due to the humid phase also promoting performance recovery during the dry phase. Hence, this work showed that a tailored hybridization of natural fibers with glass fibers represents a suitable approach to extend the service-life of natural fiber reinforced composites exposed to discontinuous humid conditions, thus allowing their employment in practical indoor and outdoor applications. Finally, a simplified theoretical pseudo-second-order model that aimed to forecast the performance recovery shown by composites was proposed and experimentally validated, highlighting good agreement with the experimental data.

While mitral stenosis of rheumatic origin has been effectively treated percutaneously for more than 20 years, transcatheter treatment of mitral (MR) and tricuspid (TR) regurgitation appears as a contemporary unmet clinical need. The advent of new transcatheter therapies offers several treatment options for elderly and frail patients at high surgical risk. MitraClip is now consolidated as a therapy for functional MR in selected patients. Transcatheter mitral valve replacement is a promising alternative to transcatheter repair, for both functional and degenerative forms. However, further developments and new evidence are needed. Transcatheter treatment of the tricuspid valve has arrived late compared to similar technologies that have been developed for the aortic and mitral valve, and is currently in its infancy. This is likely due, in part, to the previously underreported impact of TR on patient outcomes. Edge-to-edge repair is the most advanced transcatheter solution in development. Data on annuloplasty and tricuspid valve replacement are limited and more evidence is needed. The future looks promising for transcatheter mitral and tricuspid valve therapies, although their place in clinical practice has yet to be clearly defined., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Biocatalyzed oxidations are an important target in sustainable synthesis since chemical oxidations often require harsh conditions and metal-based catalysts. A raw peroxygenase-containing enzymatic preparation from oat flour was tested as a biocatalyst for the enantioselective oxidation of sulfides to sulfoxides and the variations of some reaction parameters were evaluated. Under optimal conditions, thioanisole was fully converted into the corresponding ( R )-sulfoxide with high optical purity (80% ee ) and the same stereopreference was maintained in the oxidation of some other sulfides. Changes in the substituent on the sulfur atom affected the selectivity of the enzyme and the best results were obtained with phenyl methoxymethyl sulfide, which gave the corresponding sulfoxide in 92% ee as exclusive product. The over-oxidation of sulfides to sulfones was instead detected in all the other cases and preferential oxidation of the ( S )-enantiomer of the sulfoxide intermediate was observed, albeit with low selectivity. Carrying out the oxidation of thioanisole up to the 29% formation of sulfone led to enhancement of the sulfoxide optical purity (89% ee ). The activity in sulfoxidation reactions, in addition to that reported in the epoxidation of different substrates, makes this plant peroxygenase a promising and useful tool in organic synthesis.

Neurological complications of AIDS (NeuroAIDS) include primary HIV-associated neurocognitive disorder (HAND). OAS3 is an enzyme belonging to the 2', 5' oligoadenylate synthase family induced by type I interferons and involved in the degradation of both viral and endogenous RNA. Here, we used microarray datasets from NCBI of brain samples of non-demented HIV-negative controls (NDC), HIV, deceased patients with HAND and encephalitis (HIVE) (treated and untreated with antiretroviral therapy, ART), and with HAND without HIVE. The HAND/HIVE patients were stratified according to the OAS3 gene expression. The genes positively and negatively correlated to the OAS3 gene expression were used to perform a genomic deconvolution analysis using neuroimmune signatures (NIS) belonging to sixteen signatures. Expression analysis revealed significantly higher OAS3 expression in HAND/HIVE and HAND/HIVE/ART compared with NDC. OAS3 expressed an excellent diagnostic ability to discriminate NDC from HAND/HIVE, HAND from HAND/HIVE, HAND from HAND/HIVE/ART, and HIV from HAND/HIVE. Noteworthy, OAS3 expression levels in the brains of HAND/HIVE patients were positively correlated with viral load in both peripheral blood and cerebrospinal fluid (CSF). Furthermore, deconvolution analysis revealed that the genes positively correlated to OAS3 expression were associated with inflammatory signatures. Neuronal activation profiles were significantly activated by the genes negatively correlated to OAS3 expression levels. Moreover, gene ontology analysis performed on genes characterizing the microglia signature highlighted an immune response as a main biological process. According to our results, genes positively correlated to OAS3 gene expression in the brains of HAND/HIVE patients are associated with inflammatory transcriptomic signatures and likely worse cognitive impairment., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Alzheimer's disease (AD) is the most common form of progressively disabling dementia. The chitinases CHI3L1 and CHI3L2 have long been known as biomarkers for microglial and astrocytic activation in neurodegeneration. Here, we collected microarray datasets from the National Center for Biotechnology Information (NCBI) brain samples of non-demented controls (NDC) (n = 460), and of deceased patients with AD (n = 697). The AD patients were stratified according to sex. Comparing the high CHI3L1 and CHI3L2 expression group (75 th percentile), and low CHI3L1 and CHI3L2 expression group (25 th percentile), we obtained eight signatures according to the sex of patients and performed a genomic deconvolution analysis using neuroimmune signatures (NIS) belonging to twelve cell populations. Expression analysis revealed significantly higher CHI3L1 and CHI3L2 expression in AD compared with NDC, and positive correlations of these genes with GFAP and TMEM119. Furthermore, deconvolution analysis revealed that CHI3L1 and CHI3L2 high expression was associated with inflammatory signatures in both sexes. Neuronal activation profiles were significantly activated in AD patients with low CHI3L1 and CHI3L2 expression levels. Furthermore, gene ontology analysis of common genes regulated by the two chitinases unveiled immune response as a main biological process. Finally, microglia NIS significantly correlated with CHI3L2 expression levels and were more than 98% similar to microglia NIS determined by CHI3L1. According to our results, high levels of CHI3L1 and CHI3L2 in the brains of AD patients are associated with inflammatory transcriptomic signatures. The high correlation between CHI3L1 and CHI3L2 suggests strong co-regulation., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

Background: Cholinergic hypofunction and sleep disturbance are hallmarks of Alzheimer's disease (AD), a progressive disorder leading to neuronal deterioration. Muscarinic acetylcholine receptors (M1-5 or mAChRs), expressed in hippocampus and cerebral cortex, play a pivotal role in the aberrant alterations of cognitive processing, memory, and learning, observed in AD. Recent evidence shows that two mAChRs, M1 and M3, encoded by CHRM1 and CHRM3 genes, respectively, are involved in sleep functions and, peculiarly, in rapid eye movement (REM) sleep., Methods: We used twenty microarray datasets extrapolated from post-mortem brain tissue of nondemented healthy controls (NDHC) and AD patients to examine the expression profile of CHRM1 and CHRM3 genes. Samples were from eight brain regions and stratified according to age and sex., Results: CHRM1 and CHRM3 expression levels were significantly reduced in AD compared with ageand sex-matched NDHC brains. A negative correlation with age emerged for both CHRM1 and CHRM3 in NDHC but not in AD brains. Notably, a marked positive correlation was also revealed between the neurogranin (NRGN) and both CHRM1 and CHRM3 genes. These associations were modulated by sex. Accordingly, in the temporal and occipital regions of NDHC subjects, males expressed higher levels of CHRM1 and CHRM3, respectively, than females. In AD patients, males expressed higher levels of CHRM1 and CHRM3 in the temporal and frontal regions, respectively, than females., Conclusion: Thus, substantial differences, all strictly linked to the brain region analyzed, age, and sex, exist in CHRM1 and CHRM3 brain levels both in NDHC subjects and in AD patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Glial activation and related neuroinflammatory processes play a key role in the aging and progression of Alzheimer's disease (AD). CHI3L1/ YKL40 is a widely investigated chitinase in neurodegenerative diseases and recent studies have shown its involvement in aging and AD. Nevertheless, the biological function of CHI3L1 in AD is still unknown. Here, we collected microarray datasets from the National Center for Biotechnology Information (NCBI) brain samples of not demented healthy controls (NDHC) who died from causes not attributable to neurodegenerative disorders (n = 460), and of deceased patients suffering from Alzheimer's disease (AD) (n = 697). The NDHC and AD patients were stratified according to CHI3L1 expression levels as a cut-off. We identified two groups both males and females, subsequently used for our statistical comparisons: the high CHI3L1 expression group (HCEG) and the low CHI3L1 expression group (LCEG). Comparing HCEG to LCEG, we attained four signatures according to the sex of patients, in order to identify the healthy and AD brain cellular architecture, performing a genomic deconvolution analysis. We used neurological signatures (NS) belonging to six neurological cells populations and nine signatures that included the main physiological neurological processes. We discovered that, in the brains of NDHC the high expression levels of CHI3L1 were associated with astrocyte activation profile, while in AD males and females we showed an inflammatory profile microglia-mediated. The low CHI3L1 brain expression levels in NDHC and AD patients highlighted a neuronal activation profile. Furthermore, using drugs opposing CHI3L1 transcriptomic signatures, we found a specific drug profile for AD males and females characterized by high levels of CHI3L1 composed of fostamatinib, rucaparib, cephaeline, prednisolone, and dinoprostone. Brain levels of CHI3L1 in AD patients represent a biological signature that allows distinguishing between males and females and their likely cellular brain architecture., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Colorectal cancer (CRC) is one of the most common cancers in the world. Here, we undertook an analysis of microarray datasets consisting of colon biopsies of healthy subjects and of patients affected by CRC, in order to analyze the expression levels of Chitinase domain-containing protein 1 (CHID1) and to correlate them with the clinical data available in the datasets. Analysis of expression levels showed a significant increase of CHID1 in CRC biopsies compared to the mucosa of healthy subjects. Patients' stratification by TNM staging revealed significant increases in CHID1 expression levels as the disease progressed. Furthermore, we found that mutated BRAF patients exhibit higher levels of CHID1 expression. Patients with a poor surviving prognosis at 5 years expressed high levels of CHID1 compared to wild-type. The histochemical analysis carried out by the Human Protein Atlas web tool documented moderate to strong-intensity staining detection of CHID1 protein in CRC biopsies. Furthermore, CRC patients were selected and clustered into two groups, high and low CHID1 expression levels (HCEL and LCEL). We obtained two signatures, the genes significant positive (GSPC-CHID1) and negative (GSNC-CHID1) correlated to CHID1 expression levels. The genomic deconvolution analysis between the GSPC-CHID1, GSNC-CHID1, and 17 cell immunological signatures, highlighted the potential infiltration of Macrophages M0 in HCEL patients, and potential infiltration of Macrophages M1 cells in LCEL patients. In addition, the signature GSPC-CHID1 expressed unfavorable genes to the CRC patient's survival. Mirror results were obtained for the GSNC-CHID1 signature. From the outcome of our investigation, it is possible to conclude that HCEL are associated with an unfavorable prognosis for CRC patients., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

The ability of lipases to display activity beyond their physiological reactions, so-called "catalytic promiscuity", has gained increasing interest in the last two decades as an important tool for expanding the application of these enzymes in organic synthesis. Some lipases have been shown to be effective in catalyzing a variety of C-C bond formation reactions and most of the investigations have been directed to the optimization of the products yield through a careful tuning of the experimental parameters. Despite the fact that new stereogenic carbons are formed in many of the tested reactions, the target products have been often obtained in racemic form and examples of an efficient asymmetric induction by the used lipases are quite limited. The aim of this review, mainly focused on those lipase-catalyzed promiscuous reactions in which optically active products have been obtained, is to offer a current state of art together with a perspective in this field of asymmetric synthesis.

Introduction: BCG and MMC shortage and Covid-19 pandemic, more recently, limit accessibility to maintenance regimen in intravesical prophylaxis against recurrence of non-muscle invasive bladder cancer (NMIBC). Ellagic acid (EA) and Annona muricata (AM) exert antitumor activity against different human tumours. An observational prospective study on the prophylactic effect of oral administration of EA+AM in patients avoiding maintenance regimen is presented., Materials and Methods: Patients affected by NMIBC and not undergoing maintenance after a 6-week course of intravesical prophylaxis with MMC or BCG were entered. Tis and very high-risk tumours were excluded. After informed consent, the patients were subdivided in relation to the oral assumption or not of EA (100 mg) plus AM (100 mg), daily for 6 months. All patients were submitted to 3-month cytology and cystoscopy., Results: 162 (90%) of 180 entered patients are evaluable, 90 and 72 receiving or not EA+AM. No difference emerged in patients' characteristics between the two groups. BCG was given in 86 (54%) and chemotherapy in 74 (46%) patients. The recurrence free rate at 3, 6 and 12 months in patients assuming or not EA was 96.5% versus 84.6% ( p  = 0.003), 85.4% versus 64.8% ( p  = 0.005) and 74.2% versus 60.6% ( p  = 0.246), respectively. The recurrence free survival at 12 months in patients assuming or not EA was 63.0% versus 34.5% ( p  < 0.0001)., Discussion and Conclusions: Our study suffers several limits: not randomized trial although prospective, limited number of patients and short follow-up, nevertheless it shows the prophylactic effect of oral EA+AM in absence of maintenance after intravesical chemotherapy or immunotherapy induction.

Introduction: Abdominal wall complications are common after kidney transplantation, and although they have a minor impact on patient and graft survival, they increase the patient's morbidity and may have an impact on quality of life. Abdominal wall complications have an overall incidence of 7.7-21%., Methods: This review will explore the natural history of abdominal wall complications in the kidney transplant setting, with a special focus on wound dehiscence and incisional herni, with a particular emphasis on risk factors, clinical characteristics, and treatment., Results: Many patient-related risk factors have been suggested, including older age, obesity, and smoking, but kidney transplant recipients have an additional risk related to the use of immunosuppression. Wound dehiscence usually does not require surgical intervention. However, for deep dehiscence involving the fascial layer with concomitant infection, surgical treatment and/or negative pressure wound therapy may be required., Conclusions: Incisional hernia (IH) may affect 1.1-18% of kidney transplant recipients. Most patients require surgical treatment, either open or laparoscopic. Mesh repair is considered the gold standard for the treatment of IH, since it is associated with a low rate of postoperative complications and an acceptable rate of recurrence. Biologic mesh could be an attractive alternative in patients with graft exposition or infection., (© 2021 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Limonene is one of the most abundant naturally occurring cyclic monoterpenes and has recently emerged as a sustainable alternative to petroleum-based solvents as well as a chemical platform for the production of value-added compounds. The biocatalytic epoxidation of both enantiomers of limonene was carried out in the presence of a peroxygenase-containing preparation from oat ( Avena sativa ) flour. Different reaction profiles were observed depending on the starting enantiomer of limonene, but in both cases the 1,2-monoepoxide was obtained as the main product with excellent diastereoselectivity. Trans -1,2-monoepoxide and cis -1,2-monoepoxide were isolated from the reaction of ( R )-limonene and ( S )-limonene, respectively, and the reactions were scaled-up to 0.17 M substrate concentration. The process is valuable for operational simplicity, lack of toxic metal catalysts, and cost-effectiveness of the enzymatic source. Pure stereoisomers of 1,2-monoepoxides of limonene constitute a useful starting material for biorenewable polymers, but can be also converted into other chiral derivatives by epoxide ring opening with nucleophiles. As a proof of concept, a tandem protocol for the preparation of enantiopure (1 S ,2 S ,4 R )-1,2-diol from ( R )-limonene and (1 R ,2 R ,4 S )-1,2-diol from ( S )-limonene was developed.

The biocatalytic epoxidation of ethanolamides of ω-3 fatty acids EPA and DHA, regarded as biologically active ω-3 endocannabinoids, in the presence of a peroxygenase-containing preparation from oat flour was investigated. Good regio- and steroselectivity toward the formation of the epoxide on the terminal double bond in the chain was observed with both these fatty acid derivatives and chiral monoepoxides 1 or 2 in 74% optical purity and 51-53% yields were isolated and spectroscopically characterized. The use of acetone as cosolvent in the reaction medium allowed to increase the concentration of starting substrates up to 40 mM and to further improve the selectivity in the epoxidation of DHA-EA. Due to the easy availability of the enzymatic preparation, the method offers a valuable strategy for the access to oxyfunctionalized derivatives of fatty acids., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Human behavior is influenced by both genetic and environmental factors. Monoamine oxidase A (MAOA) is among the most investigated genetic determinants of violent behaviors, while the monoamine oxidase B (MAOB) is explored in Parkinson's disease. We collected twenty-four post-mortem brain tissue datasets of 3871 and 1820 non-demented males and females, respectively, who died from causes not attributable to neurodegenerative diseases. The gene expressions of MAOA and MAOB (MAO genes) were analyzed in these subjects, who were further stratified according to age into eleven groups ranging from late Infancy (5-9 months) to centenarians (>100 years). MAO genes were differently expressed in brains during the entire life span. In particular, maximal and minimal expression levels were found in early life and around the teen years. Females tended to have higher MAO gene levels throughout their lives than those found in age-matched males, even when expressions were separately measured in different brain regions. We demonstrated the existence of age- and sex- related variations in the MAO transcript levels in defined brain regions. More in-depth protein studies are needed to confirm our preliminary results obtained only on messenger RNAs in order to establish the role played by MAO genes in human development., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Brain regions such as the cerebellum (CB) have been neglected for a long time in the study of Alzheimer's disease (AD) pathogenesis. In reference to a new emerging hypothesis according to which there is an altered cerebellar synaptic processing in AD, we verified the possible role played by new biomarkers in the CB of AD patients compared with not-demented healthy control subjects (NDHS). Using a bioinformatics approach, we have collected several microarray datasets and obtained 626 cerebella sample biopsies belonging to subjects who did not die from causes related to neurological diseases and 199 cerebella belonging to AD. The analysis of logical relations between the transcriptome dataset highlighted guanine nucleotide-binding protein (G protein) gamma 13 (GNG13) as a potential new biomarker for Purkinje cells (PCs). We have correlated GNG13 expression levels with already widely existing bibliography of PC marker genes, such as Purkinje cell protein 2 (PCP2), Purkinje cell protein 4 (PCP4), and cerebellin 3 (CBLN3). We showed that expression levels of GNG13 and PCP2, PCP4, and CBLN3 were significantly correlated with each other in NDHS and in AD and significantly reduced in AD patients compared with NDHS subjects. In addition, we highlighted a negative correlation between the expression levels of PC biomarkers and age. From the outcome of our investigation, it is possible to conclude that the identification of GNG13 as a potentially biomarker in PCs represents also a state of health of CB, in association with the expression of PCP2, PCP4, and CBLN3.

Alzheimer's disease is a progressive, devastating, and irreversible brain disorder that, day by day, destroys memory skills and social behavior. Despite this, the number of known genes suitable for discriminating between AD patients is insufficient. Among the genes potentially involved in the development of AD, there are the chitinase-like proteins (CLPs) CHI3L1, CHI3L2, and CHID1. The genes of the first two have been extensively investigated while, on the contrary, little information is available on CHID1. In this manuscript, we conducted transcriptome meta-analysis on an extensive sample of brains of healthy control subjects (n = 1849) (NDHC) and brains of AD patients (n = 1170) in order to demonstrate CHID1 involvement. Our analysis revealed an inverse correlation between the brain CHID1 expression levels and the age of NDHC subjects. Significant differences were highlighted comparing CHID1 expression of NDHC subjects and AD patients. Exclusive in AD patients, the CHID1 expression levels were correlated positively to calcium-binding adapter molecule 1 ( IBA1 ) levels. Furthermore, both in NDHC and in AD patient's brains, the CHID1 expression levels were directly correlated with calbindin 1 ( CALB1 ) and neurogranin ( NRGN ). According to brain regions, correlation differences were shown between the expression levels of CHID1 in prefrontal, frontal, occipital, cerebellum, temporal, and limbic system. Sex-related differences were only highlighted in NDHC. CHID1 represents a new chitinase potentially involved in the principal processes underlying Alzheimer's disease.

Recent findings demonstrated that physical exercise has a powerful role in improving cognitive function and delaying age-associated neurological decline. However, to date, there is a lack of information regarding the effect of physical activity (PA) on brain cells architecture. In this paper, we hypothesized that PA could play a role in the transcriptional changes of genes that enrich the main cells of central nervous system (CNS). From NCBI, we selected a microarray dataset composed of the human hippocampi (GSE110298) from 23 cognitively intact clinical cases (NDHSs) (aged 87.4 ± 6.3 years) selected to from the Rush Memory and Aging Project (MAP). The significantly expressed genes, obtained comparing hippocampi from subjects who underwent Low Physical Activity (LPA) vs those who performed High Physical Activity (HPA), were overlapped with the main genes enriching the CNS cells, obtained from the public human brain single-cell RNA-sequencing dataset (GSE67835), in order to determine the respective weighted percentages of significantly expression genes modulation (WPSEG). In NDHSs underwent HPA, the WPSEG was higher for Neurons, Dendritic Development, Synaptic transmission genes and Axon Development. In addition, in NDHSs underwent LPA we observed high expression of genes enriching Oligodendrocytes, Microglia, and Endothelial cells. Furthermore, neurogenesis and the decreasing of the T cell-mediated inflammatory process were the two main molecular mechanisms activated in the brains of NDHSs underwent HPA. From our results, it is possible to conclude that, in elderly subjects, the transcriptional profile of CNS cells changes as a function of the PA conducted during life. Performing PA periodically supports the maintenance of the physiological balance of neuronal cells and, consequently, improves the quality of life of the elderly., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Gender-related factors might affect vulnerability to Covid-19. The aim of this study was to describe the role of gender on clinical features and 28-day mortality in Covid-19 patients., Methods: Observational study of Covid-19 patients hospitalized in Bergamo, Italy, during the first three weeks of the outbreak. Medical records, clinical, radiological and laboratory findings upon admission and treatment have been collected. Primary outcome was 28-day mortality since hospitalization., Results: 431 consecutive adult patients were admitted. Female patients were 119 (27.6%) with a mean age of 67.0 ± 14.5 years (vs 67.8 ± 12.5 for males, p = 0.54). Previous history of myocardial infarction, vasculopathy and former smoking habits were more common for males. At the time of admission PaO 2 /FiO 2 was similar between men and women (228 [IQR, 134-273] vs 238 mmHg [150-281], p = 0.28). Continuous Positive Airway Pressure (CPAP) assistance was needed in the first 24 h more frequently in male patients (25.7% vs 13.0%; p = 0.006). Overall 28-day mortality was 26.1% in women and 38.1% in men (p = 0.018). Gender did not result an independent predictor of death once the parameters related to disease severity at presentation were included in the multivariable analysis (p = 0.898). Accordingly, the Kaplan-Meier survival analysis in female and male patients requiring CPAP or non-invasive ventilation in the first 24 h did not find a significant difference (p = 0.687)., Conclusion: Hospitalized women are less likely to die from Covid-19; however, once severe disease occurs, the risk of dying is similar to men. Further studies are needed to better investigate the role of gender in clinical course and outcome of Covid-19.

Background: A marker of urothelial damage could be helpful for early detection and monitoring of local toxicity due to intravesical therapy for non-muscle invasive bladder cancer (NMIBC). The aim of the study was to investigate the correlation between fibronectin (FN) gene expression in bladder washings and local toxicity secondary to adjuvant intravesical therapy., Materials and Methods: Patients undergoing adjuvant intravesical therapy for NMIBC and age-matched healthy patients were enrolled. Real time polymerase chain reaction was performed to analyze FN expression in bladder washings. Local toxicity was classified as: 0-1 mild (no medical therapy), 2 moderate (medical therapy and/or instillation postponed), 3 severe (discontinuation of therapy)., Results: Seventy-two patients and 21 controls entered the study. A useful pellet was obtained in 58 patients and 18 controls. Intravesical Bacillus Calmette-Guerin (BCG), Epirubicin and Mitomycin C was offered to 69%, 13.8% and 17.2% of patients respectively. Compared with healthy controls (FN = 1.0 fold), overall median FN expression before adjuvant intravesical therapy was 1.73 fold [interquartile range (IQR) 0.8-2.3], while during therapy median FN expression increased to 3.41 (IQR: 1.6-6.1) fold. Considering 40 intermediate and high-risk patients undergoing intravesical BCG, median FN expression before adjuvant treatment was 1.92 [(IQR: 1.0-2.7) fold, increasing up to 4.1 (IQR: 1.9-6.6) during therapy. In more detail, FN increased during BCG therapy, showing a median expression of 4.22 (IQR: 2.2-5.5) and 6.16 (IQR: 2.6-8.7) fold in presence of grade 2 and 3 toxicity respectively, while remaining more or less stable in asymptomatic patients. After receiver operating characteristic curve analysis, FN value of 3.6 fold resulted, corresponding to 75% sensitivity and 69% specificity to predict grade 2-3 toxicity events (area under the curve 0.74, 95% confidence interval 0.63-0.85, p  = 0.001)., Conclusion: Our study validated the correlation between FN expression and urothelial damage. BCG seems to induce a urothelial activation with FN overexpression during adjuvant intravesical therapy. Grade of toxicity was related to FN expression., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

The goal of this paper is to evaluate the effectiveness of a cost-effective and eco-friendly treatment based on the use of sodium citrate (Na 3 C 6 H 5 O 7 ) on the mechanical properties of flax fiber reinforced composites. To this scope, flax fibers were soaked in mildly alkaline solutions of the sodium salt at different weight concentration (i.e., 5%, 10% and 20%) for 120 h at 25 °C. The modifications on fibers surface induced by the proposed treatment were evaluated through Fourier transform infrared analysis (FTIR), whereas scanning electron microscope (SEM) and helium pycnometer were used to obtain useful information about composites morphology. The effect of the concentration of the treating solution on the mechanical response of composites was determined through quasi-static tensile and flexural tests, Charpy impact tests and dynamical mechanical thermal (DMTA) tests. The results revealed that composites reinforced with flax fibers treated in 10% solution exhibit the best mechanical performances as well as the lowest void contents. SEM analysis supported these findings showing that, by treating fibers in solutions with concentration up to 10%, composites having better morphology can be manufactured, in comparison to untreated ones. Conversely, higher Na 3 C 6 H 5 O 7 concentrations negatively affect both the morphology and the mechanical properties of composites.

Alzheimer's disease (AD) is one of the most common forms of dementia with still unknown pathogenesis. Several cytokines and chemokines are involved in the pathogenesis of AD. Among the chemokines, the CXCR4/CXCL12 complex has been shown to play an important role in the pathogenetic development of AD. We investigated the expression levels of CXCR4 / CXCL12 in fifteen brain regions of healthy non-demented subjects (NDHC) (2139 sample) and AD patients (1170 sample) stratified according to sex and age. Furthermore, we correlated their expressions with the Neurogranin (NRGN) and CHI3L1 levels, two inflamm-aging markers. We highlighted that CXCR4 gene expression levels were age-correlated in the brain of NDHC subjects and that AD nullified this correlation. A similar trend, but diametrically opposite was observed for CXCL12. Its expression was decreased during the aging in both sexes, and in the brains of AD patients, it underwent an inversion of the trend, only and exclusively in females. Brains of AD patients expressed high CXCR4 and CHI3L1, and low CXCL12 and Neurogranin levels compared to NDHC subjects. Both CXCR4 and CXCL12 correlated significantly with CHI3L1 and Neurogranin expression levels, regardless of disease. Furthermore, we showed a selective modulation of CXCL12 and CXCR4 only in specific brain regions. Taken together our results demonstrate that CXCL12 and CXCR4 are linked to Neurogranin and CHI3L1 expression levels and the relationship between postsynaptic damage and microglial activation in AD could be shown using all these genes. Further confirmations are needed to demonstrate the close link between these genes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: SARS-CoV2, the agent responsible for the current pandemic, is also causing respiratory distress syndrome (RDS), hyperinflammation and high mortality. It is critical to dissect the pathogenetic mechanisms in order to reach a targeted therapeutic approach., Methods: In the present investigation, we evaluated the effects of SARS-CoV 2 on human bronchial epithelial cells (HBEC). We used RNA-seq datasets available online for identifying SARS-CoV 2 potential genes target on human bronchial epithelial cells. RNA expression levels and potential cellular gene pathways have been analyzed. In order to identify possible common strategies among the main pandemic viruses, such as SARS-CoV 2 , SARS-CoV1, MERS-CoV, and H1N1, we carried out a hypergeometric test of the main genes transcribed in the cells of the respiratory tract exposed to these viruses., Results: The analysis showed that two mechanisms are highly regulated in HBEC: the innate immunity recruitment and the disassembly of cilia and cytoskeletal structure. The granulocyte colony-stimulating factor (CSF3) and dynein heavy chain 7, axonemal (DNAH7) represented respectively the most upregulated and downregulated genes belonging to the two mechanisms highlighted above. Furthermore, the carcinoembryonic antigen-related cell adhesion molecule 7 (CEACAM7) that codifies for a surface protein is highly specific of SARS-CoV 2 and not for SARS-CoV1, MERS-CoV, and H1N1, suggesting a potential role in viral entry. In order to identify potential new drugs, using a machine learning approach, we highlighted Flunisolide, Thalidomide, Lenalidomide, Desoximetasone, xylazine, and salmeterol as potential drugs against SARS-CoV 2 infection., Conclusions: Overall, lung involvement and RDS could be generated by the activation and down regulation of diverse gene pathway involving respiratory cilia and muscle contraction, apoptotic phenomena, matrix destructuration, collagen deposition, neutrophil and macrophages recruitment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) represents one of the main forms of dementia that afflicts our society. The expression of several genes has been associated with disease development. Despite this, the number of genes known to be capable of discriminating between AD patients according to sex remains deficient. In our study, we performed a transcriptomes meta-analysis on a large court of brains of healthy control subjects (n = 2139) (NDHC) and brains of AD patients (n = 1170). Our aim was to verify the brain expression levels of CHI3L2 and its correlation with genes associated with microglia-mediated neuroinflammation (IBA1), alteration of the blood-brain barrier (PECAM1), and neuronal damage (CALB1). We showed that the CHI3L2, IBA1, PECAM1, and CALB1 expression levels were modulated in the brains of patients with AD compared to NDHC subjects. Furthermore, both in NDHC and in AD patient's brains, the CHI3L2 expression levels were directly correlated with IBA1 and PECAM1 and inversely with CALB1. Additionally, the expression levels of CHI3L2, PECAM1, and CALB1 but not of IBA1 were sex-depended. By stratifying the samples according to age and sex, correlation differences emerged between the expression levels of CHI3L2, IBA1, PECAM1, and CALB1 and the age of NDHC subjects and AD patients. CHI3L2 represents a promising gene potentially involved in the key processes underlying Alzheimer's disease. Its expression in the brains of sex-conditioned AD patients opens up new possible sex therapeutic strategies aimed at controlling imbalance in disease progression.

The stability of the anti-inflammatory drug nepafenac was investigated in aqueous solutions containing hydroxypropyl-β-cyclodextrin at three different values of pH and degradation products were identified. (2-Amino-3-benzoyl)-oxoacetic acid, previously not reported as nepafenac-related impurity, was isolated and structurally characterized by NMR and ESI-MS analyses. It was also shown that the formation of this α-ketoacid from nepafenac in alkaline water/organic cosolvent solution occurs through an aerobic oxidation of the key intermediate 7-benzoyl-1,3-dihydro-indol-2-one, which in some extent is protected from oxidation in the presence of the cyclodextrin additive., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Falls in the elderly are a major public health concern because of their high incidence, the involvement of many risk factors, the considerable post-fall morbidity and mortality, and the health-related and social costs. Given that many falls are preventable, the early identification of older adults at risk of falling is crucial in order to develop tailored interventions to prevent such falls. To date, however, the fall-risk assessment tools currently used in the elderly have not shown sufficiently high predictive validity to distinguish between subjects at high and low fall risk. Consequently, predicting the risk of falling remains an unsolved issue in geriatric medicine. This one-year prospective study aims to develop and validate, by means of a cross-validation method, a multifactorial fall-risk model based on clinical and robotic parameters in older adults., Methods: Community-dwelling subjects aged ≥ 65 years were enrolled. At the baseline, all subjects were evaluated for history of falling and number of drugs taken daily, and their gait and balance were evaluated by means of the Timed "Up & Go" test (TUG), Gait Speed (GS), Short Physical Performance Battery (SPPB) and Performance-Oriented Mobility Assessment (POMA). They also underwent robotic assessment by means of the hunova robotic device to evaluate the various components of balance. All subjects were followed up for one-year and the number of falls was recorded. The models that best predicted falls-on the basis of: i) only clinical parameters; ii) only robotic parameters; iii) clinical plus robotic parameters-were identified by means of a cross-validation method., Results: Of the 100 subjects initially enrolled, 96 (62 females, mean age 77.17±.49 years) completed the follow-up and were included. Within one year, 32 participants (33%) experienced at least one fall ("fallers"), while 64 (67%) did not ("non-fallers"). The best classifier model to emerge from cross-validated fall-risk estimation included eight clinical variables (age, sex, history of falling in the previous 12 months, TUG, Tinetti, SPPB, Low GS, number of drugs) and 20 robotic parameters, and displayed an area under the receiver operator characteristic (ROC) curve of 0.81 (95% CI: 0.72-0.90). Notably, the model that included only three of these clinical variables (age, history of falls and low GS) plus the robotic parameters showed similar accuracy (ROC AUC 0.80, 95% CI: 0.71-0.89). In comparison with the best classifier model that comprised only clinical parameters (ROC AUC: 0.67; 95% CI: 0.55-0.79), both models performed better in predicting fall risk, with an estimated Net Reclassification Improvement (NRI) of 0.30 and 0.31 (p = 0.02), respectively, and an estimated Integrated Discrimination Improvement (IDI) of 0.32 and 0.27 (p<0.001), respectively. The best model that comprised only robotic parameters (the 20 parameters identified in the final model) achieved a better performance than the clinical parameters alone, but worse than the combination of both clinical and robotic variables (ROC AUC: 0.73, 95% CI 0.63-0.83)., Conclusion: A multifactorial fall-risk assessment that includes clinical and hunova robotic variables significantly improves the accuracy of predicting the risk of falling in community-dwelling older people. Our data suggest that combining clinical and robotic assessments can more accurately identify older people at high risk of falls, thereby enabling personalized fall-prevention interventions to be undertaken., Competing Interests: A.D.L., V.S., J.S. and C.S. are employees of Movendo Technology (Genova, Italy). S.P. is a consultant for Movendo Technology (Genova, Italy). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: To investigate the physiopathology of ejaculatory disorders (EjD) and discriminate between retrograde ejaculation (REj) and anejaculation (AEj) induced by α1A-blockers, through the association between the mean postorgasm seminal vesicle volume and the presence of sperm in midstream urine, in patients with moderate-to-severe lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement., Materials and Methods: Therapy-naïve male patients with LUTS and without previous EjD were treated with α1A-blockers. Pre- and post-treatment EjD were investigated through question 4 of the 4-item Male Sexual Function questionnaire and the Male Sexual Health Questionnaire for Ejaculatory Dysfunction Short Form (MSHQ-EjD-SF). After 12 weeks, postorgasm urine was collected for sperm count and seminal vesicle volume was calculated through transrectal ultrasound., Results: All 42 patients reported with EjD after treatment with α1A-blockers: 4-item Male Sexual Function questionnaire and MSHQ-EjD-SF Q4 scores were significantly higher (P <.001) and MSHQ-EjD-SF Q1-3 score was significantly lower (P <.001) than before. Postorgasm seminal vesicle volume was significantly higher in patients with postorgasm sperm-negative urine (AEj), and lower in patients with postorgasm sperm-positive urine (REj; P <.001)., Conclusion: We clearly demonstrated an association between the presence of sperm in the midstream urine and seminal vesicle volume after orgasm, strongly confirming and differentiating the hypothesis of a dual etiology for EjD (REj vs AEj) secondary to α1A-blockers therapy for LUTS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Over the last decades, natural fiber-reinforced polymer composites (NFRPs) gained great attention in several engineering fields thanks to the reduction of the environmental impact and the end-of-life cost disposal. Unfortunately, the use of NFRPs is limited, mainly due to their weak resistance against humid environments. Since limited literature is available about the evolution of the dynamic mechanical response of NFRPs under aggressive environments, this paper aims to investigate the damping properties of flax, jute and flax/jute epoxy composites exposed to salt-fog up to 60 days. Furthermore, sodium bicarbonate fiber treatment was performed to improve the composites' durability. The effectiveness of treatment was evidenced for full flax-reinforced composites, whereas no beneficial effect was found for jute composites. Moreover, treated hybrid laminates having outer laminae reinforced with flax showed better damping behavior than their hybrid counterparts during the whole aging campaign.

Background: Impaired physical performance is common in older adults and has been identified as a major risk factor for falls. To date, there are no conclusive data on the impairment of balance parameters in older subjects with different levels of physical performance., Aims: The aim of this study was to investigate the relationship between different grades of physical performance, as assessed by the Short Physical Performance Battery (SPPB), and the multidimensional balance control parameters, as measured by means of a robotic system, in community-dwelling older adults., Methods: This study enrolled subjects aged ≥ 65 years. Balance parameters were assessed by the hunova robot in static and dynamic (unstable and perturbating) conditions, in both standing and seated positions and with the eyes open/closed., Results: The study population consisted of 96 subjects (62 females, mean age 77.2 ± 6.5 years). According to their SPPB scores, subjects were separated into poor performers (SPPB < 8, n = 29), intermediate performers (SPPB = 8-9, n = 29) and good performers (SPPB > 9, n = 38). Poor performers displayed significantly worse balance control, showing impaired trunk control in most of the standing and sitting balance tests, especially in dynamic (both with unstable and perturbating platform/seat) conditions., Conclusions: For the first time, multidimensional balance parameters, as detected by the hunova robotic system, were significantly correlated with SPPB functional performances in community-dwelling older subjects. In addition, balance parameters in dynamic conditions proved to be more sensitive in detecting balance impairments than static tests.