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Background The prevalence and prognostic implications of pre-existing dyslipidaemia in patients infected by the SARS-CoV-2 remain unclear. Aim To assess the prevalence and mortality risk in COVID-19 patients with pre-existing dyslipidaemia. Design Systematic review and meta-analysis. Methods Preferred reporting items for systematic reviews and meta-analyses guidelines were followed in abstracting data and assessing validity. We searched MEDLINE and Scopus to locate all the articles published up to 31 January 2021, reporting data on dyslipidaemia among COVID-19 survivors and non-survivors. The pooled prevalence of dyslipidaemia was calculated using a random-effects model and presenting the related 95% confidence interval (CI), while the mortality risk was estimated using the Mantel–Haenszel random-effect models with odds ratio (OR) and related 95% CI. Statistical heterogeneity was measured using the Higgins I2 statistic. Results Of about 18 studies, enrolling 74 132 COVID-19 patients (mean age 70.6 years), met the inclusion criteria and were included in the final analysis. The pooled prevalence of dyslipidaemia was 17.5% of cases (95% CI: 12.3–24.3%, P  < 0.0001), with high heterogeneity (I 2 = 98.7%). Pre-existing dyslipidaemia was significantly associated with higher risk of short-term death (OR: 1.69, 95% CI: 1.19–2.41, P  = 0.003), with high heterogeneity (I 2 = 88.7%). Due to publication bias, according to the Trim-and-Fill method, the corrected random-effect ORs resulted 1.61, 95% CI 1.13–2.28, P  < 0.0001 (one studies trimmed). Conclusion Dyslipidaemia represents a major comorbidity in about 18% of COVID-19 patients but it is associated with a 60% increase of short-term mortality risk. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a β-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.

High levels of blood homocysteine (HCy), a well-known cardiovascular risk factor and promoter of oxidative stress, have been associated with the incidence of cognitive impairment and dementia. Nonetheless, contrasting data are still present on its involvement in the progression from Mild Cognitive Impairment (MCI) to overt dementia. In this study we aimed to observe whether blood HCy level are associated with the evolution from MCI, divided into amnestic MCI (aMCI) and non-amnestic MCI (naMCI), to dementia. Blood HCy was measured in 311 MCI subjects (aMCI: 64%, naMCI: 36%) followed-up for a median of 33 months (range 10-155 months). At follow-up, 137 individuals converted to dementia (naMCI, n = 34; aMCI, n = 103). Based on HCy distribution, subjects in the highest tertile had a greater risk to convert to dementia compared to tertile I (Hazard Ratio (95% confidence interval): 2.25 (1.05-4.86); p = 0.04). aMCI subjects did not show increased risk to convert to dementia with increasing HCy concentration, but was significant in naMCI (p = 0.04). We observed a non-significant increase in the risk of progression to dementia from naMCI/low HCy (reference group, HCy cutoff value = 16 μmol/L) to naMCI/high HCy, but it was significant from aMCI/low HCy (HR: 2.73; 95%CI: 1.06-7.0; p:0.03), to aMCI/high HCy (HR: 3.24; 95%CI: 1.17-8.47; p:0.02). Our results suggest that HCy levels are associated with the progression from MCI to dementia. This association seems significant only for the naMCI group, indirectly supporting the notion that hyperhomocysteinemia damages the nervous system through its role as a vascular risk factor., 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 © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Neutrophil-lymphocyte ratio (NLR) is a noninvasive, inexpensive, and easily applicable marker of inflammation. Since immune dysregulation leading to inflammation is regarded as a hallmark of dementia, in particular Alzheimer's disease (AD), we decided to investigate the potentials of NLR as a diagnostic and predictive biomarker in this clinical setting., Materials and Methods: NLR was measured in the blood of patients with AD ( n  = 103), amnestic type mild cognitive impairment (aMCI, n  = 212), vascular dementia (VAD, n  = 34), and cognitively healthy Controls ( n  = 61). One hundred twelve MCI patients underwent a regular clinical follow-up. Over a 36-months median follow-up, 80 remained stable, while 32 progressed to overt dementia., Results: NLR was higher in patients with aMCI or dementia compared to Controls; however, the difference was statistically significant only for aMCI (+13%, p =0.04) and AD (+20%, p =0.03). These results were confirmed by multivariate logistic analysis, which showed that high NLR was associated with an increase in the likelihood of receiving a diagnosis of aMCI (odd ratio (OR): 2.58, 95% confidence interval (CI): 1.36-4.89) or AD (OR: 3.13, 95%CI: 1.47-6.70), but not of VAD. NLR did not differ when comparing stable vs. progressing aMCI., Conclusions: This is the first report showing that NLR is significantly increased in MCI and AD but not in VAD. We also found that NLR was unable to predict the conversion from aMCI to AD. Further research on larger cohorts is warranted to definitely ascertain the application of NLR as a possible marker for aMCI and AD., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2024 Carlo Cervellati et al.)

Introduction: The accurate distinction between periprosthetic joint infections (PJI) and aseptic failures (AF) is of paramount importance due to differences in treatment. However, this could be challenging by using the current criteria. Various synovial fluid biomarkers are being assessed to improve the diagnostic accuracy. Myeloperoxidase (MPO), an enzyme contained in the granules of neutrophils, may be a promising biomarker for PJI., Methods: Synovial fluids of 99 patients ( n = 65 PJI according to EBJIS criteria; n = 34 AF) were collected in two specialized orthopedic centers. PJI were divided into acute ( n = 33) and low-grade ( n = 32) according to previously published classification. An activity assay specific for active MPO was performed in each sample. Ability of MPO to correctly discriminate patients with PJI from AF was determined by ROC analysis. The best discriminating cut-off value was determined by calculating the J Youden index. For all analyses, a P value < 0.05 was considered statistically significant., Results: Active MPO was higher in PJI than AF ( P < 0.0001). The ROC analysis revealed a significant area under the curve (AUC: 0.86; 95% CI: 0.78-0.93, P < 0.0001). A cut-off value of 561.9 U/mL, with good sensitivity (0.69) and specificity (0.88), discriminated between AF and PJI (accuracy 75.76%, 95% CI: 66.11-83.81%, positive likelihood ratio 5.88, 95% CI: 2.31-14.98 and negative likelihood ratio 0.35, 95%CI: 0.24-0.51). No difference in MPO levels was found between acute and chronic low-grade PJI., Conclusion: The proposed assay appears to be a reliable and affordable tool for detecting the active MPO in synovial fluid, with promising characteristics of sensitivity and specificity in discriminating both acute and low-grade PJI from AF. Further studies are needed to confirm MPO diagnostic cut-off values and validate their use in the routine clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Maritati, De Rito, Rosta, Cervellati, Cristina Manfrinato, Alberto Zanoli, De Giorgio, Guarino, Costanzini, Contini, Ning, Trampuz and Trentini.)

HDL-cholesterol quality, including cholesterol distribution in HDL subfractions, is emerging as a key discriminant in dictating the effects of these lipoproteins on cardiovascular health. This study aims at elucidating the relationship between cholesterol distribution in HDL subfractions and CVD risk factors as well as diet quality and energy density in a population of pre- and postmenopausal women. Seventy-two women aged 52 ± 6 years were characterized metabolically and anthropometrically. Serum HDL-C subfractions were quantified using the Lipoprint HDL System. Cholesterol distribution in large HDL subfractions was lower in overweight individuals and study participants with moderate to high estimated CVD risk, hypertension, or insulin resistance. Cholesterol distribution in large, as opposed to small, HDL subfractions correlated negatively with insulin resistance, circulating triglycerides, and visceral adipose tissue (VAT). VAT was an independent positive and negative predictor of cholesterol distribution in large and small HDL subfractions, respectively. Furthermore, an increase in energy intake could predict a decrease in cholesterol levels in large HDL subfractions while lipid intake positively predicted cholesterol levels in small HDL subfractions. Cholesterol distribution in HDL subfractions may represent an additional player in shaping CVD risk and a novel potential mediator of the effect of diet on cardiovascular health.

Transglutaminase 2 (TG2) performs many functions both under physiological and pathological conditions. In cancer, its expression is associated with aggressiveness, propensity to epithelial-mesenchymal transition, and metastasis. Since TG2 performs key functions both outside and inside the cell, using inhibitors with different membrane permeability we analyzed the changes in the transcriptome induced in two triple-negative cell lines (MDA-MB-436 and MDA-MB-231) with aggressive features. By characterizing pathways and gene networks, we were able to define the effects of TG2 inhibitors (AA9, membrane-permeable, and NCEG2, impermeable) in relation to the roles of the enzyme in the intra- and extracellular space within the context of breast cancer. The deregulated genes revealed p53 and integrin signaling to be the common pathways with some genes showing opposite changes in expression. In MDA-MB-436, AA9 induced apoptosis, modulated cadherin, Wnt, gastrin and cholecystokinin receptors (CCKR) mediated signaling, with RHOB and GNG2 playing significant roles, and affected the Warburg effect by decreasing glycolytic enzymes. In MDA-MB-231 cells, AA9 strongly impacted HIF-mediated hypoxia, including AKT and mTOR pathway. These effects suggest an anti-tumor activity by blocking intracellular TG2 functions. Conversely, the use of NCEG2 stimulated the expression of ATP synthase and proteins involved in DNA replication, indicating a potential promotion of cell proliferation through inhibition of extracellular TG2. To effectively utilize these molecules as an anti-tumor strategy, an appropriate delivery system should be evaluated to target specific functions and avoid adverse effects. Additionally, considering combinations with other pathway modulators is crucial., 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 © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Data regarding the trends in Alzheimer's disease (AD) mortality in the modern European Union (EU-27) member states are lacking. We assess the sex- and age-specific trends in AD mortality in the EU-27 member states between years 2012 and 2020., Methods: Data on cause-specific deaths and population numbers by sex for each country of the EU-27 were retrieved through publicly available European Statistical Office (EUROSTAT) dataset from 2012 to 2020. AD-related deaths were ascertained when the ICD-10 code G30 was listed as the primary cause of death in the medical death certificate. To calculate annual trends, we assessed the average annual percent change (AAPC) with relative 95% confidence intervals (CIs) using Joinpoint regression., Results: During the study period, 751,493 deaths (1.7%, 233,271 males and 518,222 females) occurred in the EU-27 because of AD. Trends in the proportion of AD-related deaths per 1000 total deaths slightly increased from 16.8% to 17.5% (p for trend <0.001). The age-adjusted mortality rate was higher in women over the entire study period. Joinpoint regression analysis revealed a stagnation in age-adjusted AD-related mortality from 2012 to 2020 among EU-27 Member States (AAMR: -0.1% [95% CI: -1.8-1.79], p = 0.94). Stratification by Country showed relevant regional disparities, especially in the Northern and Eastern EU-27 member states., Conclusions: Over the last decade, the age-adjusted AD-related mortality rate has plateaued in EU-27. Important disparities still exist between Western and Eastern European countries., (© 2024 John Wiley & Sons Ltd.)

The real efficacy of Acetyl-cholinesterase-inhibitors (AChEI) has been questioned. In this narrative review we evaluated their effect on cognitive decline, measured by Mini Mental State Examination (MMSE), and on total mortality rates in patients with Alzheimer's disease (AD) recruited into post-marketing open/non-randomized/retrospective studies. In AD patients treated with AChEI, the mean MMSE loss ranged from 0.2 to 1.37 points/years, compared with 1.07-3.4 points/years in non-treated patients. Six studies also reported data about survival; a reduction in total mortality relative risk between 27% and 42% was observed, over a period of 2-8 years. The type of studies and the use of MMSE to assess cognitive decline, may have introduced several biases. However, the clinical effects of AChEI seem to be of the same order of magnitude as the drugs currently used in most common chronic disorders, as regards progression of the disease and total mortality. In the absence of long-term randomized trials on "standard" unselected AD outpatients, open/retrospective studies and health databases represent the best available evidence on the possible effect of AChEI in the real-word setting. Our data support the clinical benefit of AChEI in older patients affected by AD., (© 2024. The Author(s).)

Paraoxonase (PON) enzymes (PON1, PON2 and PON3) exert antioxidant properties through arylesterase, lactonase and paraoxonase activities. Increasing findings suggested their potential involvement, particularly PON1 and PON2, in Alzheimer's disease (AD), a neurodegenerative pathology characterized by early oxidative stress. Specifically, decreased serum PON1-arylesterase and lactonase activities seem to be associated with an increased brain oxidative damage in early AD, leading to hypothesize that PON activity alterations might be an early event in AD. To address this hypothesis, the levels of 4-hydroxynonenal (4-HNE; i.e. a marker of oxidative stress damage) along with the protein expression and enzymatic activity of PON1 and PON2 have been investigated in the brain and serum of young [Postnatal day (PD)8-10, 20-25 and 60-65] asymptomatic 3xTg-AD female mice, one of the most used transgenic models of AD. At PD 8-10, there were no differences in hippocampus and prefrontal cortex (PFC) 4-HNE expression levels between 3xTg-AD mice compared to controls (Non-Tg mice). On the other hand, significant increased levels of 4-HNE were detected in PD 20-30 3xTg-AD mice hippocampus, while a significant reduction was observed in 3xTg-AD group at PD 60-65. In the PFC, 4-HNE levels were significantly reduced in 3xTg-AD mice brain at PD 20-30, while no differences in 4-HNE levels were detected at PD 60-65. No significant differences in arylesterase and lactonase activities were observed in the plasma of 3xTg-AD and Non-Tg mice at the different considered ages. Compared to Non-Tg mice, a reduction of brain arylesterase activity was found in 3xTg-AD female at PD 20-30 and PD 60-65, but it was significant only in the younger group. Finally, a similar trend was observed also for PON1 and PON2 protein levels, with both significantly, and solely, decreased in 3xTg-AD mice brain at PD 20-30. Overall, these findings suggest that the altered oxidative stress homeostasis in the 3xTg-AD female mice may be related to an early reduction in activity and expression of PONs enzymes most likely via a reduced brain arylesterases activity., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: None

Cumulating evidence links environmental toxicants, such as organophosphate (OP) pesticides, to the pathogenesis of Alzheimer's disease (AD). The calcium-dependent Paraoxonase 1 (PON1) can neutralize these toxicants with good catalytic efficiency, thus protecting from OP-induced biological damage. Although different previous studies have already partially described an association between PON1 activity and AD, this intriguing relationship has not yet been comprehensively examined. To fill this gap, we performed a meta-analysis of existing data comparing the PON1 arylesterase activity in AD and healthy subjects from the general population. Data were obtained by searching MEDLINE, Embase and CENTRAL, Google Scholar, and SCOPUS electronic databases for all studies published at any time up to February 2023, reporting and comparing the PON1- paraoxonase activity between AD patients and controls. Seven studies, based on 615 subjects (281 AD and 356 controls) met the inclusion criteria and were included into the final analysis. A random effect model revealed that PON1 arylesterase activity was significantly lower in the AD group compared to controls, exhibiting low level of heterogeneity (SMD = - 1.62, 95% CI = -2.65 to -0.58, p = 0.0021, I 2  = 12%). These findings suggest that PON1 activity might be reduced in AD reflecting a major susceptibility to OPs neurotoxicity. Further studies should be conducted to definitely ascertain this link and to establish the cause-effect relationship between PON1 reduction and AD onset., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: Zonulin is involved in the integrity and functioning of both intestinal-epithelial barrier and blood-brain barrier (BBB) by regulating tight junction molecular assembly., Aim: Since changes in microbiota and BBB may play a role in neurodegenerative disorders, we aimed to determine whether serum zonulin levels change in older patients affected by different types of dementia or mild cognitive impairment (MCI)., Methods: We evaluated serum zonulin levels in patients with late-onset AD (LOAD), vascular dementia (VAD), MIXED (AD + VAD) dementia, amnestic MCI, and in healthy controls., Results: Compared with controls, serum zonulin increased in LOAD, MIXED dementia, and aMCI but not in VAD, independent of potential confounders (ANCOVA p = 0.01; LOAD vs controls, p = 0.01; MIXED vs. controls, p = 0.003; aMCI vs. controls, p = 0.04). Notably, aMCI converting to dementia showed significantly higher levels of zonulin compared with stable aMCI (p = 0.04). Serum zonulin inversely correlated with the standardized Mini-Mental State Examination (MMSE) score (p < 0.05), regardless of potential confounders., Discussion: We found increased serum zonulin levels in patients with aMCI, LOAD and MIXED dementia, but not in VAD; moreover, zonulin levels were higher in aMCI converting to AD compared with stable ones., Conclusions: Our findings suggest that a dysregulation of intestinal-epithelial barrier and/or BBB may be an early specific event in AD-related neurodegeneration., (© 2023. The Author(s).)

While human and animal leishmaniasis affect several millions of people worldwide, L. infantum is the species responsible for visceral leishmaniasis in Europe, Middle East, and America. Antileishmanial drugs present issues associated with drug toxicity and increasing parasite resistance. Therefore, the study of this parasite with a focus on new potential drug targets is extremely useful. Accordingly, we purified and characterized a transglutaminase (TGase) from L. infantum promastigotes. While Tgases are known to be involved in cell death and autophagy, it appears that these functions are very important for parasites' virulence. For the first time, we showed a Ca 2+ - and GTP-dependent TGase in Leishmania corresponding to a 54 kDa protein, which was purified by two chromatographic steps: DEAE-Sepharose and Heparin-Sepharose. Using polyclonal antibodies against a 50-amino-acid conserved region of the catalytic core of human TGase 2, we revealed two other bands of 66 and 75 kDa. The 54 kDa band appears to be different from the previously reported TGase, which was shown to be Ca 2+ - independent. Future research should address the identification of the purified enzyme sequence and, subsequently, its cloning to more comprehensively investigate its pathophysiological function and possible differences from mammal enzymes.

A wealth of evidence suggests that Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays a relevant role in atherogenesis and inflammation, which in turn are associated with the risk of developing dementia. The aim of this study was to evaluate whether serum Lp-PLA2 activity might be an early and/or late biomarker for different forms of dementia. Serum Lp-PLA2 activity was assessed in older patients with mild cognitive impairment (MCI, n = 166; median clinical follow-up = 29 months), Late-Onset Alzheimer's disease (LOAD, n = 176), vascular dementia (VAD, n = 43), dementia characterized by an overlap between LOAD and VAD (AD-VAD MIXED dementia) ( n = 136), other dementia subtypes ( n = 45), and cognitively normal controls ( n = 151). We found a significant trend towards higher levels of Lp-PLA2 activity in VAD compared with the other groups (ANOVA, p = 0.028). Similarly, Lp-PLA2 activity was greater in MCI converting to VAD compared with those that did not or did convert to the other types of dementia (ANOVA, p = 0.011). After adjusting for potential confounders, high levels of Lp-PLA2 activity were associated with the diagnosis of VAD (O.R. = 2.38, 95% C.I. = 1.06-5.10), but not with other types of dementia. Our data suggest that increased serum Lp-PLA2 activity may represent a potential biomarker for the diagnosis of VAD.

Cerebrovascular diseases and the subsequent brain hypoperfusion are at the basis of vascular dementia. Dyslipidemia, marked by an increase in circulating levels of triglycerides and LDL-cholesterol and a parallel decrease in HDL-cholesterol, in turn, is pivotal in promoting atherosclerosis which represents a common feature of cardiovascular and cerebrovascular diseases. In this regard, HDL-cholesterol has traditionally been considered as being protective from a cardiovascular and a cerebrovascular prospective. However, emerging evidence suggests that their quality and functionality play a more prominent role than their circulating levels in shaping cardiovascular health and possibly cognitive function. Furthermore, the quality of lipids embedded in circulating lipoproteins represents another key discriminant in modulating cardiovascular disease, with ceramides being proposed as a novel risk factor for atherosclerosis. This review highlights the role of HDL lipoprotein and ceramides in cerebrovascular diseases and the repercussion on vascular dementia. Additionally, the manuscript provides an up-to-date picture of the impact of saturated and omega-3 fatty acids on HDL circulating levels, functionality and ceramide metabolism.

Background: In earlier studies, it has been observed that 8-week treatment with a novel nutraceutical compound (NC) containing low monacolin K dose, polymethoxyflavones, phenolic acids, flavonoids, and hydroxytyrosol improves lipid profile and endothelial function and reduces the level of oxidized low-density lipoprotein (oxLDL). We hypothesize that this effect might be, at least in part, explained by positive modulation exerted by the NC on the atheroprotective function of high-density lipoprotein (HDL)., Aim: This study aimed to evaluate whether the NC could influence determinants of HDL function., Methods: Forty-five subjects with low-moderate dyslipidaemia were enrolled and treated for 8 weeks with the NC, followed by 4 weeks of washout. Blood samples were collected at every time point to evaluate changes in lipid profile, endothelial function, oxLDL, and markers of HDL function, such as the anti-oxidant activities of paraoxonase-1, glutathione peroxidase-3 (Gpx3), lipoprotein-phospholipase A2 (Lp-PLA2), and pro-oxidant activity of myeloperoxidase (MPO)., Results: Although the concentration of HDL-C did not change, the activity of Lp-PLA2 significantly decreased upon treatment (-11.6%, p<0.001) and returned to baseline level 4 weeks after the end of treatment. In contrast, Gpx3 increased after treatment (+5%, p<0.01) and remained unvaried after 4 weeks. Both MPO activity and concentration significantly decreased after the washout period (-33 and 32%, p<0.001)., Conclusion: For the first time, it was found that the administration of an NC with beneficial effects on lipid homeostasis also positively impacts HDL function by improving the balance between protective and damaging determinants. Further investigation is required to corroborate our findings., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: The success of total joint arthroplasty (TJA) has led to consistent growth in the use of arthroplasty in progressively younger patients. However, more than 10 percent of patients require revision surgery due to implant failure caused by aseptic or septic inflammation. Among the latter, surgical site infection (SSI) represents one of the worst complications of TJA, potentially resulting in the removal of the prosthesis. The aim of our study was to identify potential risk factors for SSIs in a population of patients undergoing TJA., Methods: TJA were prospectively recruited at Casa di Cura Santa Maria Maddalena from February 2019 to April 2020. Age, sex, major comorbidities, American Society of Anesthesiologists (ASA) class, length of surgery, type of surgical suture, total hospital length of stay, and clinical laboratory data were collected. The study population was then divided into two groups: Group A, normal postoperative course, and Group B, patients who developed SSI at follow-up (17-25 days)., Results: 25/760 (3.3%) patients developed SSIs at follow-up. Clinical and demographic parameters were not different between the two groups. Total leucocyte and neutrophil values at discharge resulted to be significatively higher in Group B compared to Group A ( p = 0.025 and p = 0.016, respectively). Values of 7860/ μ L for total leucocyte and 5185/ μ L for neutrophil count at discharge significantly predicted the future development of SSI (AUC 0.623 and AUC 0.641, respectively; p < 0.05) independently from confounding factors (total leukocytes: O.R. = 3, 69 [95% C.I. 1,63-8,32]; neutrophils: O.R. = 3, 98 [95% C.I. 1,76-8,97]). Deep SSIs has been diagnosed significantly before superficial SSIs ( p = 0,008), with a median advance of 9 days., Conclusion: Total leukocytes and neutrophils at discharge seem useful to identify a population at risk for the development of septic inflammation at the surgical site following TJA. Further studies with larger populations are needed to develop a predictive SSIs risk score that should include those variables., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Martina Maritati et al.)

Background: The aim of the present study was to examine the prevalence of dementia, related comorbidities, and mortality rates in hospitalized elderly patients in Italy., Methods: Data were obtained from the Italian Ministry of Health and included all discharge records from Italian hospitals concerning subjects aged 65 years or above admitted to acute Internal Medicine during 2 years (n=3,695,278 admissions). Discharge diagnoses were re-classified into 24 clusters, each including homogeneous diseases by the ICD-9-CM code classification. Dementia was identified by the presence of ICD-9-CM codes 290, 294, or 331 series., Results: Patients with dementia represented 7.5% of the sample; compared with those without dementia, they were older and more often female, had a greater length of hospital stay and higher mortality rate. Besides delirium [odds ratio (OR): 54.20], enthesopaties (OR: 2.19), diseases of fluids and electrolytes (OR:1.96), diseases of arteries (OR: 1.69), skin diseases (OR: 1.64), and pneumonia and pleurisy (OR: 1.53) were the diseases more strongly associated with the diagnosis of dementia, independent of other clusters, age, sex, and length of stay., Conclusions: Some comorbidities are specifically associated with the diagnosis of dementia among hospitalized elderly patients. Overall, these comorbidities describe the typical clinical profile of the patient with advanced dementia and could be treated in the context of the primary care, since they do not require specific skills belonging to hospital settings., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aims:  To evaluate the relationship between comorbidity and in-hospital mortality in elderly patients affected by dementia., Methods: Data were obtained from the Italian Ministry of Health and included all discharge records from Italian hospitals concerning subjects aged ≥ 65 years admitted to acute Internal Medicine or Geriatrics wards between January 2015 and December 2016 (3.695.278 admissions). The variables analyzed included age, sex, and in-hospital death. Twenty-five homogeneous clusters of diseases were identified in discharge codes according to the ICD-9-CM classification., Results: Patients with dementia represented 7.5% of the sample (n. 278.149); they were older, more often males (51.9%), and had a higher in-hospital mortality (24.3%) compared to patients without dementia (9.7%). Dementia per se doubled the odds of death (OR 1.98; 95% CI 1.95-2.00), independent of age, sex, and comorbidities. Seven clusters of disease (pneumonia, heart failure, kidneys disease, cancer, infectious diseases, diseases of fluids/electrolytes and general symptoms) were associated with increased in-hospital mortality, independent of the presence/absence of dementia. Among patients with dementia, heart failure, pneumonia and kidney disease on their own substantially doubled/tripled mortality risk. The risk increased from 10.1% (none of selected conditions), up to 28.9% when only one of selected comorbidities was present, rising to 52.3% (OR: 9.34; p < 0.001) when two or more comorbidities were simultaneously diagnosed, besides general symptoms., Conclusions: Our study confirmed an important increase of in-hospital mortality in older subjects with dementia. Despite a different comorbidity, the conditions associated with in-hospital mortality were substantially the same in patients with or without dementia. Heart failure, pneumonia, and kidney disease identified a high risk of in-hospital mortality among subjects with dementia., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Accumulating evidence suggests that high consumption of natural antioxidants promotes health by reducing oxidative stress and, thus, the risk of developing cardiovascular diseases. Similarly, fermentation of natural compounds with lactic acid bacteria (LAB), such as Lactiplantibacillus plantarum , enhances their beneficial properties as regulators of the immune, digestive, and cardiovascular system. We investigated the effects of fermentation with Lactiplantibacillus plantarum on the antioxidant and immunomodulatory effects of Pushgay berries ( Vaccinium floribundum , Ericaceae family) in human umbilical vein endothelial cells (HUVECs) and macrophage cell line RAW264.7. Polyphenol content was assayed by Folin-Ciocalteu and HPLC-MS/MS analysis. The effects of berries solutions on cell viability or proliferation were assessed by WST8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt and Lactate dehydrogenase (LDH) release, Trypan blue exclusion test, and Alamar blue assay. Antioxidant activity was evaluated by a cell-based chemiluminescent probe for the detection of intracellular H 2 O 2 production in HUVECs. Heme oxygenase-1 (HO-1) expression levels were investigated by RT-qPCR. Glutathione reductase (GR), glutathione peroxidase (Gpx), superoxide dismutase (SOD), and catalase (CAT) activities, as markers of intracellular antioxidant defense, were evaluated by spectrophotometric analysis. The immunomodulatory activity was examined in RAW 264.7 by quantification of inducible nitric oxide synthase (iNOS) and Tumor Necrosis Factor-alpha (TNFα) by RT-qPCR. Data showed that fermentation of Pushgay berries ( i ) enhances the content of quercetin aglycone, and ( ii ) increases their intracellular antioxidant activity, as indicated by the reduction in H 2 O 2 -induced cell death and the decrease in H 2 O 2 -induced HO-1 gene expression in HUVECs treated for 24 h with fermented berries solution (10 µg/mL). Moreover, treatment with Pushgay berries for 72 h (10 µg/mL) promotes cells growth in RAW 264.7, and only fermented Pushgay berries increase the expression of iNOS in the same cell line. Taken together, our results show that LAB fermentation of Pushgay berries enhances their antioxidant and immunomodulatory properties.

Apricot breeding programs could be strongly improved by the availability of molecular markers linked to the main fruit quality traits. Fruit acidity is one of the key factors in consumer acceptance, but despite its importance, the molecular bases of this trait are still poorly understood. In order to increase the genetic knowledge on the fruit acidity, an F1 apricot population ('Lito' × 'BO81604311') has been phenotyped for titratable acidity and juice pH for the three following years. In addition, the contents of the main organic acids of the juice (malate, citrate, and quinate) were also evaluated. A Gaussian distribution was observed for most of the traits in this progeny, confirming their quantitative inheritance. An available simple sequence repeat (SSR)-based molecular map, implemented with new markers in specific genomic regions, was used to perform a quantitative trait loci (QTL) analysis. The molecular map was also anchored to the recently published apricot genome sequence of 'Stella.' Several major QTLs linked to fruit acidity-related traits have been identified both in the 'Lito' (no. 21) and 'BO81604311' (no. 13), distributed in five linkage groups (LG 4, 5, 6, 7, and 8). Some of these QTLs show good stability between years and their linked markers were used to identify candidate genes in specific QTLs genomic regions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dondini, Domenichini, Dong, Gennari, Bassi, Foschi, Lama, Adami, De Franceschi, Cervellati, Bergonzoni, Alessandri and Tartarini.)

Aim: To review and compare the PON-1 arylesterase activity between coronary artery disease (CAD) and non-CAD patients., Methods: Data were obtained by searching MEDLINE and Scopus for all investigations published between January 1, 2000 and March 1, 2021 comparing PON-1 arylesterase activity between CAD and controls., Results: Twenty studies, based on 5417 patients, met the inclusion criteria and were included in the analysis. A random effect model revealed that PON-1 arylesterase activity was significantly lower in the CAD group compared to controls (SMD = -0.587, 95%CI = -0.776 to -0.339, p < 0.0001, I 2 = 92.3%). In CAD patients, the PON-1 arylesterase activity was significantly higher among CAD patients without diabetes mellitus (DM) compared to those with diabetes (SMD: 0.235, 95% CI: 0.014 to 0.456, p = 0.03, I 2 = 0%)., Conclusions: PON-1 activity is significantly lower in CAD patients, and those without DM presented a significantly higher PON-1 arylesterase activity., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022 Marco Zuin et al.)

Rett syndrome (RTT), a devastating neurodevelopmental disorder, is caused in 95% of the cases by mutations in the X-chromosome-localized MECP2 gene. To date, RTT is considered a broad-spectrum disease, due to multisystem disturbances affecting patients, associated with mitochondrial dysfunctions, subclinical inflammation and an overall OxInflammatory status. Inflammasomes are multi-protein complexes crucially involved in innate immune responses against pathogens and oxidative stress mediators. The assembly of NLRP3:ASC inflammasome lead to pro-caspase 1 activation, maturation of interleukins (IL)-1β and 18 and proteolytic cleavage of Gasdermin D leading eventually to pyroptosis and systemic inflammation. The possible de-regulation of this system, in parallel with upstream nuclear factor (NF)-κB p65 pathway, were analyzed in peripheral blood mononuclear cells (PBMCs) and plasma isolated from RTT patients and matching controls. RTT PBMCs showed a constitutive activation of the axis TLR4 (Toll-like receptor 4)-IRAK1 (interleukin-1 receptor associated kinase 1)-NF-κB p65, together with augmented ROS generation and enhanced IL-18 mRNA levels and NLRP3:ASC co-localization. The deregulation of inflammasome components was even found in THP-1 cells silenced for MECP2 and importantly, in plasma compartment of RTT subjects, from the earliest stages of the pathology or in correlation with the severity of MeCP2 mutations. Taken together, these data provide new insights into the mechanisms involved in RTT sub-clinical inflammatory status present in RTT patients, thus helping to reveal new targets for future therapeutic approaches., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The role of transglutaminase type 2 in cell physiology is related to protein transamidation and signal transduction (affecting extracellular, intracellular and nuclear processes) aided by the expression of truncated isoforms and of two lncRNAs with regulatory functions. In breast cancer TG2 is associated with disease progression supporting motility, epithelial-mesenchymal transition, invasion and drug resistance. The aim of his work is to clarify these issues by emphasizing the interconnections among TGM2 variants and transcription factors associated with an aggressive phenotype, in which the truncated TGH isoform correlates with malignancy. TGM2 transcripts are upregulated by several drugs in MCF-7, but only Doxorubicin is effective in MDA-MB-231 cells. These differences reflect the expression of GATA3, as demonstrated by silencing, suggesting a link between this transcription factor and gene dysregulation. Of note, NC9, an irreversible inhibitor of enzymatic TG2 activities, emerges to control NF-ĸB and apoptosis in breast cancer cell lines, showing potential for combination therapies with Doxorubicin., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Beta-site APP cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid-β (Aβ) plaques formation. BACE1 activity is increased in brains of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) and plasma levels of BACE1 appears to reflect those in the brains., Objective: In this work, we investigated the role of serum BACE1 activity as biomarker for AD, estimating the diagnostic accuracy of the assay and assessing the correlation of BACE1 activity with levels of Aβ1 - 40, Aβ1 - 42, and Aβ40/42 ratio in serum, known biomarkers of brain amyloidosis., Methods: Serum BACE1 activity and levels of Aβ1 - 40, Aβ1 - 42, were assessed in 31 AD, 28 MCI, diagnosed as AD at follow-up (MCI-AD), and 30 controls. The BACE1 analysis was performed with a luciferase assay, where interpolation of relative fluorescence units with a standard curve of concentration reveals BACE1 activity. Serum levels of Aβ1 - 40, Aβ1 - 42 were measured with the ultrasensitive Single Molecule Array technology., Results: BACE1 was increased (higher than 60%) in AD and MCI-AD: a cut-off of 11.04 kU/L discriminated patients with high sensitivity (98.31%) and specificity (100%). Diagnostic accuracy was higher for BACE1 than Aβ40/42 ratio. High BACE1 levels were associated with worse cognitive performance and earlier disease onset, which was anticipated by 8 years in patients with BACE1 values above the median value (> 16.67 kU/L)., Conclusion: Our results provide new evidence supporting serum/plasma BACE1 activity as an early biomarker of AD.

Competing Interests: None

Beta-secretase 1 (BACE1) is considered as the key enzyme in amyloid-β formation. Previous works suggest that high BACE1 activity may be present in brain, cerebrospinal fluid and serum of patients with late-onset Alzheimer's disease (LOAD) as well as mild cognitive impairment (MCI). Therefore, we evaluated whether serum BACE1 activity increases in MCI patients and is associated with the progression from MCI to dementia. BACE1 activity was measured in the serum of 259 MCI patients (162 amnestic-aMCI, 97 non-amnestic-naMCI) and 204 healthy Controls. After a median follow-up of 32 months (range: 10-153), 116 MCI progressed to dementia (87 aMCI and 29 naMCI). Serum BACE1 activity was higher in MCI compared with Controls (p < 0.001), and in aMCI with brain atrophy compared with naMCI without brain atrophy (p = 0.04). No difference in BACE1 activity emerged between converter and non-converter MCI, and this was true for both aMCI and naMCI. However, among aMCI with better cognitive performance (n. 163, MMSE score ≥24/30) those converting to dementia had higher BACE1 activity compared to stable ones (p = 0.05). This was not associated with an increased risk to develop dementia (hazard ratio: 1.65; 95% confidence interval: 0.67-4.01). In conclusion, serum BACE1 activity significantly increased in MCI patients (both amnestic and non-amnestic) compared with Controls. Moreover, higher serum BACE1 activity was observed only among aMCI with a better cognitive performance who progressed to dementia, suggesting that a dysregulation of this enzyme might be an early event primarily associated with neurodegeneration., (© 2021 International Society for Neurochemistry.)

Background: The prevalence and prognostic implications of pre-existing dyslipidaemia in patients infected by the SARS-CoV-2 remain unclear., Aim: To assess the prevalence and mortality risk in COVID-19 patients with pre-existing dyslipidaemia., Design: Systematic review and meta-analysis., Methods: Preferred reporting items for systematic reviews and meta-analyses guidelines were followed in abstracting data and assessing validity. We searched MEDLINE and Scopus to locate all the articles published up to 31 January 2021, reporting data on dyslipidaemia among COVID-19 survivors and non-survivors. The pooled prevalence of dyslipidaemia was calculated using a random-effects model and presenting the related 95% confidence interval (CI), while the mortality risk was estimated using the Mantel-Haenszel random-effect models with odds ratio (OR) and related 95% CI. Statistical heterogeneity was measured using the Higgins I2 statistic., Results: Of about 18 studies, enrolling 74 132 COVID-19 patients (mean age 70.6 years), met the inclusion criteria and were included in the final analysis. The pooled prevalence of dyslipidaemia was 17.5% of cases (95% CI: 12.3-24.3%, P < 0.0001), with high heterogeneity (I2 = 98.7%). Pre-existing dyslipidaemia was significantly associated with higher risk of short-term death (OR: 1.69, 95% CI: 1.19-2.41, P = 0.003), with high heterogeneity (I2 = 88.7%). Due to publication bias, according to the Trim-and-Fill method, the corrected random-effect ORs resulted 1.61, 95% CI 1.13-2.28, P < 0.0001 (one studies trimmed)., Conclusion: Dyslipidaemia represents a major comorbidity in about 18% of COVID-19 patients but it is associated with a 60% increase of short-term mortality risk., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: No previous meta-analyses have compared the risk of dementia, due to an underlying atrial fibrillation (AF), in the short-term versus the long-term period., Aim: To perform an update meta-analysis of studies examining the association between AF and dementia and the relative impact of follow-up period., Methods: Data were obtained searching MEDLINE and Scopus for all investigations published between 1 January 2000 and March 1, 2021 reporting the risk of dementia in AF patients. The following MeSH terms were used for the search: "Atrial Fibrillation" AND "Dementia" OR "Alzheimer's disease". From each study, the adjusted hazard ratio (aHR) with the related 95% confidence interval (CI) was pooled using a random effect model., Results: The analysis was carried out on 18 studies involving 3.559.349 subjects, of which 902.741 (25.3%) developed dementia during follow-up. A random effect model revealed an aHR of 1.40 (95% CI: 1.27-1.54, p < 0.0001; I 2  = 93.5%) for dementia in subjects with AF. Stratifying the studies according to follow-up duration, those having a follow-up ≥10 years showed an aHR for dementia of 1.37 (95% CI: 1.21-1.55, p < 0.0001, I 2  = 96.6%), while those with a follow-up duration <10 years has a slightly higher aHR for dementia (HR: 1.59, 95%CI: 1.51-1.67, p < 0.0001, I 2  = 49%). Nine studies showed that the aHR for Alzheimer's disease (AD) in AF patients was 1.30 (95%CI: 1.12-1.51, p < 0.0001, I 2  = 87.6%)., Conclusions: Evidence suggests that patients with AF have an increased risk of developing dementia and AD. The risk of dementia was slightly higher when the follow-up was shorter than 10 years., (© 2021 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Background: The prevalence and prognostic implications of metabolic syndrome (MetS) in patients infected by the SARS-CoV-2 remain unclear. We performed a systematic review and meta-analysis of prevalence and mortality risk in COVID-19 patients with MetS., Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed in abstracting data and assessing validity. We searched MEDLINE and Scopus to locate every article published up to 1 September 2021, reporting data on MetS among COVID-19 patients. The pooled prevalence of MetS was calculated using a random effects model and presented using the related 95% confidence interval (CI), while the mortality risk was estimated using the Mantel-Haenszel random effects models with odds ratio (OR) and related 95% CI. Statistical heterogeneity was measured using the Higgins I 2 statistic., Results: Six studies, enrolling 209.569 COVID-19 patients [mean age 57.2 years, 114.188 males (54.4%)] met the inclusion criteria and were included in the final analysis. The pooled prevalence of dyslipidaemia was 20.5% of cases (95% CI: 6.7-47.8%, p = 0.03), with high heterogeneity (I 2 = 98.9%). Pre-existing MetS was significantly associated with higher risk of short-term mortality (OR: 2.30, 95% CI: 1.52-3.45, p < 0.001), with high heterogeneity (I 2 = 89.4%). Meta-regression showed a direct correlation with male gender ( p = 0.03), hypertension ( p < 0.001), DM ( p = 0.01) and hyperlipidaemia ( p = 0.04), but no effect when considering age ( p = 0.75) and chronic pulmonary disease ( p = 0.86) as moderators., Conclusions: MetS represents a major comorbidity in about 20% of COVID-19 patients and it is associated with a 230% increased risk of short-term mortality.

Background: Apolipoprotein J (ApoJ) is present in both plasma and tissues, including brain. Growing evidence suggest that this protein may play an early role on the development of the two most common forms of dementia, Alzheimer's disease (AD) and vascular dementia (VD)., Objective: To evaluate whether serum ApoJ levels might be able to predict the progression to AD, VD, or mixed dementia (AD&VD) in individuals with mild cognitive impairment (MCI)., Methods: Serum ApoJ was measured in 196 MCI subjects (aged ≥60 years) with a median follow up of 2.9 years., Results: One hundred thirty-two of the enrolled MCI subjects converted to dementia. Among these, 45% developed AD, 33% mixed dementia, 13% VD (VD), and 9% other forms of dementia. A significant trend toward a progressive reduction in the incidence of dementia, regardless of the type, from tertile I (83.1%), to tertile II (63.1%), to tertile III (56.1%) was observed (p = 0.003). After adjustment for potential confounders, a twofold increase in the risk of conversion to dementia was found in subjects belonging to tertile I of Apo J compared with tertile III; the risk increased after two years of follow up, while no differences emerged within the first 2 years., Conclusions: Our results suggest that in MCI subjects, low APOJ levels may be associated with increased risk of developing dementia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Cholangiocarcinoma (CCA) is an aggressive disease with poor prognosis. A molecular classification based on mutational, methylation and transcriptomic features could allow identifying tailored therapies to improve CCA patient outcome. Proteomic remains partially unexplored; here, we analyzed the proteomic profile of five intrahepatic cholangiocarcinoma (ICC) derived from Italian patients undergone surgery and one normal bile duct cell line., Methods: Proteome profile was investigated by using 2D electrophoresis followed by Mass Spectrometry (MS). To validate proteomic data, the expression of four overexpressed proteins (CAT, SOD, PRDX6, DBI/ACBP) was evaluated by immunohistochemistry in an independent cohort of formalin fixed, paraffin-embedded (FFPE) ICC tissues. We also compared proteomic data with those obtained by transcriptomic profile evaluated by microarray analysis of the same tissues., Results: We identified 19 differentially expressed protein spots, which were further characterized by MS; 13 of them were up- and 6 were down-regulated in ICC. These proteins are mainly involved in redox processes (CAT, SODM, PRDX2, PRDX6), in metabolism (ACBP, ACY1, UCRI, FTCD, HCMS2), and cell structure and organization (TUB2, ACTB). CAT is overexpressed in 86% of patients, PRDX6 in 73%, SODM in 100%, and DBI/ACBP in 81% compared to normal adjacent tissues. A concordance of 50% between proteomic and transcriptomic data was observed., Conclusions: This study pointed out that the impairment of the metabolic and antioxidant systems, with a subsequent accumulation of free radicals, might be a key step in CCA development and progression., (© 2021. The Author(s).)

Aims: This study aims to provide an updated systematic review and meta-analysis on the risk of Alzheimer's disease (AD) in patients with metabolic syndrome (MetS) and to analyze the contribution of each MetS component on AD onset., Data Synthesis: The study was performed according to the PRISMA guideline. Data were obtained searching MEDLINE, Scopus, Web of Science, and EMBASE for studies published between January 1, 2010 and July 30, 2020, evaluating the association between MetS and AD risk. A total of 255 articles were retrieved and 6 investigations (4 prospective and 2 retrospective) met the inclusion criteria. Overall, 9.788.021 patients with a mean follow-up of 4.5 years were analyzed. The pooled analysis revealed a slight increased risk of AD in MetS (hazard ratio, HR: 1.10, 95% and confidence interval, CI: 1.05-1.15). Egger's test indicated the absence of publication bias (t = 2.095 and p = 0.104). However, while analysis based on prospective studies failed to show a significant association between MetS and AD (HR: 0.80 and 95% CI: 0.61-1.05), analysis based on retrospective studies demonstrated a significant, slight increased risk (HR:1.11 and 95% CI: 1.08-1.66). With regard to MetS components, the risk was: arterial hypertension, HR: 1.05 (95% CI: 1.04-10.6); hyperglycemia/diabetes, HR: 1.19 (95% CI: 1.18-1.99); low high-density lipoprotein cholesterol (HDL-C), HR: 1.07 (95% CI: 1.06-1.07); hypertriglyceridemia, HR: 1.06 (95% CI: 1.05-1.06); and abdominal obesity, HR: 0.84 (95% CI: 0.74-0.95)., Conclusions: We found a significant association between MetS and AD, mainly driven by large retrospective studies. Our data also support the association of single MetS components with AD incidence, while increased waist circumference seems to have a "protective role" probably due to reverse causality., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)