Sympathovagal quotient and resting-state functional connectivity of control networks are related to gut Ruminococcaceae abundance in healthy men.

INTRODUCTION: Heart rate variability (HRV), brain resting-state functional connectivity (rsFC), and gut microbiota (GM) are three recognized indicators of health status, whose relationship has not been characterized. We aimed to identify the GM genera and families related to HRV and rsFC, the interaction effect of HRV and rsFC on GM taxa abundance, and the mediation effect of diet on these relationships. METHODS: Eighty-eight healthy, young Colombian men were included in this cross-sectional study. HRV metrics were extracted from 24-hour Holter monitoring data and the resting functional connectivity strength (FCS) of 15 networks were derived from functional magnetic resonance imaging. Gut microbiota composition was assessed using the sequences of the V3-V4 regions of the 16 S rRNA gene, and diet was evaluated using a food frequency questionnaire. Multivariate linear regression analyses were performed to evaluate the correlations between the independent variables (HRV metrics and FCS) and the dependent variables (GM taxa abundance or alpha diversity indexes). Mediation analyses were used to test the role of diet in the relationship between HRV and GM. RESULTS: The sympathovagal quotient (SQ) and the FCS of control networks were positively correlated with the abundance of the gut Ruminococcaceae family and an unclassified Ruminococcaceae genus (Ruminococcaceae_unc). Additionally, the interaction between the FCS of the control network and SQ reduced the individual main effects on the Ruminococcaceae_unc abundance. Finally, reduced habitual fiber intake partially mediated the relationship between SQ and this genus. CONCLUSION: Two indicators of self-regulation, HRV and the rsFC of control networks, are related to the abundance of gut microbiota taxa in healthy men. However, only HRV is related to habitual dietary intake; thus, HRV could serve as a marker of food choice and GM composition in the future.

Cardiovascular Complications in Patients with Heart Failure and COVID-19: CARDIO COVID 19-20 Registry.

Since early 2020, different studies have shown an increased prevalence of COVID-19 and poorer prognosis in older adults with cardiovascular comorbidities. This study aimed to assess the impact of heart failure (HF) on cardiovascular complications, intensive care unit (ICU) admissions, and in-hospital mortality in patients hospitalized with COVID-19. The CARDIO COVID 19-20 registry includes 3260 hospitalized patients with a COVID-19 serological diagnosis between May 2020 and June 2021 from Latin American countries. A history of HF was identified in 182 patients (5.6%). In patients with and without previous HF, the incidence of supraventricular arrhythmia was 16.5% vs. 6.3%, respectively (p = 0.001), and that of acute coronary syndrome was 7.1% vs. 2.7%, respectively (p = 0.001). Patients with a history of HF had higher rates of ICU admission (61.5% vs. 53.1%, respectively; p = 0.031) and in-hospital mortality (41.8% vs. 24.5%, respectively; p = 0.001) than patients without HF. Cardiovascular mortality at discharge (42.1% vs. 18.5%, respectively; p < 0.001) and at 30 days post-discharge (66.7% vs. 18.0%, respectively) was higher for patients with a history of HF than for patients without HF. In patients hospitalized with COVID-19, previous history of HF was associated with a more severe cardiovascular profile, with increased risk of cardiovascular complications, and poor in-hospital and 30-day outcomes.

Impacto de las lesiones accidentales e intencionales en México. Hallazgos del estudio Global Burden of Disease para 1990 y 2021 / Impact of accidental and intentional injuries in Mexico. Findings of the Global Burden of Disease study for 1990 and 2021

Resumen Antecedentes: Análisis previos sobre la carga de la enfermedad en México identificaron que las lesiones afectan de manera diferenciada a hombres, personas jóvenes y en edad productiva. Objetivo: Analizar la carga de la enfermedad por lesiones intencionales y no intencionales en México durante 1990 y 2021 en los ámbitos nacional y estatal. Material y métodos: Se utilizaron los resultados del Global Burden of Disease respecto al período 1990-2021 para describir la carga de la enfermedad por las principales causas de lesiones en México; se analizaron los años perdidos por muerte prematura (APMP), los años vividos con discapacidad (AVD) y los años de vida saludable perdidos (AVISA). Resultados: La carga de la enfermedad relacionada con lesiones intencionales se ha incrementado, al igual que los AVD y AVISA por lesiones no intencionales. Los hombres continúan presentando tasas de mortalidad y AVISA más altas comparados con las mujeres. La violencia interpersonal y el suicidio se han incrementado de manera sostenida El análisis por estados mostró patrones con variaciones importantes. Conclusiones: Las lesiones generan consecuencias catastróficas en términos de mortalidad y discapacidad en México. Es indispensable impulsar y reforzar los programas y políticas para mejorar el sistema de datos y la prevención de lesiones.

Abstract Background: Previous analyses on the burden of disease in Mexico identified that injuries differentially affect young people, males and working-age people. Objective: To analyze the burden of disease due to intentional and unintentional injuries in Mexico during 1990 and 2021, at the national and state levels. Material and methods: The results of the Global Burden of Disease study for the 1990-2021 period were used to describe the burden of disease attributed to injuries in Mexico. The life years lost (YLL) due to premature mortality, years lived with disability (YLD) and disability-adjusted life years (DALY) were analyzed. Results: The burden of disease related to intentional injuries has increased, as also have YLDs and DALYs associated with unintentional injuries. Men continue to have higher mortality and DALY rates compared to women. Interpersonal violence and suicide have steadily increased. The analysis by state showed patterns with important variations. Conclusions: Injuries generate catastrophic consequences in terms of mortality and disability in Mexico. It is necessary to promote and strengthen programs and policies in order to improve the data system and injury prevention.

Índice neutrófilo linfocito como predictor de infección del sitio quirúrgico en cirugía abdominal urgente

Introducción: Las infecciones del sitio quirúrgico representan una carga significativa en relación con la morbilidad, la mortalidad y costos adicionales. Por lo tanto, la prevención es importante. Objetivo: Comparar el índice neutrófilos-linfocitos con la escala SENIC para predecir infección del sitio quirúrgico en pacientes que sufrieron una cirugía abdominal de urgencia. Materiales y Métodos: Estudio transversal analítico, realizado en el Hospital de Alta Especialidad de Veracruz en expedientes de pacientes post-operados de urgencia, valorándose la escala SENIC (que incluye tipo de cirugía, duración del procedimiento, grado de asepsia de la intervención y 3 o más diagnósticos posoperatorios) y el índice neutrófilos-linfocitos (definido como la razón neutrófilos sobre linfocitos). Resultados: La edad promedio de los pacientes fue de 47,7 ± 18,7 años, con un predominio del sexo masculino 83 (62%), la estancia hospitalaria media fue de 29,7 ± 14,7 días, los procedimientos fueron la laparotomía exploradora en 57 (42,2%) y la apendicectomía en 26 (19,2%). Se aisló Escherichia coli en 27 (30%). Se obtuvo una sensibilidad de 69% y especificidad de 58% para el índice neutrófilos-linfocitos y para SENIC una sensibilidad 45% y una especificidad de 73%. Las estadísticas C para el índice neutrófilos-linfocitos y SENIC fueron 0,603 (IC: 0,524 − 0,682) y 0,668 (IC 95%: 0,588 − 0,749), respectivamente. Discusión y Conclusión: Ambos métodos muestran una precisión predictiva similar para infección del sitio quirúrgico, si bien calcular el índice neutrófiloslinfocitos es mucho más rápido y sencillo.

Introduction: Surgical site infections represent a significant burden in relation to morbidity, mortality, and additional costs. Therefore, prevention is important. Objective: To compare the neutrophil-lymphocyte index with the SENIC scale to predict surgical site infection in patients who underwent emergency abdominal surgery. Materials and Methods: Analytical cross-sectional study, carried out at the Hospital de Alta Especialidad de Veracruz in records of emergency post-operative patients, evaluating the SENIC scale (which includes type of surgery, duration of the procedure, degree of asepsis of the intervention and 3 or more postoperative diagnoses) and the neutrophil-to-lymphocyte ratio (defined as the ratio of neutrophils to lymphocytes). Results: The average age of the patients was 47.7 ± 18.7 years, with a predominance of males 83 (62%); the mean hospital stay was 29.7 ± 14.7 days, the procedures were exploratory laparotomy in 57 (42.2%) and appendectomy in 26 (19.2%). Escherichia coli was isolated in 27 (30%). A sensitivity of 69% and specificity of 58% was obtained for the neutrophil-lymphocyte index and for SENIC a sensitivity of 45% and a specificity of 73%. The C statistics for the neutrophil-lymphocyte ratio and SENIC were 0.603 (CI: 0.524 − 0.682) and 0.668 (95% CI: 0.588 − 0.749), respectively. Discussion and Conclusion: Both methods show similar predictive accuracy for surgical site infection, although calculating the neutrophil-lymphocyte ratio is much faster and easier.

Safe Zones and Trajectory of Femoral Pin Placement in Robotic Total Knee Arthroplasty.

Background: Robotic-assisted total knee arthroplasty may result in array pin-related complications. Lack of knowledge on ideal pin placement results in varied insertion sites and trajectory, with unknown risks to surrounding neurovascular structures. Methods: This study included 10 lower-extremity magnetic resonance images. Images were subdivided into 6 zones of study. Zones consisted of a correlating axial image with femoral pin placement replicated by drawing a line angled 45° from the anterior to posterior reference in the anteromedial to posterolateral femoral quadrants. The distances from the pin paths to the neurovascular structures were measured. Results: Zone 2C demonstrated femoral pin trajectory an average of 14 mm from the femoral artery/vein. In Zone 2B, proximity increased to an average of 30 mm to the femoral artery and 29 mm to the femoral vein. At Zone 1A, the popliteal artery and vein were on average 22 mm from the femoral pin, while the common peroneal nerve was an average of 21 mm. Placing pins in Zone 1A poses a high risk of injury to the genicular arteries. Women demonstrated greater proximity to neurovascular structures than men in 66% of the sites (P < .05). Conclusions: This classification system for safe zones and trajectory of femoral pin placement in robotic-assisted total knee arthroplasty demonstrates that proximally, the profunda femoris and femoral artery/vein are at risk of injury, while distally, the genicular arteries, common peroneal nerve, and popliteal artery/vein are at risk. Caution should be exercised if femoral pins are inserted with an angle less than 45°, especially in women.

Impairments in hippocampal oscillations accompany the loss of LTP induced by GIRK activity blockade.

Learning and memory occurrence requires of hippocampal long-term synaptic plasticity and precise neural activity orchestrated by brain network oscillations, both processes reciprocally influencing each other. As G-protein-gated inwardly rectifying potassium (GIRK) channels rule synaptic plasticity that supports hippocampal-dependent memory, here we assessed their unknown role in hippocampal oscillatory activity in relation to synaptic plasticity induction. In alert male mice, pharmacological GIRK modulation did not alter neural oscillations before long-term potentiation (LTP) induction. However, after an LTP generating protocol, both gain- and loss-of basal GIRK activity transformed LTP into long-term depression, but only specific suppression of constitutive GIRK activity caused a disruption of network synchronization (δ, α, γ bands), even leading to long-lasting ripples and fast ripples pathological oscillations. Together, our data showed that constitutive GIRK activity plays a key role in the tuning mechanism of hippocampal oscillatory activity during long-term synaptic plasticity processes that underlies hippocampal-dependent cognitive functions.

Targeting epigenetics: A novel promise for Alzheimer's disease treatment.

So far, the search for a cure for Alzheimer Disease (AD) has been unsuccessful. The only approved drugs attenuate some symptoms, but do not halt the progress of this disease, which affects 50 million people worldwide and will increase its incidence in the coming decades. Such scenario demands new therapeutic approaches to fight against this devastating dementia. In recent years, multi-omics research and the analysis of differential epigenetic marks in AD subjects have contributed to our understanding of AD; however, the impact of epigenetic research is yet to be seen. This review integrates the most recent data on pathological processes and epigenetic changes relevant for aging and AD, as well as current therapies targeting epigenetic machinery in clinical trials. Evidence shows that epigenetic modifications play a key role in gene expression, which could provide multi-target preventative and therapeutic approaches in AD. Both novel and repurposed drugs are employed in AD clinical trials due to their epigenetic effects, as well as increasing number of natural compounds. Given the reversible nature of epigenetic modifications and the complexity of gene-environment interactions, the combination of epigenetic-based therapies with environmental strategies and drugs with multiple targets might be needed to properly help AD patients.

Efficacy and safety of anti-amyloid-ß monoclonal antibodies in current Alzheimer's disease phase III clinical trials: A systematic review and interactive web app-based meta-analysis.

The risk-benefit profile of anti-Aß monoclonal antibodies (mAbs) in Alzheimer's disease (AD) remains unclear, especially concerning their safety and overall effects on AD progression and cognitive function. Here, we investigated cognitive, biomarker and side effects of anti-Aß mAbs in large phase III randomized placebo-controlled clinical trials (RCTs) in sporadic AD. The search was performed on Google Scholar, PubMed and ClinicalTrials.gov by applying Jadad score to evaluate the methodological quality of the reports. Studies were excluded if they scored < 3 on Jadad scale or if they analyzed less than 200 sporadic AD patients. We followed PRISMA guidelines and DerSimonian-Laird random-effects model in R. Primary outcomes were cognitive: AD Assessment Scale-Cognitive Subscale (ADAS-Cog), Mini Mental State Examination (MMSE) and Clinical Dementia Rating Scale-sum of Boxes (CDR-SB). Secondary and tertiary outcomes included biomarkers of Aß and tau pathology, adverse events, and performance on Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale. The meta-analysis included 14,980 patients in 14 studies and four mAbs: Bapineuzumab, Aducanumab, Solanezumab and Lecanemab. The results of this study suggest that anti-Aß mAbs statistically improved cognitive and biomarker outcomes, particularly Aducanumab and Lecanemab. However, while cognitive effects were of small effect sizes, these drugs considerably increased risk of side effects such as Amyloid Related Imaging Abnormalities (ARIA), especially in APOE-ε4 carriers. Meta-regression revealed that higher (better) baseline MMSE score was associated with improved ADAS Cog and CDR-SB. In order to improve reproducibility and update the analysis in the future, we developed AlzMeta.app, web-based application freely available at https://alzmetaapp.shinyapps.io/alzmeta/.

Effect of the Early Combination of Continuous Positive Airway Pressure and High-Flow Nasal Cannula on Mortality and Intubation Rates in Patients With COVID-19 and Acute Respiratory Distress Syndrome. The DUOCOVID Study.

INTRODUCTION: Non invasive respiratory support (NIRS) is useful for treating acute respiratory distress syndrome (ARDS) secondary to COVID-19, mainly in mild-moderate stages. Although continuous positive airway pressure (CPAP) seems superior to other NIRS, prolonged periods of use and poor adaptation may contribute to its failure. The combination of CPAP sessions and high-flow nasal cannula (HFNC) breaks could improve comfort and keep respiratory mechanics stable without reducing the benefits of positive airway pressure (PAP). Our study aimed to determine if HFNC+CPAP initiates early lower mortality and endotracheal intubation (ETI) rates. METHODS: Subjects were admitted to the intermediate respiratory care unit (IRCU) of a COVID-19 monographic hospital between January and September 2021. They were divided according to Early HFNC+CPAP (first 24h, EHC group) and Delayed HFNC+CPAP (after 24h, DHC group). Laboratory data, NIRS parameters, and the ETI and 30-day mortality rates were collected. A multivariate analysis was performed to identify the risk factors associated with these variables. RESULTS: The median age of the 760 included patients was 57 (IQR 47-66), who were mostly male (66.1%). The median Charlson Comorbidity Index was 2 (IQR 1-3) and 46.8% were obese. The median PaO2/FiO2 upon IRCU admission was 95 (IQR 76-126). The ETI rate in the EHC group was 34.5%, with 41.8% for the DHC group (p=0.045), while 30-day mortality was 8.2% and 15.5%, respectively (p=0.002). CONCLUSIONS: Particularly in the first 24h after IRCU admission, the HFNC+CPAP combination was associated with a reduction in the 30-day mortality and ETI rates in patients with ARDS secondary to COVID-19.

Spatial Memory Training Counteracts Hippocampal GIRK Channel Decrease in the Transgenic APPSw,Ind J9 Alzheimer's Disease Mouse Model.

G-protein-gated inwardly rectifying potassium (GIRK) channels are critical determinants of neuronal excitability. They have been proposed as potential targets to restore excitatory/inhibitory balance in acute amyloidosis models, where hyperexcitability is a hallmark. However, the role of GIRK signaling in transgenic mice models of Alzheimer's disease (AD) is largely unknown. Here, we study whether progressive amyloid-ß (Aß) accumulation in the hippocampus during aging alters GIRK channel expression in mutant ß-amyloid precursor protein (APPSw,Ind J9) transgenic AD mice. Additionally, we examine the impact of spatial memory training in a hippocampal-dependent task, on protein expression of GIRK subunits and Regulator of G-protein signaling 7 (RGS7) in the hippocampus of APPSw,Ind J9 mice. Firstly, we found a reduction in GIRK2 expression (the main neuronal GIRK channels subunit) in the hippocampus of 6-month-old APPSw,Ind J9 mice. Moreover, we found an aging effect on GIRK2 and GIRK3 subunits in both wild type (WT) and APPSw,Ind J9 mice. Finally, when 6-month-old animals were challenged to a spatial memory training, GIRK2 expression in the APPSw,Ind J9 mice were normalized to WT levels. Together, our results support the evidence that GIRK2 could account for the excitatory/inhibitory neurotransmission imbalance found in AD models, and training in a cognitive hippocampal dependent task may have therapeutic benefits of reversing this effect and lessen early AD deficits.

Recognition Memory Induces Natural LTP-like Hippocampal Synaptic Excitation and Inhibition.

Synaptic plasticity is a cellular process involved in learning and memory by which specific patterns of neural activity adapt the synaptic strength and efficacy of the synaptic transmission. Its induction is governed by fine tuning between excitatory/inhibitory synaptic transmission. In experimental conditions, synaptic plasticity can be artificially evoked at hippocampal CA1 pyramidal neurons by repeated stimulation of Schaffer collaterals. However, long-lasting synaptic modifications studies during memory formation in physiological conditions in freely moving animals are very scarce. Here, to study synaptic plasticity phenomena during recognition memory in the dorsal hippocampus, field postsynaptic potentials (fPSPs) evoked at the CA3-CA1 synapse were recorded in freely moving mice during object-recognition task performance. Paired pulse stimuli were applied to Schaffer collaterals at the moment that the animal explored a new or a familiar object along different phases of the test. Stimulation evoked a complex synaptic response composed of an ionotropic excitatory glutamatergic fEPSP, followed by two inhibitory responses, an ionotropic, GABAA-mediated fIPSP and a metabotropic, G-protein-gated inwardly rectifying potassium (GirK) channel-mediated fIPSP. Our data showed the induction of LTP-like enhancements for both the glutamatergic and GirK-dependent components of the dorsal hippocampal CA3-CA1 synapse during the exploration of novel but not familiar objects. These results support the contention that synaptic plasticity processes that underlie hippocampal-dependent memory are sustained by fine tuning mechanisms that control excitatory and inhibitory neurotransmission balance.

Clinical characteristics and respiratory care in hospitalized vaccinated SARS-CoV-2 patients.

Background: The main objective of the present study was to analyze both clinical characteristics and evolution during hospitalization of a cohort of patients admitted for COVID-19 pneumonia who were not vaccinated, or with a complete or incomplete vaccination schedule. Methods: This COVID-19 specialized single-center cohort study of 1888 COVID-19 patients hospitalized at the "Enfermera Isabel Zendal" Emergencies Hospital (HEEIZ), Madrid (Spain) was performed between July 1 and September 30, 2021. It compared the results of 1327 hospitalized unvaccinated patients to 209 hospitalized fully vaccinated and 352 hospitalized partially vaccinated patients. The four different COVID-19 vaccines authorized in Spain during the time-period studied were: BNT162b2 (Pfizer); ChAdOx1 nCoV-19 (AstraZeneca), mRNA-1273 (Moderna); Ad26.COV2.S (Janssen). Findings: Hospitalized patients' median age was 41 years (IQR 33-50) for the unvaccinated and 61 years (IQR 53-67) for the fully vaccinated ones. The main comorbidities were obesity, hypertension and diabetes mellitus. 20% of unvaccinated patients (266) required noninvasive respiratory care, as did 14% (51) of partially and 14% (30) of fully vaccinated; 6% (78) of the unvaccinated patients also needed invasive respiratory care, as did 5% (16) of partially and 11 (5%) fully vaccinated. Interpretation: Fully vaccinated patients were 84% (95% CI: 82-86%) less likely to be admitted to hospital, and protection rose for those aged <50 years. Once hospitalized, vaccinated patients displayed more protection against requiring respiratory care than unvaccinated ones, despite being older and having more comorbidities. No differences appeared for the four studied COVID-19 vaccines and complying with vaccination recommendations proved relevant. Funding: The research was funded by the "Plan Propio de Investigación" Program of the Castilla-La Mancha University /European Regional Development Fund (2021-GRIN-31,039).

A retrospective study evaluating the association between hypoalbuminemia and postoperative outcomes for patients receiving open rotator cuff repair.

PURPOSE: Malnutrition has historically been shown to influence surgical outcomes. Although the diagnosis of malnutrition can be multifactorial, serum albumin levels serve as a useful indicator of malnutrition in patients undergoing orthopaedic surgery. The purpose of this study is to examine the prevalence of post-operative complications in patients with malnutrition (hypoalbuminemia) who underwent open rotator cuff repair. We hypothesized that patients with low preoperative albumin levels will have an increased risk for postoperative complications, readmission, reoperation, and prolonged hospital stay. METHODS: The National Surgical Quality Improvement Program database was queried for patients undergoing open rotator cuff repair from 2006 to 2019. Two patient cohorts were defined: patients with hypoalbuminemia (<3.5 g/dL) and patients with normal preoperative serum albumin (≥3.5 g/dL), with the former being an indicator for malnutrition. In this analysis, demographics, comorbidities, and postoperative complications were compared between the two cohorts using bivariate analyses. Confounding factors found in the control group included sex, race, age, body mass index, smoking status, chronic obstructive pulmonary disease, hypertension, dialysis, diabetes, and dyspnea. To eliminate potential biases, multivariable logistic regression was used to adjust for these confounding factors. RESULTS: Of 3,052 patients undergoing open rotator cuff repair with serum albumin levels recorded within 90 days before the surgery, 2,914 patients (95.5%), with an age range of 21-90 years, had normal albumin levels and 138 patients (4.5%), with an age range of 24-87 years, were hypoalbuminemic. Following adjustment on multivariate analyses, compared to patients with normal preoperative serum albumin, those with hypoalbuminemia had an increased risk of extended length of hospital stay (OR 7.47; p < 0.001) and hospital readmission (OR 4.16; p = 0.002). CONCLUSION: Hypoalbuminemia is associated with extended length of stay and readmission after receiving open rotator cuff repair surgery.

Acquisition-dependent modulation of hippocampal neural cell adhesion molecules by associative motor learning.

It is widely accepted that some types of learning involve structural and functional changes of hippocampal synapses. Cell adhesion molecules neural cell adhesion molecule (NCAM), its polysialylated form polysialic acid to NCAM (PSA-NCAM), and L1 are prominent modulators of those changes. On the other hand, trace eyeblink conditioning, an associative motor learning task, requires the active participation of hippocampal circuits. However, the involvement of NCAM, PSA-NCAM, and L1 in this type of learning is not fully known. Here, we aimed to investigate the possible time sequence modifications of such neural cell adhesion molecules in the hippocampus during the acquisition of a trace eyeblink conditioning. To do so, the hippocampal expression of NCAM, PSA-NCAM, and L1 was assessed at three different time points during conditioning: after one (initial acquisition), three (partial acquisition), and six (complete acquisition) sessions of the conditioning paradigm. The conditioned stimulus (CS) was a weak electrical pulse separated by a 250-ms time interval from the unconditioned stimuli (US, a strong electrical pulse). An acquisition-dependent regulation of these adhesion molecules was found in the hippocampus. During the initial acquisition of the conditioning eyeblink paradigm (12 h after 1 and 3 days of training), synaptic expression of L1 and PSA-NCAM was transiently increased in the contralateral hippocampus to the paired CS-US presentations, whereas, when the associative learning was completed, such increase disappeared, but a marked and bilateral upregulation of NCAM was found. In conclusion, our findings show a specific temporal pattern of hippocampal CAMs expression during the acquisition process, highlighting the relevance of NCAM, PSA-NCAM, and L1 as learning-modulated molecules critically involved in remodeling processes underlying associative motor-memories formation.

Past, present and future of therapeutic strategies against amyloid-ß peptides in Alzheimer's disease: a systematic review.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD is still puzzling, and new drugs development and clinical trials have high failure rates. Urgent outline of an integral (multi-target) and effective treatment of AD is needed. Accumulation of amyloid-ß (Aß) peptides is considered one of the fundamental neuropathological pillars of the disease, and its dyshomeostasis has shown a crucial role in AD onset. Therefore, many amyloid-targeted therapies have been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up and review studies focused on anti-amyloid strategies to summarize and analyze their current clinical potential. Combination of anti-Aß therapies with new developing early detection biomarkers and other therapeutic agents acting on early functional AD changes will be highlighted in this review. Near-term approval seems likely for several drugs acting against Aß, with recent FDA approval of a monoclonal anti-Aß oligomers antibody -aducanumab- raising hopes and controversies. We conclude that, development of oligomer-epitope specific Aß treatment and implementation of multiple improved biomarkers and risk prediction methods allowing early detection, together with therapies acting on other factors such as hyperexcitability in early AD, could be the key to slowing this global pandemic.

G-Protein-Gated Inwardly Rectifying Potassium (Kir3/GIRK) Channels Govern Synaptic Plasticity That Supports Hippocampal-Dependent Cognitive Functions in Male Mice.

The G-protein-gated inwardly rectifying potassium (Kir3/GIRK) channel is the effector of many G-protein-coupled receptors (GPCRs). Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimer's and Parkinson's diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. In the hippocampus, GIRK channels decrease excitability of the cells and contribute to resting membrane potential and inhibitory neurotransmission. Here, to elucidate the role of GIRK channels activity in the maintenance of hippocampal-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined in C57BL/6 male mice. For that purpose, GIRK activity in the dorsal hippocampus CA3-CA1 synapse was pharmacologically modulated by two drugs: ML297, a GIRK channel opener, and Tertiapin-Q (TQ), a GIRK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied the effect of pharmacological GIRK modulation on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation. In vivo, we performed acute intracerebroventricular (i.c.v.) injections of the two GIRK modulators to study their contribution to electrophysiological properties and synaptic plasticity of dorsal hippocampal CA3-CA1 synapse, and to learning and memory capabilities during hippocampal-dependent tasks. We found that pharmacological disruption of GIRK channel activity by i.c.v. injections, causing either function gain or function loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in the induction and maintenance of long-term synaptic plasticity processes. These results support the contention that an accurate control of GIRK activity must take place in the hippocampus to sustain cognitive functions.SIGNIFICANCE STATEMENT Cognitive processes of learning and memory that rely on hippocampal synaptic plasticity processes are critically ruled by a finely tuned neural excitability. G-protein-gated inwardly rectifying K+ (GIRK) channels play a key role in maintaining resting membrane potential, cell excitability and inhibitory neurotransmission. Here, we demonstrate that modulation of GIRK channels activity, causing either function gain or function loss, transforms high-frequency stimulation (HFS)-induced long-term potentiation (LTP) into long-term depression (LTD), inducing deficits in hippocampal-dependent learning and memory. Together, our data show a crucial GIRK-activity-mediated mechanism that governs synaptic plasticity direction and modulates subsequent hippocampal-dependent cognitive functions.

Inhibition of PAD4 mediated neutrophil extracellular traps prevents fibrotic osseointegration failure in a tibial implant murine model : an animal study.

AIMS: Aseptic loosening is a leading cause of uncemented arthroplasty failure, often accompanied by fibrotic tissue at the bone-implant interface. A biological target, neutrophil extracellular traps (NETs), was investigated as a crucial connection between the innate immune system's response to injury, fibrotic tissue development, and proper bone healing. Prevalence of NETs in peri-implant fibrotic tissue from aseptic loosening patients was assessed. A murine model of osseointegration failure was used to test the hypothesis that inhibition (through Pad4-/- mice that display defects in peptidyl arginine deiminase 4 (PAD4), an essential protein required for NETs) or resolution (via DNase 1 treatment, an enzyme that degrades the cytotoxic DNA matrix) of NETs can prevent osseointegration failure and formation of peri-implant fibrotic tissue. METHODS: Patient peri-implant fibrotic tissue was analyzed for NETs biomarkers. To enhance osseointegration in loose implant conditions, an innate immune system pathway (NETs) was either inhibited (Pad4-/- mice) or resolved with a pharmacological agent (DNase 1) in a murine model of osseointegration failure. RESULTS: NETs biomarkers were identified in peri-implant fibrotic tissue collected from aseptic loosening patients and at the bone-implant interface in a murine model of osseointegration failure. Inhibition (Pad4-/- ) or resolution (DNase 1) of NETs improved osseointegration and reduced fibrotic tissue despite loose implant conditions in mice. CONCLUSION: This study identifies a biological target (NETs) for potential noninvasive treatments of aseptic loosening by discovering a novel connection between the innate immune system and post-injury bone remodelling caused by implant loosening. By inhibiting or resolving NETs in an osseointegration failure murine model, fibrotic tissue encapsulation around an implant is reduced and osseointegration is enhanced, despite loose implant conditions. Cite this article: Bone Joint J 2021;103-B(7 Supple B):135-144.

Therapeutic potential of targeting G protein-gated inwardly rectifying potassium (GIRK) channels in the central nervous system.

G protein-gated inwardly rectifying potassium channels (Kir3/GirK) are important for maintaining resting membrane potential, cell excitability and inhibitory neurotransmission. Coupled to numerous G protein-coupled receptors (GPCRs), they mediate the effects of many neurotransmitters, neuromodulators and hormones contributing to the general homeostasis and particular synaptic plasticity processes, learning, memory and pain signaling. A growing number of behavioral and genetic studies suggest a critical role for the appropriate functioning of the central nervous system, as well as their involvement in many neurologic and psychiatric conditions, such as neurodegenerative diseases, mood disorders, attention deficit hyperactivity disorder, schizophrenia, epilepsy, alcoholism and drug addiction. Hence, GirK channels emerge as a very promising tool to be targeted in the current scenario where these conditions already are or will become a global public health problem. This review examines recent findings on the physiology, function, dysfunction, and pharmacology of GirK channels in the central nervous system and highlights the relevance of GirK channels as a worthful potential target to improve therapies for related diseases.

Response to the Comment on "A Systematic Review and Meta-Analysis of Hospitalised Current Smokers and COVID-19".

This is a reply to the comment by Ivan Berlin and Daniel Thomas on our recently published work [...].