The glutamatergic system in Alzheimer's disease: a systematic review with meta-analysis.

Glutamatergic neurotransmission system dysregulation may play an important role in the pathophysiology of Alzheimer's disease (AD). However, reported results on glutamatergic components across brain regions are contradictory. Here, we conducted a systematic review with meta-analysis to examine whether there are consistent glutamatergic abnormalities in the human AD brain. We searched PubMed and Web of Science (database origin-October 2023) reports evaluating glutamate, glutamine, glutaminase, glutamine synthetase, glutamate reuptake, aspartate, excitatory amino acid transporters, vesicular glutamate transporters, glycine, D-serine, metabotropic and ionotropic glutamate receptors in the AD human brain (PROSPERO #CDRD42022299518). The studies were synthesized by outcome and brain region. We included cortical regions, the whole brain (cortical and subcortical regions combined), the entorhinal cortex and the hippocampus. Pooled effect sizes were determined with standardized mean differences (SMD), random effects adjusted by false discovery rate, and heterogeneity was examined by I2 statistics. The search retrieved 6 936 articles, 63 meeting the inclusion criteria (N = 709CN/786AD; mean age 75/79). We showed that the brain of AD individuals presents decreased glutamate (SMD = -0.82; I2 = 74.54%; P < 0.001) and aspartate levels (SMD = -0.64; I2 = 89.71%; P = 0.006), and reuptake (SMD = -0.75; I2 = 83.04%; P < 0.001. We also found reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)-GluA2/3 levels (SMD = -0.63; I2 = 95.55%; P = 0.046), hypofunctional N-methyl-D-aspartate receptor (NMDAR) (SMD = -0.60; I2 = 91.47%; P < 0.001) and selective reduction of NMDAR-GluN2B subunit levels (SMD = -1.07; I2 = 41.81%; P < 0.001). Regional differences include lower glutamate levels in cortical areas and aspartate levels in cortical areas and in the hippocampus, reduced glutamate reuptake, reduced AMPAR-GluA2/3 in the entorhinal cortex, hypofunction of NMDAR in cortical areas, and a decrease in NMDAR-GluN2B subunit levels in the entorhinal cortex and hippocampus. Other parameters studied were not altered. Our findings show depletion of the glutamatergic system and emphasize the importance of understanding glutamate-mediated neurotoxicity in AD. This study has implications for the development of therapies and biomarkers in AD.

The GABAergic system in Alzheimer's disease: a systematic review with meta-analysis.

The γ-aminobutyric acid (GABA)ergic system is the primary inhibitory neurotransmission system in the mammalian brain. Its dysregulation has been shown in multiple brain conditions, but in Alzheimer's disease (AD) studies have provided contradictory results. Here, we conducted a systematic review with meta-analysis to investigate whether the GABAergic system is altered in AD patients compared to healthy controls (HC), following the PRISMA 2020 Statement. We searched PubMed and Web of Science from database inception to March 18th, 2023 for studies reporting GABA, glutamate decarboxylase (GAD) 65/67, GABAA, GABAB, and GABAC receptors, GABA transporters (GAT) 1-3 and vesicular GAT in the brain, and GABA levels in the cerebrospinal fluid (CSF) and blood. Heterogeneity was estimated using the I2 index, and the risk of bias was assessed with an adapted questionnaire from the Joanna Briggs Institute Critical Appraisal Tools. The search identified 3631 articles, and 48 met the final inclusion criteria (518 HC, mean age 72.2, and 603 AD patients, mean age 75.6). Random-effects meta-analysis [standardized mean difference (SMD)] revealed that AD patients presented lower GABA levels in the brain (SMD = -0.48 [95% CI = -0.7, -0.27], adjusted p value (adj. p) < 0.001) and in the CSF (-0.41 [-0.72, -0.09], adj. p = 0.042), but not in the blood (-0.63 [-1.35, 0.1], adj. p = 0.176). In addition, GAD65/67 (-0.67 [-1.15, -0.2], adj. p = 0.006), GABAA receptor (-0.51 [-0.7, -0.33], adj. p < 0.001), and GABA transporters (-0.51 [-0.92, -0.09], adj. p = 0.016) were lower in the AD brain. Here, we showed a global reduction of GABAergic system components in the brain and lower GABA levels in the CSF of AD patients. Our findings suggest the GABAergic system is vulnerable to AD pathology and should be considered a potential target for developing pharmacological strategies and novel AD biomarkers.

Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer's disease pathophysiology in cognitively unimpaired older adults.

Attention-deficit/hyperactivity disorder (ADHD) persists in older age and is postulated as a risk factor for cognitive impairment and Alzheimer's Disease (AD). However, these findings rely primarily on electronic health records and can present biased estimates of disease prevalence. An obstacle to investigating age-related cognitive decline in ADHD is the absence of large-scale studies following patients with ADHD into older age. Alternatively, this study aimed to determine whether genetic liability for ADHD, as measured by a well-validated ADHD polygenic risk score (ADHD-PRS), is associated with cognitive decline and the development of AD pathophysiology in cognitively unimpaired (CU) older adults. We calculated a weighted ADHD-PRS in 212 CU individuals without a clinical diagnosis of ADHD (55-90 years). These individuals had baseline amyloid-ß (Aß) positron emission tomography, longitudinal cerebrospinal fluid (CSF) phosphorylated tau at threonine 181 (p-tau181), magnetic resonance imaging, and cognitive assessments for up to 6 years. Linear mixed-effects models were used to test the association of ADHD-PRS with cognition and AD biomarkers. Higher ADHD-PRS was associated with greater cognitive decline over 6 years. The combined effect between high ADHD-PRS and brain Aß deposition on cognitive deterioration was more significant than each individually. Additionally, higher ADHD-PRS was associated with increased CSF p-tau181 levels and frontoparietal atrophy in CU Aß-positive individuals. Our results suggest that genetic liability for ADHD is associated with cognitive deterioration and the development of AD pathophysiology. Findings were mostly observed in Aß-positive individuals, suggesting that the genetic liability for ADHD increases susceptibility to the harmful effects of Aß pathology.

Exploring the mechanism of the reductive amination of acetophenones via the Borch approach: the role of the acid catalyst.

The energetic viability of several mechanistic variations of the reductive amination of acetophenones via the Borch approach was re-examined through density functional theory calculations. The crucial involvement of the acid catalyst is evident not only in the elimination of water, but also in the initial nucleophilic step. This role increases with the electron-donating capability of the substituent positioned at the para-position of acetophenone.

Epileptogenesis and drug-resistant in focal cortical dysplasias: Update on clinical, cellular, and molecular markers.

Focal cortical dysplasia (FCD) is a cortical malformation in brain development and is considered as one of the major causes of drug-resistant epilepsiesin children and adults. The pathogenesis of FCD is yet to be fully understood. Imaging markers such as MRI are currently the surgeons major obstacle due to the difficulty in delimiting the precise dysplasic area and a mosaic brain where there is epileptogenic tissue invisible to MRI. Also increased gene expression and activity may be responsible for the alterations in cell proliferation, migration, growth, and survival. Altered expressions were found, particularly in the PI3K/AKT/mTOR pathway. Surgery is still considered the most effective treatment option, due to drug-resistance, and up to 60 % of patients experience complete seizure control, varying according to the type and location of FCD. Both genetic and epigenetic factors may be involved in the pathogenesis of FCD, and there is no conclusive evidence whether these alterations are inherited or have an environmental origin.

Aetiology and use of antibiotics in pregnancy-related infections: results of the WHO Global Maternal Sepsis Study (GLOSS), 1-week inception cohort.

BACKGROUND: Pregnancy-related infections are important contributors to maternal sepsis and mortality. We aimed to describe clinical, microbiological characteristics and use of antibiotics by source of infection and country income, among hospitalized women with suspected or confirmed pregnancy-related infections. METHODS: We used data from WHO Global Maternal Sepsis Study (GLOSS) on maternal infections in hospitalized women, in 52 low-middle- and high-income countries conducted between November 28th and December 4th, 2017, to describe the frequencies and medians of maternal demographic, obstetric, and clinical characteristics and outcomes, methods of infection diagnosis and causative pathogens, of single source pregnancy-related infection, other than breast, and initial use of therapeutic antibiotics. We included 1456 women. RESULTS: We found infections of the genital (n = 745/1456, 51.2%) and the urinary tracts (UTI) (n = 531/1456, 36.5%) to be the most frequent. UTI (n = 339/531, 63.8%) and post-caesarean skin and soft tissue infections (SSTI) (n = 99/180, 55.0%) were the sources with more culture samples taken and microbiological confirmations. Escherichia coli was the major uropathogen (n = 103/118, 87.3%) and Staphylococcus aureus (n = 21/44, 47.7%) was the commonest pathogen in SSTI. For 13.1% (n = 191) of women, antibiotics were not prescribed on the same day of infection suspicion. Cephalosporins (n = 283/531, 53.3%) were the commonest antibiotic class prescribed for UTI, while metronidazole (n = 303/925, 32.8%) was the most prescribed for all other sources. Ceftriaxone with metronidazole was the commonest combination for the genital tract (n = 98/745, 13.2%) and SSTI (n = 22/180, 12.2%). Metronidazole (n = 137/235, 58.3%) was the most prescribed antibiotic in low-income countries while cephalosporins and co-amoxiclav (n = 129/186, 69.4%) were more commonly prescribed in high-income countries. CONCLUSIONS: Differences in antibiotics used across countries could be due to availability, local guidelines, prescribing culture, cost, and access to microbiology laboratory, despite having found similar sources and pathogens as previous studies. Better dissemination of recommendations in line with antimicrobial stewardship programmes might improve antibiotic prescription.

Efficacy of a novel three-step decontamination protocol for titanium-based dental implants: An in vitro and in vivo study.

AIM: The aim of the study was to evaluate several mechanical and chemical decontamination methods associated with a newly introduced biofilm matrix disruption strategy for biofilm cleaning and preservation of implant surface features. MATERIALS AND METHODS: Titanium (Ti) discs were obtained by additive manufacturing. Polymicrobial biofilm-covered Ti disc surfaces were decontaminated with mechanical [Ti curette, Teflon curette, Ti brush, water-air jet device, and Er:YAG laser] or chemical [iodopovidone (PVPI) 0.2% to disrupt the extracellular matrix, along with amoxicillin; minocycline; tetracycline; H2 O2 3%; chlorhexidine 0.2%; NaOCl 0.95%; hydrocarbon-oxo-borate-based antiseptic] protocols. The optimal in vitro mechanical/chemical protocol was then tested in combination using an in vivo biofilm model with intra-oral devices. RESULTS: Er:YAG laser treatment displayed optimum surface cleaning by biofilm removal with minimal deleterious damage to the surface, smaller Ti release, good corrosion stability, and improved fibroblast readhesion. NaOCl 0.95% was the most promising agent to reduce in vitro and in vivo biofilms and was even more effective when associated with PVPI 0.2% as a pre-treatment to disrupt the biofilm matrix. The combination of Er:YAG laser followed by PVPI 0.2% plus NaOCl 0.95% promoted efficient decontamination of rough Ti surfaces by disrupting the biofilm matrix and killing remnants of in vivo biofilms formed in the mouth (the only protocol to lead to ~99% biofilm eradication). CONCLUSION: Er:YAG laser + PVPI 0.2% + NaOCl 0.95% can be a reliable decontamination protocol for Ti surfaces, eliminating microbial biofilms without damaging the implant surface.

Immediate effect of extracorporeal shockwave therapy in patients with chronic non-specific low back pain: A randomised placebo-controlled triple-blind trial.

OBJECTIVE: To compare the immediate effects of shockwave therapy using two different tips in patients with chronic non-specific low back pain. DESIGN: Randomised placebo-controlled study with three intervention groups. SETTING: The patients recruited for this study were sent for physiotherapy treatment at primary care between May and July 2022. PARTICIPANTS: Eighty-one patients with chronic non-specific low back pain aged 18-80 years with pain for ≥3 months and pain intensity ≥3 were randomly recruited for the study. INTERVENTION: The patients received a single intervention of radial shockwave therapy with 2000 discharges at 100 mJ energy and 5 Hz frequency using concave or convex tips or placebo treatment. MAIN MEASURES: The primary outcome was pain intensity immediately post-intervention. The secondary outcomes were pressure pain threshold, temporal summation of pain, and functional performance. Data were collected at baseline and post-intervention. RESULTS: The post-intervention pain intensity in the concave tip group is an average of two points lower (95% CI = -3.6, -0.4; p < 0.01) than that in the placebo group. The post-intervention pressure pain threshold for the concave tip group was an average of 62.8 kPa higher (95% CI = 0.4, 125.1; p < 0.05) than for the convex tip group and 76.4 kPa higher (95% CI = 14, 138.7; p < 0.01) than in the placebo group. CONCLUSION: The concave tip shockwave therapy is effective in reducing pain and local hyperalgesia in patients with chronic non-specific low back pain.

Characterisation of an area of coexistent visceral and cutaneous leishmaniasis transmission in the State of Piauí, Brazil.

BACKGROUND: In Brazil, transmission of visceral and cutaneous leishmaniasis has expanded geographically over the last decades, with both clinical forms occurring simultaneously in the same area. OBJECTIVES: This study characterised the clinical, spatial, and temporal distribution, and performed entomological surveillance and natural infection analysis of a leishmaniasis-endemic area. METHODS: In order to characterise the risk of leishmaniasis transmission in Altos, Piauí, we described the clinical and socio-demographic variables and the spatial and temporal distribution of cases of American visceral leishmaniasis (AVL) and American cutaneous leishmaniasis (ACL) cases and identified potential phlebotomine vectors. FINDINGS: The urban area concentrated almost 54% of ACL and 86.8% of AVL cases. The temporal and spatial distribution of AVL and ACL cases in Altos show a reduction in the number of risk areas, but the presence of permanent disease transmission foci is observed especially in the urban area. 3,808 phlebotomine specimens were captured, with Lutzomyia longipalpis as the most frequent species (98.45%). Of the 35 females assessed for natural infection, one specimen of Lu. longipalpis tested positive for the presence of Leishmania infantum and Leishmania braziliensis DNA. MAIN CONCLUSION: Our results indicate the presence of risk areas for ACL and AVL in the municipality of Altos and highlight the importance of entomological surveillance to further understand a possible role of Lu. longipalpis in ACL transmission.

Deciphering the Absolute Configuration of Murgantiol Isomers in the Pheromone Blend of the Rice Stink Bug, Mormidea v-luteum (Hemiptera, Pentatomidae).

The males-produced pheromone blend of the Mormidea v-luteum (Hemiptera, Pentatomidae) consists in two isomers of zingiberenol (1) and three of murgantiol (2). While the absolute configuration of the zingiberenol isomers has been described, the configurations of the murgantiol isomers remained unexplored. So, our objective was to identify the absolute configuration of the murgantiol isomers (2 a-c) in the pheromone blend. To achieve this, we initially performed dehydration of the natural extract followed by enantiomeric resolution and, as a result, the three isomers was identified as (4R,1'S)-murgantiol. By leveraging the fixed cis and trans relationships among all pheromone components, we established the configuration at C-1 for isomers 2 a and 2 b is S, while that of 2 c is R. Finally, employing microchemical Sharples asymmetric dihydroxylation and epoxide ring closure, we determined the absolute configuration of the epoxide ring. Consequently, the natural isomers 2 a, 2 b, and 2 c were identified as (1S,4R,1'S,4'R)-, (1S,4R,1'S,4'S)-, and (1R,4R,1'S,4'S)-murgantiol, respectively.

Determination of intraocular pressure and Schirmer tear test and the comparison between the applanation tonometer (Tono-Pen AVIA®) and the rebound tonometer (TonoVet Plus®) in mini lionhead rabbits.

OBJECTIVE: To determine intraocular pressure (IOP) and tear production, as well as to compare the IOP obtained with the TonoVet Plus® (rebound) with the Tono-Pen Avia® (applanation) tonometers. ANIMALS: Twenty-five Mini Lionhead rabbits (n = 50 eyes). PROCEDURE: Tear production was measured at 6:00 a.m. and 6:00 p.m. by using the STT. The IOP reading was performed with the rebound tonometer, followed by the applanation tonometer, at 6:00 a.m., 9:00 a.m., 12:00 p.m., 3:00 p.m., and 6:00 p.m. Regression analysis, analysis of variance (anova) and Bland-Altman statistics were used. RESULTS: Daily tear production was 10.25 ± 3.75 mm/min, with no differences among the moments evaluated. Average daily IOP was 17.7 ± 3.08 mmHg with the TonoVet Plus® and 11.5 ± 4.56 mmHg with the Tono-Pen Avia®. IOP values were higher at the beginning and end of the day with both tonometers. CONCLUSION: The IOP values are higher with the TonoVet Plus® tonometer. The reference values of IOP and tear production obtained in this work may support the diagnosis, treatment, and monitoring of ocular disorders in pet Mini Lionhead rabbits.

Exploring colorant production by amazonian filamentous fungi: Stability and applications.

The aim of this study was to investigate the production, stability and applicability of colorants produced by filamentous fungi isolated from soil samples from the Amazon. Initially, the isolates were evaluated in a screening for the production of colorants. The influences of cultivation and nutritional conditions on the production of colorants by fungal isolates were investigated. The colorants produced by selected fungal isolates were chemically characterized using the Liquid Chromatography-Mass Spectrometry technique. The antimicrobial and cytotoxic activities, stability evaluation and applicability of the colorants were investigated. As results, we observed that the isolates Penicillium sclerotiorum P3SO224, Clonostachys rosea P2SO329 and Penicillium gravinicasei P3SO332 stood out since they produced the most intense colorants. Compounds produced by Penicillium sclerotiorum P3SO224 and Clonostachys rosea P2SO329 were identified as sclerotiorin and penicillic acid. The colorant fraction (EtOAc) produced by these species has antimicrobial activity, stability at temperature and at different pHs, stability when exposure to light and UV, and when exposed to different concentrations of salts, as well as being nontoxic and having the ability to dye fabrics and be used as a pigment in creams and soap. Considering the results found in this study, it was concluded that fungi from the soil in the Amazon have the potential to produce colorants with applications in the textile and pharmaceutical industries.

State-Dependent Blockade of Dorsal Root Ganglion Voltage-Gated Na+ Channels by Anethole.

Anethole is a phenolic compound synthesized by many aromatic plants. Anethole is a substance that humans can safely consume and has been studied for years as a biologically active molecule to treat a variety of conditions, including nerve damage, gastritis, inflammation, and nociception. Anethole is thought to carry out its biological activities through direct interaction with ion channels. Anethole is beneficial for neurodegenerative Alzheimer's and Parkinson's diseases. Nevertheless, nothing has been investigated regarding the effects of anethole on voltage-gated Na+ channels (VGSCs), which are major players in neuronal function. We used cultured dorsal root ganglion neurons from neonatal rats as a source of natively expressed VGSCs for electrophysiological studies using the whole-cell patch-clamp technique. Our data show that anethole interacts directly with VGSCs. Anethole quickly blocks and unblocks (when removed) voltage-activated Na+ currents in this preparation in a fully reversible manner. Anethole's binding affinity to these channels increases when the inactive states of these channels are populated, similar to lidocaine's effect on the same channels. Our data show that anethole inhibits neuronal activity by blocking VGSCs in a state-dependent manner. These findings relate to the putative anesthetic activity attributable to anethole, in addition to its potential benefit in neurodegenerative diseases.

Rational Approach toward COVID-19's Main Protease Inhibitors: A Hierarchical Biochemoinformatics Analysis.

This study investigated the potential of selected compounds as inhibitors of SARS-CoV-2 Mpro through pharmacokinetic and toxicological analyses, molecular docking, and molecular dynamics simulations. In silico molecular docking simulations revealed promising ligands with favorable binding affinities for Mpro, ranging from -6.2 to -9.5 kcal/mol. Moreover, molecular dynamics simulations demonstrated the stability of protein-ligand complexes over 200 ns, maintaining protein secondary structures. MM-PBSA analysis revealed favorable interactions between ligands and Mpro, with negative binding energy values. Hydrogen bond formation capacity during molecular dynamics was confirmed, indicating consistent interactions with Mpro catalytic residues. Based on these findings, selected ligands show promise for future studies in developing COVID-19 treatments.

Peri-implantitis: Knowledge and attitudes of implantology clinicians regarding the disease management: Peri-implantitis knowledge.

OBJECTIVES: Since peri-implantitis is an increasing and prevalent concern in clinical practice and there is no consensus regarding the best therapeutic protocol, this study evaluated the knowledge and behaviours of dentists working in Implantology regarding implant-related infections modulating factors and therapeutic protocols used in the management of peri-implantitis. METHODS: Cross-sectional study was conducted with 86 Brazilian Implantology clinicians. Data were collected using a structured and online questionnaire evaluating socioeconomic characteristics, education, work/clinical practice, knowledge and attitudes regarding the risk factors and management of peri-implantitis. The reliability of the questionnaire was evaluated by test-retest technique. The questionnaire was developed based on the last consensus on peri-implant diseases (2018) and the current evidence related to implant-related infections. Descriptive, bivariate and logistic regression analyses were conducted adopting a significance level of 5%. RESULTS: In this study, 89.5% of included dentists reported that already treated patients with peri-implantitis. Approximately 80% of dentists use antibiotics and mouth rinses during the treatment, and surgical procedures seem the main choice to treat peri-implantitis (91.8%) by dentists. As a preventive approach, 94.2% of dentists reported that routinely assessed biofilm accumulation in the follow-up visits after implant placement. Logistic regression showed that the self-reported ability to treat peri-implantitis was statistically (p < 0.05) higher among dentists who reported abilities to diagnose the disease and use laser for peri-implantitis treatment. CONCLUSION: Dentists working in Implantology have a good level of knowledge and behaviors in the management of peri-implantitis. However, the lack of consensus regarding the best treatment protocols may reflect dentist's behaviours because different treatment protocols have been used by evaluated clinicians.

Effect of Processing Methods of Human Saliva on the Proteomic Profile and Protein-Mediated Biological Processes.

The use of saliva as a protein source prior to microbiological and biological assays requires previous processing. However, the effect of these processing methods on the proteomic profile of saliva has not been tested. Stimulated human saliva was collected from eight healthy volunteers. Non-processed saliva was compared with 0.22 µm filtered, 0.45 µm filtered, and pasteurized saliva, by liquid chromatography-mass spectrometry. Data are available via ProteomeXchange with identifier PXD039248. The effect of processed saliva on microbial adhesion was tested using bacterial and fungus species and in biological cell behavior using HaCaT immortalized human keratinocytes. Two hundred and seventy-eight proteins were identified in non-processed saliva, of which 54 proteins (≈19%) were exclusive. Saliva processing reduced identified proteins to 222 (≈80%) for the 0.22 µm group, 219 (≈79%) for the 0.45 µm group, and 201 (≈72%) for the pasteurized saliva, compared to non-processed saliva. The proteomic profile showed similar molecular functions and biological processes. The different saliva processing methods did not alter microbial adhesion (ANOVA, p > 0.05). Interestingly, pasteurized saliva reduced keratinocyte cell viability. Saliva processing methods tested reduced the proteomic profile diversity of saliva but maintained similar molecular functions and biological processes, not interfering with microbial adhesion and cell viability, except for pasteurization, which reduced cell viability.

Recent advances in the synthesis of insect pheromones: an overview from 2013 to 2022.

Covering: 2013 to June 2022Pheromones are usually produced by insects in sub-microgram amounts, which prevents the elucidation of their structures by nuclear magnetic resonance (NMR). Instead, a synthetic reference material is needed to confirm the structure of the natural compounds. In addition, the provision of synthetic pheromones enables large-scale field trials for the development of environmentally friendly pest management tools. Because of these potential applications in pest control, insect pheromones are attractive targets for the development of synthetic procedures and the synthesis of these intraspecific chemical messengers has been at the core of numerous research efforts in the field of pheromone chemistry. The present review is a quick reference guide for the syntheses of insect pheromones published from 2013 to mid-2022, listing the synthesized compounds and highlighting current methodologies in organic synthesis, such as carbon-carbon coupling reactions, organo-transition metal chemistry including ring-closing olefin metathesis, asymmetric epoxidations and dihydroxylations, and enzymatic reactions.

14-3-3 [Formula: see text]-reported early synaptic injury in Alzheimer's disease is independently mediated by sTREM2.

INTRODUCTION: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. METHODS: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ([Formula: see text]) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages. RESULTS: 14-3-3 [Formula: see text] was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 [Formula: see text] correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss. CONCLUSIONS: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation.

The Impact of Time, Region, and Income Level on Stillbirth and Neonatal Mortality in Brazil, 2000-2019.

OBJECTIVE: To describe trends in perinatal loss across Brazil, a country that transitioned in 2006 from a lower-middle income to an upper-middle income country, from 2000 to 2019 and analyze the effect of municipal wealth status on perinatal outcomes. STUDY DESIGN: We conducted an ecological cohort study, based on publicly available data from the Brazilian Ministry of Health's data repository on live births and deaths. The Atlas of Human Development in Brazil was used to associate each region with a World Bank income classification. RESULTS: The national neonatal mortality rate (NMR) for infants born at ≥22 weeks of gestation decreased from 21.2 in 2000 to 12.4 in 2019. The stillbirth rate (SBR) decreased from 12.0 to 10.2 during this period. For infants born between 22 and 27 weeks of gestation, worsening perinatal outcomes were seen after 2012. In 2019, the median rates of neonatal mortality and stillbirth were both 4 points higher in lower- to middle-income municipalities compared with high-income municipalities (P < .01). CONCLUSION: Brazil has made significant progress in neonatal mortality and stillbirth from 2000 to 2019, yet inequity in perinatal outcomes remains and is correlated with municipal economic status. Nationally, ongoing improvement is needed for infants <28 weeks of gestation, and closer exploration is needed into why there are increasing rates of negative perinatal outcomes among infants born at 22-27 weeks of gestation after 2012.

Polymicrobial biofilms related to dental implant diseases: unravelling the critical role of extracellular biofilm matrix.

Biofilms are complex tri-dimensional structures that encase microbial cells in an extracellular matrix comprising self-produced polymeric substances. The matrix rich in extracellular polymeric substance (EPS) contributes to the unique features of biofilm lifestyle and structure, enhancing microbial accretion, biofilm virulence, and antimicrobial resistance. The role of the EPS matrix of biofilms growing on biotic surfaces, especially dental surfaces, is largely unravelled. To date, there is a lack of a broad overview of existing literature concerning the relationship between the EPS matrix and the dental implant environment and its role in implant-related infections. Here, we discuss recent advances in the critical role of the EPS matrix on biofilm growth and virulence on the dental implant surface and its effect on the etiopathogenesis and progression of implant-related infections. Similar to other biofilms associated with human diseases/conditions, EPS-enriched biofilms on implant surfaces promote microbial accumulation, microbiological shift, cross-kingdom interaction, antimicrobial resistance, biofilm virulence, and, consequently, peri-implant tissue damage. But intriguingly, the protagonism of EPS role on implant-related infections and the development of matrix-target therapeutic strategies has been neglected. Finally, we highlight the need for more in-depth analyses of polymicrobial interactions within EPS matrix and EPS-targeting technologies' rationale for disrupting the complex biofilm microenvironment with more outstanding translation to implant applications in the near future.