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Background: Isoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aβ-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects., Methods: Targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aβ-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression., Results: Increased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR) < 0.05) with higher p-tau levels. Additionally, 8,12-iso-iPF2α VI was associated with increased total tau levels in CSF. In MCI due to AD, PGF2α was associated with both p-tau and total tau, whereases 8,12-iso-iPF2α VI was specifically associated with p-tau levels. In APOE stratified analysis, association of PGF2α with p-tau and t-tau was observed in only APOE ε4 carriers while 5-iPF2α VI showed association with both p-tau and t-tau in APOE ε33 carriers. CSF levels of 8,12- iso-iPF2α VI showed association with p-tau and t-tau in APOE ε33/APOE ε4 carriers and with t-tau in APOE ε3 carriers. None of the metabolites showed evidence of association with MCI to AD progression., Conclusions: Oxidative stress (8,12-iso-iPF2α VI) and inflammatory (PGF2α) biomarkers are correlated with biomarkers of AD pathology during the prodromal stage of AD and relation of PGF2α with tau pathology markers may be influenced by APOE genotype., (© 2024. The Author(s).)

Background: Platelet-rich plasma (PRP) and botulinum toxin type A (BTX-A) injections have proven effective in clinical trials for plantar fasciitis treatment but have not been directly compared. We aimed to compare clinical outcomes in patients undergoing PRP or BTX-A injections., Methods: We performed a randomised controlled trial (59 patients; 1-year follow-up) to assess efficacy, using pain and functional scales (VAS, AOFAS Hindfoot-scale and FAAM questionnaire) and fascia thickness reduction, in control and single ultrasound-guided BTX-A or PRP injection groups., Results: The BTX-A group showed better results at 1-month after treatment. Conversely, the PRP injection was more effective in the long-term, with significant pain reduction and functional improvement. Plantar fascia thickness significantly reduced from months 1 and 3 in the PRP and BTX-A groups, respectively., Conclusion: PRP and BTX-A injections are effective in patients with plantar fasciitis with BTX-A achieving better short-term pain reduction and PRP better long-term results., Level of Evidence: Level I; Randomised Controlled Trial., 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 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPβ1, a surface receptor that triggers amyloid-β(Aβ) phagocytosis via TYROBP., Objective: To analyze the impact of this copy-number variant in SIRPβ1 expression and how it affects AD molecular etiology., Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPβ1 isoform-specific phagocytosis assays were performed in HEK393T cells., Results: The insertion alters the SIRPβ1 protein isoform landscape compromising its ability to bind oligomeric Aβ and its affinity for TYROBP. SIRPβ1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aβ ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation., Conclusions: The SIRPβ1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aβ. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPβ1 structural variant might be considered as a potential modulator of this causative pathway.

Introduction: In the last 20 years we have doubled obesity rates. In Spain, 67 % of the population does not have an adequate weight and 40 % of the child population suffers from obesity or overweight. This leads to serious diseases. To avoid this, a national plan to fight obesity is required, with prevention and therapeutic strategies so as not to continue increasing these data in 2030. Among the factors that cause childhood obesity are poor eating habits as well as a lack of physical activity and excessive use of screens. In addition, there is a significant social gap. Childhood obesity especially affects families with lower purchasing power (54 %) who do not have access to a healthy diet or the necessary tools or knowledge to promote health to their sons and daughters through food. The World Health Organization (WHO) Regional Office for Europe developed a nutrient profile model in 2015, specifically for the purpose of restricting the marketing of foods aimed at children. This model is considered by the scientific community as a reference tool when it comes to establish policies and improvements in favor of public health, in order to provide families with access to food with a better profile and nutritional value.

Introduction: Elevated plasma levels of extracellular vesicles have been associated with impaired placentation, angiogenesis imbalance, intravascular inflammation, and endothelial dysfunction in women with preeclampsia, thus suggesting that circulating vesicles may be a good therapeutic target for the treatment of the disease. Recently, statins have been considered a potential treatment for the prevention of preeclampsia because of their pleiotropic effects, including the improvement of endothelial dysfunction and inhibition of inflammatory responses. However, the effects of these drugs on circulating vesicles concentration in women at risk of preeclampsia have not been established. Herein, we aimed to assess the effects of pravastatin on circulating extracellular vesicle generation in women at high risk of term preeclampsia. Methods: In a sample of 68 singleton pregnant women participating in the multicenter, double-blind, placebo-controlled STATIN trial (Nº EducraCT 2016-005206-19 ISRCTN), 35 women received a placebo and 33 women received a 20 mg/day dose of pravastatin for approximately 3 weeks (from 35 to 37 weeks of gestation until delivery). Large extracellular vesicles were characterized and quantified by flow cytometry using annexin V and cell-specific antibodies directed against platelet, endothelial, leukocyte, and syncytiotrophoblast cell surface markers. Results: In women who received the placebo, a significant increase in the plasma levels of large extracellular vesicles from platelets (34%, p < 0.01), leukocytes (33%, p < 0.01), monocytes (60%, p < 0.01), endothelial cells (40%, p < 0.05), and syncytiotrophoblast cells (22%, p < 0.05) were observed. However, treatment with pravastatin significantly reduced the plasma levels of large extracellular vesicles from platelets (42%, p < 0.001), leukocytes (25%, p < 0.001), monocytes (61%, p < 0.001), endothelial cells (69%, p < 0.001), activated endothelial cells (55%, p < 0.001), and syncytiotrophoblast cells (44%, p < 0.001). Discussion: These results indicate that pravastatin reduces the levels of activated cell-derived membrane vesicles from the maternal vasculature, blood, and placental syncytiotrophoblast of women at high risk of term preeclampsia, suggesting that this statin may be beneficial in reducing endothelial dysfunction and pro-inflammatory and pro-coagulatory state characteristics of the disease., 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 © 2023 Santoyo, Noguera, Avilés, Hernández-Caselles, de Paco-Matallana, Delgado, Cuevas, Llinás and Hernández.)

An 85-year-old female patient with a history of melanoma 2 years ago, with anemia and signs of upper gastrointestinal bleeding. She underwent gastroscopy in which 4 ulcerated and pigmented lesions located in the body and subcardial region were recognized. The anatomopathological study confirmed the diagnosis of metastatic melanoma.

The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) studies Latin American populations to benefit from the implementation of personalized medicine. Since 2006, it has studied ethnicity to apply pharmacogenetics knowledge in autochthonous populations of Latin America, considering ancestral medicine. The meeting 'Pharmacogenetics: ethnicity, Treatment and Health in Latin American Populations' was held in Mexico City, Mexico, and presented the relevance of RIBEF collaboration with Latin American researchers and the governments of Mexico, Spain and the Autonomous Community of Extremadura. The results of 17 years of uninterrupted work by RIBEF, the Declaration of Mérida/T'Hó and the call for the Dr José María Cantú Award for studies focused on the pharmacogenetics of native populations in Latin America were presented.

Introduction: The second-line chemotherapy in metastatic colorectal cancer (mCRC) with FOLFIRI-aflibercept demonstrated an increase in survival compared with FOLFIRI in patients previously treated with oxaliplatin-based regimens. Few data are available in patients treated previously with bevacizumab. Our objective is to evaluate the efficacy and safety of FOLFIRI-aflibercept in second-line treatment in patients who have previously received bevacizumab., Patients and Methods: This is a observational, retrospective study of patients with mCRC treated with FOLFIRI-aflibercept in 2nd line in eight hospitals in the Valencian Community. Survival, response, and toxicity were analyzed., Results: 122 patients with a median age of 61 years were included. 89% of patients had PS 0-1. The median of PFS (progression free survival) and OS (overall survival) was 5.45 (95% CI 4.74-6.15 months) and 10.15 (95% CI 7.47-12.82 months), respectively. Disease control rate 59.8%. The most common grade 3-4 adverse events were neutropenia (13,1%) and asthenia (9%). The presence of hypertension during treatment with FOLFIRI-aflibercept was associated with a survival benefit. Median of OS was 14.45 (95% CI 11.58-17.32) in patients with hypertension vs 7.78 (95% CI 5.02-10.54) in patients without hypertension (p = .001). Our results suggest that the presence of PS 0, primary tumor surgery, metachronous metastases, and the presence of only 1 metastatic location, are favorable prognostic factors associated with better OS., Conclusions: Our results confirm the value of maintaining angiogenesis inhibition with FOLFIRI-aflibercept in mCRC after progression to a first-line treatment with bevacizumab. The development of hypertension during treatment is a possible predictive marker of response., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Background: Optical coherence tomography angiography (OCT-A) is a novel method in the dementia field that allows the detection of retinal vascular changes. The comparison of OCT-A measures with established Alzheimer's disease (AD)-related biomarkers is essential to validate the former as a marker of cerebrovascular impairment in the AD continuum. We aimed to investigate the association of macular vessel density (VD) in the superficial plexus quantified by OCT-A with the AT(N) classification based on cerebrospinal fluid (CSF) Aβ1-42, p181-tau and t-tau measurements in individuals with mild cognitive impairment (MCI)., Materials and Methods: Clinical, demographic, ophthalmological, OCT-A and CSF core biomarkers for AD data from the Neuro-ophthalmology Research at Fundació ACE (NORFACE) project were analyzed. Differences in macular VD in four quadrants (superior, nasal, inferior, and temporal) among three AT(N) groups [Normal, Alzheimer and Suspected non-Alzheimer pathology (SNAP)] were assessed in a multivariate regression model, adjusted for age, APOE ε4 status, hypertension, diabetes mellitus, dyslipidemia, heart disease, chronic obstructive pulmonary disease and smoking habit, using the Normal AT(N) group as the reference category., Results: The study cohort comprised 144 MCI participants: 66 Normal AT(N), 45 Alzheimer AT(N) and 33 SNAP AT(N). Regression analysis showed no significant association of the AT(N) groups with any of the regional macular VD measures (all, p > 0.16). The interaction between sex and AT(N) groups had no effect on differentiating VD. Lastly, CSF Aβ1-42, p181-tau and t-tau measures were not correlated to VD (all r < 0.13; p > 0.13)., Discussion: Our study showed that macular VD measures were not associated with the AT(N) classification based on CSF biomarkers in patients with MCI, and did not differ between AD and other underlying causes of cognitive decline in our cohort., Competing Interests: MB has consulted for Araclon, Avid, Grifols, Lilly, Nutricia, Roche, Eisai and Servier. She received fees from lectures and funds for research from Araclon, Biogen, Grifols, Nutricia, Roche and Servier. She reports grants/research funding from Abbvie, Araclon, Biogen Research Limited, Bioiberica, Grifols, Lilly, SA, Merck Sharp & Dohme, Kyowa Hakko Kirin, Laboratorios Servier, Nutricia SRL, Oryzon Genomics, Piramal Imaging Limited, Roche Pharma SA, and Schwabe Farma Iberica SLU, all outside the submitted work. She has not received personal compensation from these organizations. AR was member of the scientific advisory board of Landsteiner Genmed and Grifols SA. AR holds stocks in Landsteiner Genmed. The remaining 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 © 2023 Marquié, García-Sánchez, Alarcón-Martín, Martínez, Castilla-Martí, Castilla-Martí, Orellana, Montrreal, de Rojas, García-González, Puerta, Olivé, Cano, Hernández, Rosende-Roca, Vargas, Tartari, Esteban-De Antonio, Bojaryn, Ricciardi, Ariton, Pytel, Alegret, Ortega, Espinosa, Pérez-Cordón, Sanabria, Muñoz, Lleonart, Aguilera, Tárraga, Valero, Ruiz and Boada.)

Cholesterol efflux capacity (CEC) is of interest given its potential relationship with several important clinical conditions including Alzheimer's disease. The inactivation of the APOE locus in mouse models supports the idea that it is involved in determining the CEC. With that in mind, we examine the impact of the plasma metabolome profile and the APOE genotype on the CEC in cognitively healthy elderly subjects. The study subjects were 144 unrelated healthy individuals. The plasma CEC was determined by exposing cultured mouse macrophages treated with BODIPY-cholesterol to human plasma. The metabolome profile was determined using NMR techniques. Multiple regression was performed to identify the most important predictors of CEC, as well as the NMR features most strongly associated with the APOE genotype. Plasma 3-hydroxybutyrate was the variable most strongly correlated with the CEC (r = 0.365; p = 7.3 × 10 -6 ). Male sex was associated with a stronger CEC (r = -0.326, p = 6.8 × 10 -5 ). Most of the NMR particles associated with the CEC did not correlate with the APOE genotype. The NMR metabolomics results confirmed the APOE genotype to have a huge effect on the concentration of plasma lipoprotein particles as well as those of other molecules including omega-3 fatty acids. In conclusion, the CEC of human plasma was associated with ketone body concentration, sex, and (to a lesser extent) the other features of the plasma lipoprotein profile. The APOE genotype exerted only a weak effect on the CEC via the modulation of the lipoprotein profile. The APOE locus was associated with omega-3 fatty acid levels independent of the plasma cholesterol level.

Few studies have addressed the impact of the association between Alzheimer's disease (AD) biomarkers and NPSs in the conversion to dementia in patients with mild cognitive impairment (MCI), and no studies have been conducted on the interaction effect of these two risk factors. AT(N) profiles were created using AD-core biomarkers quantified in cerebrospinal fluid (CSF) (normal, brain amyloidosis, suspected non-Alzheimer pathology (SNAP) and prodromal AD). NPSs were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). A total of 500 individuals with MCI were followed-up yearly in a memory unit. Cox regression analysis was used to determine risk of conversion, considering additive and multiplicative interactions between AT(N) profile and NPSs on the conversion to dementia. A total of 224 participants (44.8%) converted to dementia during the 2-year follow-up study. Pathologic AT(N) groups (brain amyloidosis, prodromal AD and SNAP) and the presence of depression and apathy were associated with a higher risk of conversion to dementia. The additive combination of the AT(N) profile with depression exacerbates the risk of conversion to dementia. A synergic effect of prodromal AD profile with depressive symptoms is evidenced, identifying the most exposed individuals to conversion among MCI patients.

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume., (© 2022. The Author(s).)

Optical coherence tomography angiography (OCT-A) allows the detection of retinal vessel density (VD) loss, which is a reflection of brain vascular pathology. We aimed to investigate differences in macular VD in the superficial plexus in a large cohort of individuals cognitively unimpaired (CU), with mild cognitive impairment due to Alzheimer´s disease (MCI-AD), MCI due to cerebrovascular pathology (MCI-Va), probable Alzheimer´s disease dementia (ADD) and Vascular Dementia (VaD). Clinical, demographical, ophthalmological and OCT-A data from the Neuro-ophthalmology Research at Fundació ACE (NORFACE) project were analyzed. Differences of macular VD in four quadrants (superior, nasal, inferior and temporal) among the five diagnostic groups were assessed in a multivariate regression model, adjusted by age, sex, education, hypertension, diabetes mellitus, heart disease and stroke. The study cohort comprised 672 participants: 128 CU, 120 MCI-AD, 111 MCI-Va, 257 ADD and 56 VaD. Regression analysis showed a significantly higher VD in the temporal quadrant in MCI-AD compared to CU participants (49.05 ± 4.91 vs 47.27 ± 4.17, p = 0.02, d = 0.40), and a significantly lower VD in the inferior quadrant in MCI-Va compared to CU participants (48.70 ± 6.57 vs 51.27 ± 6.39, p = 0.02, d = 0.40). Individuals with heart disease presented significantly lower VD in the inferior quadrant than those without (p = 0.01). The interaction of sex and diagnosis had no effect in differentiating VD. Mini-Mental State Examination (MMSE) scores were not correlated to VD (all r < 0.16; p > 0.07). In conclusion, our study showed that the MCI-AD and MCI-Va groups had significant differences in macular VD in opposite directions in the temporal and inferior quadrants, respectively, compared to CU participants, suggesting that macular VD might be able to differentiate two pathogenic pathways (AD- and cerebrovascular-related) in early stages of cognitive decline., (© 2022. The Author(s).)

Alzheimer's disease has a long asymptomatic phase that offers a substantial time window for intervention. Using this window of opportunity will require early diagnostic and prognostic biomarkers to detect Alzheimer's disease pathology at predementia stages, thus allowing identification of patients who will most probably progress to dementia of the Alzheimer's type and benefit from specific disease-modifying therapies. Consequently, we searched for CSF proteins associated with disease progression along with the clinical disease staging. We measured the levels of 184 proteins in CSF samples from 556 subjective cognitive decline and mild cognitive impairment patients from three independent memory clinic longitudinal studies (Spanish ACE, n = 410; German DCN, n = 93; German Mannheim, n = 53). We evaluated the association between protein levels and clinical stage, and the effect of protein levels on the progression from mild cognitive impairment to dementia of the Alzheimer's type. Mild cognitive impairment subjects with increased CSF level of matrix metalloproteinase 10 (MMP-10) showed a higher probability of progressing to dementia of the Alzheimer's type and a faster cognitive decline. CSF MMP-10 increased the prediction accuracy of CSF amyloid-β 42 (Aβ42), phospho-tau 181 (P-tau181) and total tau (T-tau) for conversion to dementia of the Alzheimer's type. Including MMP-10 to the [A/T/(N)] scheme improved considerably the prognostic value in mild cognitive impairment patients with abnormal Aβ42, but normal P-tau181 and T-tau, and in mild cognitive impairment patients with abnormal Aβ42, P-tau181 and T-tau. MMP-10 was correlated with age in subjects with normal Aβ42, P-tau181 and T-tau levels. Our findings support the use of CSF MMP-10 as a prognostic marker for dementia of the Alzheimer's type and its inclusion in the [A/T/(N)] scheme to incorporate pathologic aspects beyond amyloid and tau. CSF level of MMP-10 may reflect ageing and neuroinflammation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent multidrug resistance in Pseudomonas aeruginosa has favoured the adaptation and dissemination of worldwide high-risk strains. In June 2018, 15 P. aeruginosa strains isolated from patients and a contaminated multi-dose meropenem vial were characterized to assess their association to an outbreak in a Mexican paediatric hospital. The strains were characterized by antibiotic susceptibility profiling, virulence factors' production, and biofilm formation. The clonal relationship among isolates was determined with pulse-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST) sequencing. Repressor genes for the MexAB-OprM efflux pump were sequenced for haplotype identification. Of the strains, 60% were profiled as extensively drug-resistant (XDR), 33% as multidrug-resistant (MDR), and 6.6% were classified as sensitive (S). All strains presented intermediate resistance to colistin, and 80% were sensitive to aztreonam. Pyoverdine was the most produced virulence factor. The PFGE technique was performed for the identification of the outbreak, revealing eight strains with the same electrophoretic pattern. ST235 and ten new sequence types (STs) were identified, all closely related to ST233. ST3241 predominated in 26.66% of the strains. Twenty-five synonymous and seventeen nonsynonymous substitutions were identified in the regulatory genes of the MexAB-OprM efflux pump, and nalC was the most variable gene. Six different haplotypes were identified. Strains from the outbreak were metallo-β-lactamases and phylogenetically related to the high-risk clone ST233.

Oxidative and inflammatory stress, angiogenic imbalance, and endothelial dysfunction are pathophysiological mechanisms occurring in pre-eclampsia (PE) that may persist over time and predispose women to a higher risk of cardiovascular disease (CVD) in the future. However, there is little evidence on the vascular function of women at risk of PE who have not developed the disease. The main objective of this research is to study factors and biomarkers involved in endothelial dysfunction related to oxidative stress, angiogenic disbalance, and inflammation in women at high risk of term PE who do not develop the disease. An observational, analytical, retrospective, and descriptive study was carried out in a selected sample of 68 high-risk and 57 non-risk of term PE participants in the STATIN study (FFIS/2016/02/ST EUDRACT No: 2016-005206-19). A significant increase in mean arterial pressure (MAP) levels and oxidative stress biomarkers (uric acid, homocysteine, and total serum antioxidant capacity) was found. Biomarkers of inflammation (interleukin-6 and growth differentiation factor 15) and endothelial function (asymmetric dimethylarginine) were significantly elevated in the group at risk of pre-eclampsia. A significative dependence relationship was also established between MAP and interleukin-6 and uric acid. These results suggest that women at high risk of term PE may represent pregnancies with pre-existing maternal risk factors for CVD, manifested by the own cardiovascular overload of pregnancy. A better understanding of maternal cardiovascular function in pregnancy would allow the improved prediction of CVD late in life in women.

Background: Clinical diagnosis of Alzheimer's disease (AD) increasingly incorporates CSF biomarkers. However, due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, establishing in-house cutoffs defining the positivity/negativity of CSF biomarkers is recommended. However, the cutoffs currently published are usually reported by using cross-sectional datasets, not providing evidence about its intrinsic prognostic value when applied to real-world memory clinic cases., Methods: We quantified CSF Aβ1-42, Aβ1-40, t-Tau, and p181Tau with standard INNOTEST ® ELISA and Lumipulse G ® chemiluminescence enzyme immunoassay (CLEIA) performed on the automated Lumipulse G600II. Determination of cutoffs included patients clinically diagnosed with probable Alzheimer's disease (AD, n = 37) and subjective cognitive decline subjects (SCD, n = 45), cognitively stable for 3 years and with no evidence of brain amyloidosis in 18F-Florbetaben-labeled positron emission tomography (FBB-PET). To compare both methods, a subset of samples for Aβ1-42 (n = 519), t-Tau (n = 399), p181Tau (n = 77), and Aβ1-40 (n = 44) was analyzed. Kappa agreement of single biomarkers and Aβ1-42/Aβ1-40 was evaluated in an independent group of mild cognitive impairment (MCI) and dementia patients (n = 68). Next, established cutoffs were applied to a large real-world cohort of MCI subjects with follow-up data available (n = 647)., Results: Cutoff values of Aβ1-42 and t-Tau were higher for CLEIA than for ELISA and similar for p181Tau. Spearman coefficients ranged between 0.81 for Aβ1-40 and 0.96 for p181TAU. Passing-Bablok analysis showed a systematic and proportional difference for all biomarkers but only systematic for Aβ1-40. Bland-Altman analysis showed an average difference between methods in favor of CLEIA. Kappa agreement for single biomarkers was good but lower for the Aβ1-42/Aβ1-40 ratio. Using the calculated cutoffs, we were able to stratify MCI subjects into four AT(N) categories. Kaplan-Meier analyses of AT(N) categories demonstrated gradual and differential dementia conversion rates ( p = 9.815 -27 ). Multivariate Cox proportional hazard models corroborated these findings, demonstrating that the proposed AT(N) classifier has prognostic value. AT(N) categories are only modestly influenced by other known factors associated with disease progression., Conclusions: We established CLEIA and ELISA internal cutoffs to discriminate AD patients from amyloid-negative SCD individuals. The results obtained by both methods are not interchangeable but show good agreement. CLEIA is a good and faster alternative to manual ELISA for providing AT(N) classification of our patients. AT(N) categories have an impact on disease progression. AT(N) classifiers increase the certainty of the MCI prognosis, which can be instrumental in managing real-world MCI subjects.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., (© 2022. The Author(s).)

Background: FACEmemory® is the first computerized, self-administered verbal episodic memory test with voice recognition. It can be conducted under minimal supervision and contains an automatic scoring system to avoid administrator errors. Moreover, it is suitable for discriminating between cognitively healthy and amnestic mild cognitive impairment (MCI) individuals, and it is associated with Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers. This study aimed to determine whether FACEmemory scoring is related to performance on classical memory tests and to AD biomarkers of brain magnetic resonance imaging (MRI) and CSF in patients with early-onset MCI (EOMCI)., Methods: Ninety-four patients with EOMCI from the BIOFACE study completed FACEmemory, classical memory tests (the Spanish version of the Word Free and Cued Selective Reminding Test -FCSRT-, the Word List from the Wechsler Memory Scale, third edition, and the Spanish version of the Rey-Osterrieth Complex Figure Test), and a brain MRI. Eighty-two individuals also underwent a lumbar puncture., Results: FACEmemory scoring was moderately correlated with FCSRT scoring. With regard to neuroimaging MRI results, worse execution on FACEmemory was associated with lower cortical volume in the right prefrontal and inferior parietal areas, along with the left temporal and associative occipital areas. Moreover, the total FACEmemory score correlated with CSF AD biomarkers (Aβ1-42/Aβ1-40 ratio, p181-tau, and Aβ1-42/p181-tau ratio). When performance on FACEmemory was compared among the ATN classification groups, significant differences between the AD group and normal and SNAP groups were found., Conclusions: FACEmemory is a promising tool for detecting memory deficits sensitive to early-onset AD, but it also allows the detection of memory-impaired cases due to other etiologies. Our findings suggest that FACEmemory scoring can detect the AD endophenotype and that it is also associated with AD-related changes in MRI and CSF in patients with EOMCI. The computerized FACEmemory tool might be an opportunity to facilitate early detection of MCI in younger people than 65, who have a growing interest in new technologies., (© 2022. The Author(s).)

Introduction: Mild cognitive impairment is often associated with affective and other neuropsychiatric symptoms (NPS). This co-occurrence might have a relevant impact on disease progression, from MCI to dementia. Objective: The aim of this study was to explore the trajectories of cognitive decline in an MCI sample from a memory clinic, taking into consideration a perspective of isolated cognitive functions and based on NPS clusters, accounting for the different comorbid symptoms collected at their baseline visit. Methods: A total of 2,137 MCI patients were monitored over a 2.4-year period. Four clusters of NPS (i.e., Irritability, Apathy, Anxiety/Depression and Asymptomatic) were used to run linear mixed models to explore the interaction of cluster with time on cognitive trajectories using a comprehensive neuropsychological battery (NBACE) administered at baseline and at the three subsequent follow-ups. Results: A significant interaction between cluster and time in cognitive decline was found when verbal learning and cued-recall were explored ( p = 0.002 for both memory functions). For verbal learning, the Irritability cluster had the largest effect size (0.69), whereas the Asymptomatic cluster showed the smallest effect size (0.22). For cued-recall, the Irritability cluster had the largest effect size among groups (0.64), and Anxiety/Depression had the smallest effect size (0.21). Conclusions: In MCI patients, the Irritability and Apathy NPS clusters shared similar patterns of worsening in memory functioning, which could point to these NPS as risk factors of a faster cognitive decline, acting as early prognostic markers and helping in the diagnostic process., 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 © 2021 Roberto, Portella, Marquié, Alegret, Hernández, Mauleón, Rosende-Roca, Abdelnour, Esteban de Antonio, Tartari, Vargas, López-Cuevas, Bojaryn, Espinosa, Ortega, Pérez-Cordón, Sanabria, Orellana, de Rojas, Moreno-Grau, Montrreal, Alarcón-Martín, Ruíz, Tárraga, Boada and Valero.)

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region ( LZTFL1, SLC6A20 ) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.

Background: More than 40 pathogenic heterozygous PRNP mutations causing inherited prion diseases have been identified to date. Recessive inherited prion disease has not been described to date., Methods: We describe the clinical and neuropathological data of inherited early-onset prion disease caused by the rare PRNP homozygous mutation R136S. In vitro PrP Sc propagation studies were performed using recombinant-adapted protein misfolding cyclic amplification technique. Brain material from two R136S homozygous patients was intracranially inoculated in TgMet129 and TgVal129 transgenic mice to assess the transmissibility of this rare inherited form of prion disease., Results: The index case presented symptoms of early-onset dementia beginning at the age of 49 and died at the age of 53. Neuropathological evaluation of the proband revealed abundant multicentric PrP plaques and Western blotting revealed a ~ 8 kDa protease-resistant, unglycosylated PrP Sc fragment, consistent with a Gerstmann-Sträussler-Scheinker phenotype. Her youngest sibling suffered from progressive cognitive decline, motor impairment, and myoclonus with onset in her late 30s and died at the age of 48. Genetic analysis revealed the presence of the R136S mutation in homozygosis in the two affected subjects linked to homozygous methionine at codon 129. One sibling carrying the heterozygous R136S mutation, linked to homozygous methionine at codon 129, is still asymptomatic at the age of 74. The inoculation of human brain homogenates from our index case and an independent case from a Portuguese family with the same mutation in transgenic mice expressing human PrP and in vitro propagation of PrP Sc studies failed to show disease transmissibility., Conclusion: In conclusion, biallelic R136S substitution is a rare variant that produces inherited early-onset human prion disease with a Gerstmann-Sträussler-Scheinker neuropathological and molecular signature. Even if the R136S variant is predicted to be "probably damaging", heterozygous carriers are protected, at least from an early onset providing evidence for a potentially recessive pattern of inheritance in human prion diseases., (© 2021. The Author(s).)

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.

Aims: To conduct a systematic review compiling an update on the pathophysiology of burning mouth syndrome (BMS) by reviewing the theories and studies published in the last 5 years that consider BMS a neuropathic disease., Methods: A literature review was carried out in April 2020 on the PubMed database by using the following MeSH terms: "(burning mouth OR burning mouth syndrome OR burning mouth pain OR sore mouth OR burning tongue OR oral neuropathic pain OR glossodynia OR stomatopyrosis) AND (etiopathogenesis OR etiopathological factors OR etiology).", Results: The research carried out according to the methodology found 19 case-control studies (1 of which was in vivo) and 1 RCT. Of the 19 included studies, 8 showed an evidence score of 2-; 8 showed 2+; another 2 showed 2++; and 1 showed 1+. Quality studies on this topic are insufficient and heterogenous., Conclusion: In the pathogenesis of BMS, both peripheral and central neuropathies appear to play a pivotal role. Nevertheless, the balance between them varies from case to case and tends to overlap. BMS does not seem to be a result of direct damage to the somatosensory nervous system, but a dysfunction in it and in the brain network.

By the middle of 2021, we are still immersed in the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The concurrence of this new pandemic in regions where human immunodeficiency virus (HIV) and tuberculosis (TB) infections possess the same epidemiological consideration, has arisen concerns about the prognosis, clinical management, symptomatology, and treatment of patients with triple infection. At the same time, healthcare services previously devoted to diagnosis and treatment of TB and HIV are being jeopardized by the urgent need of resources and attention for COVID-19 patients. The aim of this review was to collect any article considering the three conditions (HIV, TB, and SARS-CoV-2), included in PubMed/Medline and published in the English language since the beginning of the COVID-19 pandemic. We focused on detailed descriptions of the unusual cases describing the three co-infections. Eighty-four out of 184 publications retrieved met our inclusion criteria, but only three of them reported cases (five in total) with the three concomitant infections. The clinical evolution, management, and therapy of all of them were not different from mild/severe cases with exclusive COVID-19; the outcome was not worse either, with recovery for the five patients. Cases of patients with COVID-19 besides HIV and TB infections are scarce in literature, but studies deliberately embracing the triple infection as a priori inclusion criterion should be carried out in order to provide a complete understanding of joint influence.

Background: Alzheimer disease (AD) is a progressive neurodegenerative disorder affecting the elderly with a prevalence of 7.1% in women and 3.3% in men. Sex-related patterns have been reported in prognosis, biomarker status, and risk factors. Despite this, the interaction of sex has received limited attention, with AD trials persistently recruiting lower numbers of women than the population distribution and a lack of information on the sex-disaggregated effects of anti-dementia therapies. This is the first study aiming to identify the role of sex in the selection for screening in AD clinical trials., Methods: This cross-sectional study provides a comprehensive analysis of screening eligibility according to a set of pre-selection criteria currently applied at Fundació ACE memory clinic for a more efficient trial screening process. A cohort of 6667 women and 2926 men diagnosed with AD dementia (55%) or mild cognitive impairment (45%) was analyzed. We also assessed the frequencies of men and women effectively screened for trial enrolment over a period of 10 years. Additionally, data from AddNeuroMed study was used to explore trends in eligibility based on the education criteria., Results: Women showed a significantly lower chance of being eligible for screening than men (OR = 1.26; p < 0.01). This imbalance was confirmed by a lower frequency of women screened for enrolment compared to the study population (63.0% vs. 69.5%). Education was revealed as the key criterion contributing to this unbalance, with men showing over twice the chance of being screened compared with women (OR = 2.25, p < 0.01). Education-based differences were greater in earlier born patients, but the gap narrowed and achieved balance with increasing year of birth. This observation was replicated using data from other European populations included in AddNeuroMed study. Comorbidity was the most limiting criterion with sex differences in frequencies and significant discrimination against the selection of men (OR = 0.86, p < 0.01)., Conclusions: The large number of low-educated elderly women with AD demands for a sex-focused approach in clinical research. New assessment tools insensitive to education level should be developed to enable a proportional representation of women. Although this gender education gap is mostly inexistent in developed countries, economic or cultural factors may lead to different scenarios in other regions. Overlooking the impact of sex may lead to a handicap in AD research with a direct adverse impact on women's health.

Neuropsychiatric symptoms (NPS) have been recently addressed as risk factors of conversion to Alzheimer's disease (AD) and other dementia types in patients diagnosed with Mild Cognitive Impairment (MCI). Our aim was to determine profiles based on the prominent NPS in MCI patients and to explore the predictive value of these profiles on conversion to specific types of dementia. A total of 2137 MCI patients monitored in a memory clinic were included in the study. Four NPS profiles emerged (classes), which were defined by preeminent symptoms: Irritability, Apathy, Anxiety/Depression and Asymptomatic. Irritability and Apathy were predictors of conversion to dementia (HR = 1.43 and 1.56, respectively). Anxiety/depression class showed no risk effect of conversion when compared to Asymptomatic class. Irritability class appeared as the most discriminant neuropsychiatric condition to identify non-AD converters (i.e., frontotemporal dementia, vascular dementia, Parkinson's disease and dementia with Lewy Bodies). The findings revealed that consistent subgroups of MCI patients could be identified among comorbid basal NPS. The preeminent NPS showed to behave differentially on conversion to dementia, beyond AD. Therefore, NPS should be used as early diagnosis facilitators, and should also guide clinicians to detect patients with different illness trajectories in the progression of MCI.

Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [β AVROH (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10 -5 ; β FROH (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10 -16 ). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10 -4 ), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.

Introduction : There is a paucity of information on cancer among Indigenous populations in Latin America. Methods : Guided by tenets of community engaged research and syndemic theory, we conducted eight focus groups ( n  = 59) with Kichwa men and women in the province of Imbabura, Ecuador. Data were analyzed using applied thematic analysis techniques. Results : Cancer emerged as an important health problem and was reported as a growing concern. Kichwa participants in this study attributed the rise in cancer to (1) exposure to chemicals and pesticides, (2) urbanization and development, and (3) the rise of innutritious, westernized diets. Conclusion : Our findings suggest that the Kichwa are attuned to the global phenomena in which traditional diet has been replaced by western, processed foods and fast food, which result in higher levels of chronic diseases such as cancer. More research is needed to understand the cancer burden among Indigenous peoples in Latin America.

Background: Over the last decade, teleneuropsychology has increased substantially. There is a need for valid neuropsychological batteries to be administered home-to-home. Since 2006, the neuropsychological battery of Fundació ACE (NBACE) has been administered face-to-face in our clinical settings. Recently, we adapted the NBACE for teleneuropsychology use to be administered home-to-home (NBACEtn)., Objective: The aims of the present study are: 1) to determine the home-to-home NBACE equivalence compared to its original face-to-face version; and 2) to examine home-to-home NBACE discriminant capacity by differentiating among cognitively healthy, mild cognitive impairment, or mild dementia subjects and comparing it with the face-to-face version., Methods: Data from 338 individuals assessed home-to-home (NBACEtn) were contrasted with 7,990 participants assessed with its face-to-face version (NBACE). Exploratory and confirmatory factorial structure, and invariance analysis of the two versions of the battery were performed., Results: Exploratory and confirmatory factor analysis supported the four-factor model (attention, memory, executive, and visuospatial/constructional functions). Configural, metric, and scalar measurement invariance was found between home-to-home and face-to-face NBACE versions. Significant differences in most of the neuropsychological variables assessed were observed between the three clinical groups in both versions of administration. No differences were found between the technological devices used by participants (computer or tablet and mobile devices)., Conclusion: For the first time, invariance analysis findings were addressed by determining a teleneuropsychological battery's equivalence in comparison with its face-to-face version. This study amplifies the neuropsychological assessment's applicability using a home-to-home format, maintaining the original measure's structure, interpretability, and discriminant capacity.

Objective: To attain a synthesis of the evidence on the effectiveness of invasive techniques in patients with fibromyalgia, through systematic review and meta-analysis and by assessing the methodological quality of the studies considered., Methods: A systematic review and meta-analysis were carried out as defined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The bibliographic research was carried out in the PEDro, Cochrane, PubMed, Science Direct, Web of Science, Google Academics, Dialnet, and Scielo databases from September through December of 2018., Results: Results show that invasive techniques produce a significant decrease in the pain, the impact of fibromyalgia and in the pain pressure threshold (standardized mean difference [95% confidence interval]: -0.94 [-1.44, -0.44], P of global effect= 0.0002; -0.99 [-1.69, -0.29], P of global effect= 0.006; and 0.31 [0.02, 0.61], P of global effect = 0.04, respectively). Lastly, a significant increase was observed in the quality-of-life variable after intervention (0.84 [0.30, 1.38], P of global effect = 0.002)., Conclusions: Invasive techniques are considered effective for pain relief, as well as for producing a short-term increase in the pain pressure threshold, an improvement in quality of life, and a decrease in the impact of fibromyalgia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases., Methods: We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions., Results: We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [ p = 2.17 × 10 -5 ; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [ p = 1.1 × 10 -2 ; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy., Conclusions: Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Methicillin-resistant Staphylococcus aureus (MRSA) is considered an opportunistic pathogen in humans and is mainly associated with healthcare-associated infections (HCAIs). This bacterium colonizes the skin and mucous membranes of healthy people and causes frequent hospital outbreaks. The aim of this study was to perform molecular typing of the staphylococcal cassette chromosome mec (SCC mec ) and agr loci as wells as to establish the pulsotypes and clonal complexes (CCs) for MRSA and methicillin-sensitive S . aureus (MSSA) outbreaks associated with the operating room (OR) at a pediatric hospital. Twenty-five clinical strains of S. aureus (19 MRSA and 6 MSSA strains) were recovered from the outbreak (patients, anesthesia equipment, and nasopharyngeal exudates from external service anesthesia technicians). These clinical S . aureus strains were mainly resistant to benzylpenicillin (100%) and erythromycin (84%) and were susceptible to vancomycin and nitrofurantoin. The SCC mec type II was amplified in 84% of the S . aureus strains, and the most frequent type of the agr locus was agrII , which was amplified in 72% of the strains; however, the agrI and agrIII genes were mainly detected in MSSA strains. A pulsed-field gel electrophoresis (PFGE) analysis grouped the 25 strains into 16 pulsotypes (P), the most frequent of which was P1, including 10 MRSA strains related to the anesthesia equipment, external service anesthesia technicians, and hospitalized patients. Multilocus sequence typing (MLST) identified 15 sequence types (STs) distributed in nine CCs. The most prevalent ST was ST1011, belonging to CC5, which was associated with the SCC mec type II and agrII type. We postulate that the external service anesthesia technicians were MRSA carriers and that these strains were indirectly transmitted from the contaminated anesthesia equipment that was inappropriately disinfected. Finally, the MRSA outbreak was controlled when the anesthesia equipment disinfection was improved and hand hygiene was reinforced., 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 © 2020 Ochoa, Cruz-Córdova, Mancilla-Rojano, Escalona-Venegas, Esteban-Kenel, Franco-Hernández, Parra-Ortega, Arellano-Galindo, Hernández-Castro, Perez-López, De la Rosa-Zamboni and Xicohtencatl-Cortes.)

To date, very few studies have been focused on the impact of the convergence of neuropsychiatric symptoms (NPS) and APOE ε4 on the conversion to dementia in patients with Mild Cognitive Impairment patients (MCI), and none has been based in a clinical setting. The objective of the study is to determine the predictive value of additive and multiplicative interactions of NPS and APOE ε4 status on the prediction of incident dementia among MCI patients monitored in a Memory Clinic. 1512 patients (aged 60 and older) with prevalent MCI were followed for a mean of 2 years. Neuropsychiatric symptoms were assessed at baseline using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models were calculated. Additive interactions for depression, apathy, anxiety, agitation, appetite, or irritability and a positive ε4 carrier status were obtained, significantly increasing the hazard ratios of incident dementia (HR range 1.3-2.03). Synergistic interactions between NPS and APOE ε4 are identified among MCI patients when predicting incident dementia. The combination of the behavioral status and the genetic trait could be considered a useful strategy to identify the most vulnerable MCI patients to dementia conversion in a Memory Clinic.

Background: Lysophosphatidic acids (LPAs) are bioactive signaling phospholipids that have been implicated in Alzheimer's disease (AD). It is largely unknown whether LPAs are associated with AD pathology and progression from mild cognitive impairment (MCI) to AD., Methods: The current study was performed on cerebrospinal fluid (CSF) and plasma samples of 182 MCI patients from two independent cohorts. We profiled LPA-derived metabolites using liquid chromatography-mass spectrometry. We evaluated the association of LPAs with CSF biomarkers of AD, Aβ-42, p-tau, and total tau levels overall and stratified by APOE genotype and with MCI to AD progression., Results: Five LPAs (C16:0, C16:1, C22:4, C22:6, and isomer-LPA C22:5) showed significant positive association with CSF biomarkers of AD, Aβ-42, p-tau, and total tau, while LPA C14:0 and C20:1 associated only with Aβ-42 and alkyl-LPA C18:1, and LPA C20:1 associated with tau pathology biomarkers. Association of cyclic-LPA C16:0 and two LPAs (C20:4, C22:4) with Aβ-42 levels was found only in APOE ε4 carriers. Furthermore, LPA C16:0 and C16:1 also showed association with MCI to AD dementia progression, but results did not replicate in an independent cohort., Conclusions: Our findings provide evidence that LPAs may contribute to early AD pathogenesis. Future studies are needed to determine whether LPAs play a role in upstream of AD pathology or are downstream markers of neurodegeneration.

Dirofilariasis is a vector-borne zoonotic disease caused mainly by Dirofilaria immitis and Dirofilaria repens that affect dogs and humans all over the world. Serbia is considered an endemic country to both forms of dirofilariasis, although most of the population is concentrated in the north of the country. The aims of this study were to show the prevalence of D. immitis and D. repens in dogs and the seroprevalence in humans compared to previous studies in Northern Serbia. In total, 346 dog sera samples and 265 human samples were analyzed. Dog blood samples were analyzed using the modified Knott's method to check whether there were Dirofilaria spp. microfilariae and serum samples were checked by a commercial D. immitis antigen test. Human serum samples were analyzed with a non-commercial ELISA for detection of specific anti- D. immitis , anti- D. repens , and anti- Wolbachia IgG antibodies, and confirmed by western blotting. The overall prevalence for Dirofilaria spp. in dogs was 29.19%. The overall prevalence for D. immitis was 26.30%. The percentages of D. immitis and D. repens microfilaremia in dogs were 25.72 and 1.45%, respectively, while D. immitis ./ D. repens microfilaremia co-infections were also 1.45%. The overall seroprevalence for Dirofilaria spp. in humans was 3.77%. The overall seroprevalence for D. immitis was 1.51, 1.13% for D. repens , and for D. immitis / D. repens co-infections was 1.13%. The results indicate that D. immitis and D. repens are present in dogs and humans in the province of Vojvodina, in the northern part of Serbia. It is most likely associated with the presence of many rivers, the climate, and presence of mosquitoes in the area, so there could be a real public health risk., (Copyright © 2020 Savić, Stosic, Marcic, Hernández, Potkonjak, Otasevic, Ruzic and Morchón.)

The cardiopulmonary dirofilariosis caused by Dirofilaria immitis , is a vector-borne infection, which can be transmitted to humans. The main hosts are both domestic and wild canids. This species mainly occurs in tropical and subtropical climates, and temperature and humidity are the main factors that favor the presence and proliferation of culicid mosquitoes as vectors of the disease. There are few reports of cardiopulmonary dirofilariosis in dogs and humans in Colombia, a region with favorable climatic conditions which favors the presence of mosquitoes that act as vectors of the disease. Therefore, this study aimed to examine its current prevalence in dogs and the risk of human exposure to the disease in Bucaramanga, one of the most populated areas in Colombia located at the center of the country. Furthermore, its demographic and environmental characteristics could be useful as a study model for other similar locations and neighboring countries. Serum samples from 351 dogs and 506 humans from the Bucaramanga Metropolitan area were analyzed. All dog samples were analyzed by Knott's technique and tested with a commercial immunochromatographic to detect the presence of circulating antigens of D. immitis . Human samples were analyzed using a non-commercial ELISA test kit to detect IgG against the somatic antigens of adult D. immitis and Wolbachia . Positive results were further confirmed using western blot analysis. Thirty-eight dogs tested positive with a overall prevalence of 10.82%. Of these dogs, 18 showed D. immitis microfilariae, being 5.12% of the total population. The overall seroprevalence in humans was 6.71%; seroprevalence was significantly higher in individuals aged 16-34 years-old and in women than in men. To our knowledge, this study describes seropositivity to D. immitis for the first time in a Colombian human population located in the same area as that of dogs infected with D. immitis , which represents a potential threat to public health. In humans, age and gender can be considered risk factors for exposure to D. immitis ., (Copyright © 2020 Esteban-Mendoza, Arcila-Quiceno, Albarracín-Navas, Hernández, Flechas-Alarcón and Morchón.)

Introduction: Despite the use of the new generation P2Y12 inhibitors (Ticagrelor and Prasugrel) with aspirin is the recommended therapy in acute NSTE-ACS patients, their current use in clinical practice remains quite low and might be related, among several variables, with increased comorbidity burden. We aimed to assess the prevalence of these treatments and whether their use could be associated with comorbidity., Method: A multicentric prospective registry was conducted at 8 Cardiac Intensive Care Units (October 2017-April 2018) in patients admitted with non ST elevation myocardial infarction. Antithrombotic treatment was recorded and the comorbidity risk was assessed using the Charlson Comorbidity Index. We created a multivariate model to identify the independent predictors of the use of new inhibitors of P2Y12., Results: A total of 629 patients were included, median age 67 years, 23.2% women, 359 patients (57.1%) treated with clopidogrel and 40.6% with new P2Y12 inhibitors: ticagrelor (228 patients, 36.2%) and prasugrel (30 patients, 4.8%). Among the patients with very high comorbidity (Charlson Score > 6) clopidogrel was the drug of choice (82.6%), meanwhile in patients with low comorbility (Charlson Score 0-1) was the ticagrelor or prasugrel (63.6%). Independent predictors of the use of ticagrelor or prasugrel were a low Charlson Comorbidity Index, a low CRUSADE score and the absence of prior bleeding., Conclusion: Antiplatelet treatment with Ticagrelor or Pasugrel was low in patients admitted with NSTE-ACS. Comorbidity calculated with Charlson Comorbidity Index was a powerful predictor of the use of new generation P2Y12 inhibitors in this population.

The objective of this work was to determine the risk of exposure to Dirofilaria immitis in the stray dog population and people living in the metropolitan area of Puebla City, Mexico, using serologic methods. A total of 283 blood salmples were collected from dogs and 254 salmples from people. The canine samples were analyzed using a commercial kit to detect D. immitis antigens and the Knott test to detect microfilariae. Human samples were analyzed by ELISAs to detect antibodies against D. immitis and Wolbachia anti-WSP, as well as Western blot to identify specific bands of the parasite in the adult antigenic extract of D. immitis. Positive results were represented on a GIS map that included layers with geoenvironmental information relevant to parasite transmission in the study area. The prevalence of D. immitis in the canine stray population was 2.12 %, with positive cases found in individuals aged 1-10 years. Human seroprevalence was established at 5.11 %, with women and men similarly affected. By age, a significantly higher seroprevalence was observed in younger individuals (<18 years) than in the rest of the population. The geolocation of the results showed that positive cases were found in the environment (within 2 km) of potentially favorable areas for mosquito breeding. The importance of human influence in the creation and maintenance of favorable conditions for the transmission of canine and human dirofilariosis within an urban area is highlighted, both by the lack of environmental sanitation and by the absence of measures to limit or eliminate the canine reservoir population., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau 181 , total tau, and Aβ 1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau 181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau 181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ 1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

The role of the WDFY1 protein has been studied as a TLR3/4 scaffold/recruiting protein in the immune system and in different oncogenic conditions. However, its function in brain remains poorly understood. We have found that in mice devoid of Helios (He -/- mice), a transcription factor specifically expressed during the development of the immune cells and the central nervous system, there is a permanent and sustained increase of Wdfy1 gene expression in the striatum and hippocampus. Interestingly, we observed that WDFY1 protein levels were also increased in the hippocampus and dorsolateral prefrontal cortex of schizophrenic patients, but not in the hippocampus of Alzheimer's disease patients with an associated psychotic disorder. Accordingly, young He -/- mice displayed several schizophrenic-like behaviors related to dysfunctions in the striatum and hippocampus. These changes were associated with an increase in spine density in medium spiny neurons (MSNs) and with a decrease in the number and size of PSD-95-positive clusters in the stratum radiatum of the CA1. Moreover, these alterations in structural synaptic plasticity were associated with a strong reduction of neuronal NF-κB in the pyramidal layer of the CA1 in He -/- mice. Altogether, our data indicate that alterations involving the molecular axis Helios-WDFY1 in neurons during the development of core brain regions could be relevant for the pathophysiology of neuropsychiatric disorders such as schizophrenia., (Copyright © 2020 Sancho-Balsells, Brito, Fernández, Pardo, Straccia, Ginés, Alberch, Hernández, Arranz, Canals and Giralt.)

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

Background: Optical coherence tomography (OCT) of the retina is a fast and easily accessible tool for the quantification of retinal structural measurements. Multiple studies show that patients with Alzheimer's disease (AD) exhibit thinning in several retinal layers compared to age-matched controls. Subjective cognitive decline (SCD) has been proposed as a risk factor for progression to AD. There is little data about retinal changes in preclinical AD and their correlation with amyloid-β (Aβ) uptake., Aims: We investigated the association of retinal thickness quantified by OCT with Aβ accumulation and conversion to mild cognitive impairment (MCI) over 24 months in individuals with SCD., Methods: One hundred twenty-nine individuals with SCD enrolled in Fundació ACE Healthy Brain Initiative underwent comprehensive neuropsychological testing, OCT scan of the retina and florbetaben (FBB) positron emission tomography (PET) at baseline (v0) and after 24 months (v2). We assessed the association of sixteen retinal thickness measurements at baseline with FBB-PET status (+/-) and global standardize uptake value ratio (SUVR) as a continuous measure at v0 and v2 and their predictive value on clinical status change (conversion to mild cognitive impairment (MCI)) at v2., Results: Mean age of the sample was 64.72 ± 7.27 years; 62.8% were females. Fifteen participants were classified as FBB-PET+ at baseline and 22 at v2. Every 1 μm of increased thickness in the inner nasal macular region conferred 8% and 6% higher probability of presenting a FBB-PET+ status at v0 (OR = 1.08, 95% CI = 1.02-1.14, p = 0.007) and v2 (OR = 1.06, 95% CI = 1.02-1.11, p = 0.004), respectively. Inner nasal macular thickness also positively correlated with global SUVR (at v0: β = 0.23, p = 0.004; at v2: β = 0.26, p = 0.001). No retinal measurements were associated to conversion to MCI over 24 months., Conclusions: Subtle retinal thickness changes in the macular region are already present in SCD and correlate with Aβ uptake.

Background: Computerized neuropsychological tests for early detection of Alzheimer's disease (AD) have attracted increasing interest. Memory for faces and proper names is a complex task because its association is arbitrary. It implicates associative occipito-temporal cerebral regions, which are disrupted in AD. The short form of the Face-Name Associative Memory Exam (FNAME-12), developed to detect preclinical and prodromal AD, asks individuals to learn the names and occupations associated with 12 faces. The current work advances this field by using voice recognition and touchscreen response format. The purpose of this study is to create the first self-administered episodic memory test, FACEmemory®, by adapting the FNAME-12 for tablet use with voice recognition, touchscreen answers, and automatic scoring. The test was minimally supervised by a psychologist to avoid technological problems during execution and scored manually to assess the reliability of the automatic scoring. The aims of the present study were (1) to determine whether FACEmemory® is a sensitive tool for the detection of cognitive impairment, (2) to examine whether performances on FACEmemory® are correlated with those on the S-FNAME (paper-and-pencil version with 16 images), and (3) to determine whether performances on FACEmemory® are related to AD biomarkers in the cerebrospinal fluid (CSF) (Aβ42, p-tau, and Aβ42/p-tau ratio)., Methods: FACEmemory® was completed by 154 cognitively healthy (CH) individuals and 122 subjects with mild cognitive impairment, of whom 61 were non-amnestic (naMCI) and 61 amnestic (aMCI). A subsample of 65 individuals completed the S-FNAME, and 65 subjects received lumbar punctures., Results: Performance on FACEmemory® was progressively worse from CH to the naMCI and aMCI groups. A cutoff of 31.5 in total FACEmemory® obtained 80.5% and 80.3% sensitivity and specificity values, respectively, for discriminating between CH and aMCI. Automatically corrected FACEmemory® scores were highly correlated with the manually corrected ones. FACEmemory® scores and AD CSF biomarker levels were significantly correlated as well, mainly in the aMCI group., Conclusions: FACEmemory® may be a promising memory prescreening tool for detecting subtle memory deficits related to AD. Our findings suggest FACEmemory® performance provides a useful gradation of impairment from normal aging to aMCI, and it is related to CSF AD biomarkers.

Individuals with subjective cognitive decline (SCD) have the perception of memory problems without showing impairment on standardized cognitive tests. SCD has been associated with an increased risk of developing Alzheimer's disease (AD). Neuroticism and openness personality dimensions have also been associated with SCD and AD. From the aforementioned, we aimed to ascertain whether the dimensions and traits defined by the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ) differentiate between individuals with SCD and the general population (GP). A total of 187 participants with SCD and mild affective symptomatology recruited from the Fundació ACE Health Brain Initiative (FACEHBI) project completed the ZKPQ. Each SCD participant was matched by sex and age to an individual from the GP. Both samples included 71 men and 116 women with a mean age of 65.9 years. Results indicated that the SCD group scored significantly lower in Neuroticism-Anxiety and Activity than the GP group. Only Activity remained statistically significant in a multivariate analysis. These findings suggest that individuals with SCD have a low energy level and a dislike for an active and busy life. From the obtained results and knowing additional physical activities may delay the conversion from normal aging to cognitive impairment, we encourage promoting this lifestyle in daily routine. The assessment of personality may result in an SCD plus feature, which may serve as an upgrading strategy for future research., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Nathalia Muñoz et al.)

Stenotrophomonas maltophilia , an emerging opportunistic pathogen, is widely distributed in the environment the resistance mechanisms, and virulence factors of this bacterium facilitate its dissemination in hospitals. This study aimed to characterize the molecular epidemiology of S. maltophilia strains associated with an outbreak in the Children's Hospital of México Federico Gómez (HIMFG). Twenty-one clinical S. maltophilia strains were recovered from cultures of blood and urine samples from 10 pediatric patients at the emergency department, and nine environmental S. maltophilia strains recovered from faucets in the same area were also included. Two of the 10 patients were related with health care-associated infections (HCAIs), and the other eight patients (8/10) were infected with environmental S. maltophilia strains. The outbreak was controlled by monthly disinfection of the faucets in the emergency department. Typing using pulsed-field gel electrophoresis (PFGE) showed a 52% genetic diversity with seven pulsotypes denoted P1-P7 among all S. maltophilia strains. Three pulsotypes (P2, P3, and P7) were identified among both the clinical and environmental S. maltophilia strains and associated with two type sequences (STs), namely, ST304 and ST24. Moreover, 80% (24/30) of the strains exhibited resistance mainly to tetracycline, 76.66% (23/30) to trimethoprim-sulfamethoxazole, and 23.33% (7/30) to the extended-spectrum β-lactamase (ESBL) phenotype. The main resistance genes identified by multiplex PCR were sul1 in 100% (30/30), qnr in 86.66% (26/30), and intl1 in 80% (24/30) of the samples, respectively. Furthermore, the pilU, hlylII , and rmlA genes were identified in 96.6% (29/30), 90% (27/30), and 83.33% (25/30) of the samples, respectively. Additionally, 76.66% (23/30) of the S. maltophilia strains exhibited high swimming motility, 46.66% (14/30) showed moderate biofilm formation capacity, 43.33% (13/30) displayed moderate twitching motility, and 20% (6/30) exhibited high adherence. The clinical S. maltophilia strains isolated from blood most strongly adhered to HTB-9 cells. In conclusion, the molecular epidemiology and some of the features such as resistance, and virulence genes associated with colonization patterns are pathogenic attributes that can promote S. maltophilia dissemination, persistence, and facilitate the outbreak that occurred in the HIMFG. This study supports the need for faucet disinfection as a control strategy for clinical outbreaks., (Copyright © 2020 Cruz-Córdova, Mancilla-Rojano, Luna-Pineda, Escalona-Venegas, Cázares-Domínguez, Ormsby, Franco-Hernández, Zavala-Vega, Hernández, Medina-Pelcastre, Parra-Ortega, Rosa-Zamboni, Ochoa and Xicohtencatl-Cortes.)