Heterologous mRNA/MVA delivering trimeric-RBD as effective vaccination regimen against SARS-CoV-2: COVARNA Consortium.

Despite the high efficiency of current SARS-CoV-2 mRNA vaccines in reducing COVID-19 morbidity and mortality, waning immunity and the emergence of resistant variants underscore the need for novel vaccination strategies. This study explores a heterologous mRNA/Modified Vaccinia virus Ankara (MVA) prime/boost regimen employing a trimeric form of the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein compared to a homologous MVA/MVA regimen. In C57BL/6 mice, the RBD was delivered during priming via an mRNA vector encapsulated in nanoemulsions (NE) or lipid nanoparticles (LNP), followed by a booster with a replication-deficient MVA-based recombinant virus (MVA-RBD). This heterologous mRNA/MVA regimen elicited strong anti-RBD binding and neutralizing antibodies (BAbs and NAbs) against both the ancestral SARS-CoV-2 strain and different variants of concern (VoCs). Additionally, this protocol induced robust and polyfunctional RBD-specific CD4 and CD8 T cell responses, particularly in animals primed with mLNP-RBD. In K18-hACE2 transgenic mice, the LNP-RBD/MVA combination provided complete protection from morbidity and mortality following a live SARS-CoV-2 challenge compared with the partial protection observed with mNE-RBD/MVA or MVA/MVA regimens. Although the mNE-RBD/MVA regimen only protects half of the animals, it was able to induce antibodies with Fc-mediated effector functions besides NAbs. Moreover, viral replication and viral load in the respiratory tract were markedly reduced and decreased pro-inflammatory cytokine levels were observed. These results support the efficacy of heterologous mRNA/MVA vaccine combinations over homologous MVA/MVA regimen, using alternative nanocarriers that circumvent intellectual property restrictions of current mRNA vaccine formulations.

[Meningococcal meningitis in Chile between 1990 and 2019]. / Meningitis meningocócica en Chile entre los años 1990 y 2019.

Since 1941, outbreaks of Neisseria meningitidis have been recorded in Chile which, to date, have varied according to clinical form, incidence, lethality, and the responsible serogroup. OBJECTIVE: To summarize the available evidence on the epidemiological profile of acute bacterial meningitis due to Neisseria meningitidis in Chile, analyzing the incidence between 1990 and 2019. METHOD: A systematized review of primary articles was carried out following the Cochrane Collaboration standards. The information sources were PubMed, Scielo, and LILACS. Publications on acute bacterial meningitis due to Neisseria meningitidis were included, with a descriptive design, and in English and Spanish. Studies on the effectiveness of vaccines and diagnostic techniques were excluded. RESULTS: Between 1990 and 2019, the evidence collected focuses exclusively on the year 2012. Of the 133 cases of invasive meningococcal disease (IMD) reported that year, 42 cases presented with meningitis. Of the IMD cases caused by serogroup W135 strains, 21.7% of the cases presented with meningitis (13 cases), compared with the "Non-W135" strains, in which it was 67.4% (29 cases). Lethality due to IMD was higher in patients affected by serogroup W135 (26.7%), compared with patients affected by serogroup "Non-W135" (13.9%). DISCUSSION: The year 2012 shows a change in the prevalent serogroup from serogroup B to W, with a decrease in cases of meningitis and an increase in cases of meningo- coccemia and the lethality of IMD.

Cardiorespiratory interactions during the transitional period in extremely preterm infants: a narrative review.

We aimed to review the physiology and evidence behind cardiorespiratory interactions during the transitional circulation of extremely preterm infants with fragile physiology and to propose a framework for future research. Cord clamping strategies have a great impact on initial haemodynamic changes, and appropriate transition can be facilitated by establishing spontaneous ventilation before cord clamping. Mechanical ventilation modifies preterm transitional haemodynamics, with positive pressure ventilation affecting the right and left heart loading conditions. Pulmonary vascular resistances can be minimized by ventilating with optimal lung volumes at functional residual capacity, and other pulmonary vasodilator treatments such as inhaled nitric oxide can be used to improve ventilation/perfusion mismatch. Different cardiovascular drugs can be used to provide support during transition in this population, and it is important to understand both their cardiovascular and respiratory effects, in order to provide adequate support to vulnerable preterm infants and improve outcomes. Current available non-invasive bedside tools, such as near-infrared spectroscopy, targeted neonatal echocardiography, or lung ultrasound offer the opportunity to precisely monitor cardiorespiratory interactions in preterm infants. More research is needed in this field using precision medicine to strengthen the benefits and avoid the harms associated to early neonatal interventions. IMPACT: In extremely preterm infants, haemodynamic and respiratory transitions are deeply interconnected, and their changes have a key impact in the establishment of lung aireation and postnatal circulation. We describe how mechanical ventilation modifies heart loading conditions and pulmonary vascular resistances in preterm patients, and how hemodynamic interventions such as cord clamping strategies or cardiovascular drugs affect the infant respiratory status. Current available non-invasive bedside tools can help monitor cardiorespiratory interactions in preterm infants. We highlight the areas of research in which precision medicine can help strengthen the benefits and avoid the harms associated to early neonatal interventions.

A recommendation for the use of electrical biosensing technology in neonatology.

Non-invasive cardiac output monitoring, via electrical biosensing technology (EBT), provides continuous, multi-parameter hemodynamic variable monitoring which may allow for timely identification of hemodynamic instability in some neonates, providing an opportunity for early intervention that may improve neonatal outcomes. EBT encompasses thoracic (TEBT) and whole body (WBEBT) methods. Despite the lack of relative accuracy of these technologies, as compared to transthoracic echocardiography, the use of these technologies in neonatology, both in the research and clinical arena, have increased dramatically over the last 30 years. The European Society of Pediatric Research Special Interest Group in Non-Invasive Cardiac Output Monitoring, a group of experienced neonatologists in the field of EBT, deemed it appropriate to provide recommendations for the use of TEBT and WBEBT in the field of neonatology. Although TEBT is not an accurate determinant of cardiac output or stroke volume, it may be useful for monitoring longitudinal changes of hemodynamic parameters. Few recommendations can be made for the use of TEBT in common neonatal clinical conditions. It is recommended not to use WBEBT to monitor cardiac output. The differences in technologies, study methodologies and data reporting should be addressed in ongoing research prior to introducing EBT into routine practice. IMPACT STATEMENT: TEBT is not recommended as an accurate determinant of cardiac output (CO) (or stroke volume (SV)). TEBT may be useful for monitoring longitudinal changes from baseline of hemodynamic parameters on an individual patient basis. TEBT-derived thoracic fluid content (TFC) longitudinal changes from baseline may be useful in monitoring progress in respiratory disorders and circulatory conditions affecting intrathoracic fluid volume. Currently there is insufficient evidence to make any recommendations regarding the use of WBEBT for CO monitoring in neonates. Further research is required in all areas prior to the implementation of these monitors into routine clinical practice.

Flotillin-mediated stabilization of unfolded proteins in bacterial membrane microdomains.

The function of many bacterial processes depends on the formation of functional membrane microdomains (FMMs), which resemble the lipid rafts of eukaryotic cells. However, the mechanism and the biological function of these membrane microdomains remain unclear. Here, we show that FMMs in the pathogen methicillin-resistant Staphylococcus aureus (MRSA) are dedicated to confining and stabilizing proteins unfolded due to cellular stress. The FMM scaffold protein flotillin forms a clamp-shaped oligomer that holds unfolded proteins, stabilizing them and favoring their correct folding. This process does not impose a direct energy cost on the cell and is crucial to survival of ATP-depleted bacteria, and thus to pathogenesis. Consequently, FMM disassembling causes the accumulation of unfolded proteins, which compromise MRSA viability during infection and cause penicillin re-sensitization due to PBP2a unfolding. Thus, our results indicate that FMMs mediate ATP-independent stabilization of unfolded proteins, which is essential for bacterial viability during infection.

A Search for New Biological Pathways in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy by Proteomic Research.

Background/Objectives: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary small vessel disease leading to significant morbidity and mortality. Despite advances in genetic diagnosis, the underlying pathophysiology remains incompletely understood. Proteomic studies offer insights into disease mechanisms by identifying altered protein expression patterns. Here, we conducted a proteomic analysis to elucidate molecular pathways associated with CADASIL. Methods: We enrolled genetically diagnosed CADASIL patients and healthy, genetically related controls. Plasma samples were subjected to proteomic analysis using the Olink platform, measuring 552 proteins across six panels. The data were analyzed from several approaches by using three different statistical methods: Exploratory Principal Component Analysis (PCA) and Partial Least Squares-Discriminant Analysis (PLS-DA), differential expression with moderated t-test, and gene set enrichment analysis (GSEA). In addition, bioinformatics analysis, including volcano plot, heatmap, and Variable Importance on Projection (VIP) scores from the PLS-DA model were drawn. Results: Significant differences in protein expression were observed between CADASIL patients and controls. RSPO1 and FGF-19 exhibited elevated levels (p < 0.05), while PPY showed downregulation (p < 0.05) in CADASIL patients, suggesting their involvement in disease pathogenesis. Furthermore, MIC-A/B expression varied significantly between patients with mutations in exon 4 versus exon 11 of the NOTCH3 gene (p < 0.05), highlighting potential immunological mechanisms underlying CADASIL. We identified altered pathways using GSEA, applied after ranking the study data. Conclusions: Our study provides novel insights into the proteomic profile of CADASIL, identifying dysregulated proteins associated with vascular pathology, metabolic dysregulation, and immune activation. These findings contribute to a deeper understanding of CADASIL pathophysiology and may inform the development of targeted therapeutic strategies. Further research is warranted to validate these biomarkers and elucidate their functional roles in disease progression.

LAM Test: A New Cognitive Marker for Early Detection in Preclinical Alzheimer's Disease.

Background: With the arrival of disease-modifying treatments, it is mandatory to find new cognitive markers that are sensitive to Alzheimer's disease (AD) pathology in preclinical stages. Objective: To determine the utility of a newly developed Learning and Associative Memory face test: LAM test. This study examined the relationship between AD cerebrospinal fluid (CSF) biomarkers and performance on LAM test, and assessed its potential clinical applicability to detect subtle changes in cognitively healthy subjects at risk for AD. Methods: We studied eighty cognitively healthy volunteers from the Valdecilla cohort. 61% were women and the mean age was 67.34 years (±6.416). All participants underwent a lumbar puncture for determination of CSF biomarkers and an extensive neuropsychological assessment, including performance on learning and associative memory indices of the LAM-test after 30 min and after 1 week, and two classic word lists to assess verbal episodic memory: the Rey Auditory Verbal Learning Test (RAVLT) and the Free and Cued Selective Reminding Test (FCSRT). We analyzed cognitive performance according to amyloid status (A+ versus A-) and to ATN model (A-T-N-; A+T-N-; A+T+N-/A+T+N+). Results: Performance on the LAM-test was significantly correlated with CSF Aß ratio. A+ participants performed worse on both learning (mean difference = 2.19, p = 0.002) and memory LAM measures than A- (mean difference = 2.19, p = 0.004). A decline in performance was observed along the Alzheimer's continuum, with significant differences between ATN groups. Conclusions: Our findings suggest that LAM test could be a useful tool for the early detection of subjects within the AD continuum, outperforming classical memory tests.

Neonatal ventriculomegaly: Pathophysiology and management guided with cranial ultrasonography.

Neonatal ventriculomegaly often, but not always, follows intraventricular haemorrhage in infants born preterm. Serial cranial ultrasonography (CUS) is a very useful tool to evaluate the mechanism behind ventricular dilatation, to differentiate several types of cerebrospinal fluid retention, and to guide treatment. This review examines neonatal ventriculomegaly and its definition, pathophysiology, treatment, and prognosis from the perspective of CUS assessment. It also outlines the consensus statements formulated by the EurUS.Brain group, which are based on rounds of expert opinions on neonatal ventriculomegaly management, detailing the need and timing of ventricular access device placement, in the context of posthaemorrhagic ventricular dilation. The pathophysiology of neonatal ventriculomegaly is more complex than previously considered. CUS is a valuable, non-invasive tool to determine pathophysiology, intervention thresholds, and prognosis in neonates with ventriculomegaly. Given new insights into the existence of glymphatics and water circulation in the cerebrum, further research in that area may bring new treatment options. WHAT THIS PAPER ADDS: Cranial ultrasonography has a significant role in better understanding the complex pathophysiology of neonatal ventriculomegaly. The latest research suggests that treating posthaemorrhagic ventricular dilation in its early stages has several advantages. Proper definition, management, and a follow-up plan are essential because they can impact the infant and their family, health care providers, educational systems, and society.

Access to healthcare among transgender and non-binary youth in Sweden and Spain: A qualitative analysis and comparison.

BACKGROUND: Transgender and non-binary (TGNB) people tend to report worse health than cis people, however, despite an increased need for care, they face several barriers when trying to access healthcare. These barriers might be exacerbated when young age intersects with a trans identity, and so there is a need for studies highlighting the experiences of TGNB youth. AIMS: To explore and compare how TGNB youth (15-26 years old) in Sweden and Spain experienced their access to healthcare, in order to shed light on the strengths and limitations of different kinds of healthcare systems and improve healthcare provision and policy development. METHODS: This study was based on a qualitative analysis of semi-structured interviews with TGNB youth living in Sweden (n = 16) and Spain (n = 18). Of these, 22 identified as male or transmasculine, six as non-binary, and six as women or transfeminine; 25 had undergone some type of gender-affirming care, and the rest were on the waiting list or undergoing preparatory visits and had not started hormonal treatment. The interviews were analyzed using reflexive thematic analysis. An abductive approach was applied, and the Levesque conceptual framework was used to compare the analyses of each set of materials. RESULTS: We present our findings using the structure of the accessibility framework, focusing on approachability, acceptability, availability, affordability, and appropriateness. The conceptualization of accessibility in combination with the concept of cisnormativity illustrates how specific ideals and normative expectations affect access to healthcare for TGNB people across contexts, with most barriers arising from the appropriateness of the services. DISCUSSION: Young TGNB people experience barriers to accessing healthcare both in the Spanish and the Swedish contexts. Strategies to reduce these barriers should be framed within the critique of and resistance to cisnormativity and should focus on users with intersecting marginalized identities to promote health equity.

Longitudinal assessment of coagulation potential before, during, and following an in vitro fertilization cycle.

INTRODUCTION: The association between estrogen and hypercoagulability is well-established but little is known about coagulation dynamics during IVF. Our goal was to measure coagulation potential prior to, during, and following an IVF cycle and to investigate differences by conception outcome. MATERIALS AND METHODS: Patients undergoing IVF with fresh embryo transfer at a single academic center using oral contraceptive pills for cycle batching underwent evaluation of thrombin generation using the calibrated automated thrombogram at multiple points during the IVF cycle. Multiple thrombin generation parameters were compared across timepoints and by IVF cycle outcome using ANOVA repeated measures analysis. RESULTS: Of the 17 patients included, 11 conceived. There was a significant increase in peak and total thrombin generation in the entire cohort between the pre-treatment natural follicular phase and following a short course of oral contraceptive pills used for cycle batching. Further increase in these parameters was seen at the time of oocyte retrieval. In the pre-treatment natural follicular phase, patients who conceived had lower peak thrombin generation. There were changes throughout the cycle for factors II, V, VIII, X, XI, XII, antithrombin, and tissue factor pathway inhibitor. Only Factor XI was distinguishable by conception status; values were lower at all visits in patients who conceived. CONCLUSION: Increases in coagulation potential are seen in patients undergoing IVF following a short course of oral contraceptive pills for cycle batching and continue during controlled ovarian hyperstimulation. Those who conceived were seen to have lower peak thrombin generation in the pre-treatment natural follicular phase.

Association between early echocardiography screening of low systemic blood flow and intraventricular hemorrhage in preterm infants: a multicenter cohort study.

OBJECTIVE: To determine whether early echocardiography screening of low systemic blood flow reduces intraventricular hemorrhage in preterm infants. STUDY DESIGN: Prospective multicenter study in preterm infants below 33 weeks of gestational age at nine neonatal units. Five units performed early echocardiography screening for low systemic blood flow and guided clinical management (exposure group) and 4 units did not (control group). Our main outcome was ≥grade II intraventricular hemorrhage or death within the first 7 days of life. The main analysis used the inverse probability of treatment weighting. RESULTS: Three hundred and thirty-two preterm infants (131 in the exposure group and 201 in the control group) were included. Exposure to early echocardiography screening was associated with a significant reduction in ≥grade II intraventricular hemorrhage or early death [odds ratio 0.285 (95% CI: 0.133-0.611); p = 0.001]. CONCLUSIONS: Early echocardiography screening for low systemic blood flow may reduce the incidence of intraventricular hemorrhage in preterm infants.

Factor VIII and Incident Hypertension in Black and White Adults: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort.

BACKGROUND: Nearly half of all Americans have hypertension, and Black adults experience a disproportionate burden. Hypercoagulability may relate to hypertension risk, and higher levels of factor VIII increase thrombosis risk. Black adults have higher factor VIII and more hypertension than other groups. Whether higher factor VIII associates with incident hypertension is unknown. METHODS: The Biomarkers as Mediators of Racial Disparities in Risk Factors (BioMedioR) study measured certain biomarkers in a sex-race stratified sample of 4,400 REGARDS participants who attended both visits. We included BioMedioR participants, excluding those with prevalent hypertension, missing factor VIII level, or covariates of interest. Modified Poisson regression estimated risk ratios (RR) for incident hypertension by higher log-transformed factor VIII level per SD (SD of log-transformed factor VIII, 0.33). Weighting was applied to take advantage of REGARDS sampling design. RESULTS: Among the 1,814 participants included (55% female, 24% Black race), the median follow-up was 9.5 years and 35% (2,146/6,138) developed hypertension. Black participants had a higher median (IQR) factor VIII level (105.6%; 87.1%-126.9%) than White participants (95.6%; 79.8%-115.9%; P < 0.001). The age- and sex-adjusted Black-White hypertension RR was 1.45 (95% CI 1.28, 1.63). Higher factor VIII was not associated with more hypertension (final model RR 1.01; 95% CI 0.94, 1.07). CONCLUSIONS: In a prospective study of Black and White adults without prevalent hypertension, factor VIII was not associated with greater hypertension risk.

Estrés y ansiedad en estudiantes de enfermería durante la primera ola de la pandemia de COVID-19.

OBJECTIVE: To compare anxiety and acute stress levels among nursing students who joined the labour market during the first wave of the COVID-19 pandemic   and those who did not. METHODS: A cross-sectional, multicentre descriptive study across three Spanish public universities. A total of 216 nursing students participated in our study. Data collection was carried through an online questionnaire, that included variables on conditions for entering the labour market, the Zung Anxiety Self-Assessment Scale and the Stanford Acute Stress Reaction Questionnaire. We performed univariate and multivariate analyses.  Results: Overall, 42.6% (n=92) of the students entered the labour market during the first wave of the COVID-19 pandemic. The global anxiety score was x?=36.31 (SD=5.71) and the stress score was x?=82.39 (SD=30.84). Lower anxiety levels were observed among those who joined the labour market (x?=35.67; SD=5.78) as compared to those who did not (x?=36.73; SD=5.67). Overall 92.4% of the students were acutely stressed. Acute stress was higher among those who did not work (x?=84.35; SD=32.38) and significantly in women.  Conclusions: Nursing students were able to cope with stress in situations such as the COVID-19 pandemic. A healthy worker effect could not be ruled out. Stress and anxiety among nursing students should be considered by clinical practice preceptors and at the time students first enter the labour market.

OBJETIVO: Comparar los niveles de ansiedad y estrés agudo entre los/las estudiantes de enfermería que se incorporaron al trabajo durante la primera ola de la pandemia de COVID-19 y aquellos que no lo hicieron. Métodos: Estudio descriptivo transversal multicéntrico realizado en tres universidades públicas españolas. Un total de 216 estudiantes de enfermería participaron en nuestro estudio. La recopilación de datos se realizó mediante un formulario en línea. Se recopilaron variables relacionadas con las condiciones para ingresar al mercado laboral y se incluyó la Escala de Autoevaluación de Ansiedad de Zung y el Cuestionario de Reacción Aguda al Estrés de Stanford. Se llevaron a cabo análisis univariados y multivariados. RESULTADOS: El 42,6% de los estudiantes ingresaron al mercado laboral. La puntuación global de ansiedad fue x?=36,31 (DE=5,71) y la puntuación de estrés fue x?=82,39 (DE=30,84). Los niveles más bajos de ansiedad se encontraron en aquellos que se incorporaron al mercado laboral (x?=35,67; DE=5,78), en comparación con aquellos que no lo hicieron (x?=36,73; DE=5,67). El 92,4% del total de alumnos presentaron estrés agudo. El estrés agudo fue mayor en aquellos que no trabajaron (x?=84,35; DE=32,38), y significativamente en mujeres.  Conclusiones: Los estudiantes de enfermería mostraron ser capaces de hacer frente al estrés en situaciones como la pandemia de COVID-19. No se puede descartar un efecto del trabajador sano. El estrés y ansiedad de los estudiantes de enfermería deben tenerse en cuenta por los tutores de prácticas clínicas y cuando se incorporan al mercado laboral por primera vez.

Restored glyoxylate metabolism after AGXT gene correction and direct reprogramming of primary hyperoxaluria type 1 fibroblasts.

Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder characterized by oxalate overproduction in the liver, resulting in renal damage. It is caused by mutations in the AGXT gene. Combined liver and kidney transplantation is currently the only permanent curative treatment. We combined locus-specific gene correction and hepatic direct cell reprogramming to generate autologous healthy induced hepatocytes (iHeps) from PH1 patient-derived fibroblasts. First, site-specific AGXT corrected cells were obtained by homology directed repair (HDR) assisted by CRISPR-Cas9, following two different strategies: accurate point mutation (c.731T>C) correction or knockin of an enhanced version of AGXT cDNA. Then, iHeps were generated, by overexpression of hepatic transcription factors. Generated AGXT-corrected iHeps showed hepatic gene expression profile and exhibited in vitro reversion of oxalate accumulation compared to non-edited PH1-derived iHeps. This strategy set up a potential alternative cellular source for liver cell replacement therapy and a personalized PH1 in vitro disease model.

Postbiotics of Lacticaseibacillus paracasei CECT 9610 and Lactiplantibacillus plantarum CECT 9608 attenuates store-operated calcium entry and FAK phosphorylation in colorectal cancer cells.

Store-operated Ca2+ entry (SOCE) is a major mechanism for Ca2+ influx in colorectal cancer (CRC) cells. This mechanism, regulated by the filling state of the intracellular Ca2+ stores, is mediated by the endoplasmic reticulum Ca2+ sensors of the stromal interaction molecules (STIM) family [stromal interaction molecule 1 (STIM1) and STIM2] and the Ca2+-release-activated Ca2+ channels constituted by Orai family members, with predominance of calcium release-activated calcium channel protein 1 (Orai1). CRC cells exhibit enhanced SOCE due to remodeling of the expression of the key SOCE molecular components. The enhanced SOCE supports a variety of cancer hallmarks. Here, we show that treatment of the colorectal adenocarcinoma cell lines HT-29 and Caco-2 with inanimate Lacticaseibacillus paracasei (CECT9610) and Lactiplantibacillus plantarum (CECT9608) attenuates SOCE, although no detectable effect is seen on SOCE in normal colon mucosa cells. The effect of Lacticaseibacillus paracasei and Lactiplantibacillus plantarum postbiotics was mediated by downregulation of Orai1 and STIM1, while the expression levels of Orai3 and STIM2 remained unaltered. Treatment of HT-29 and Caco-2 cells with inanimate Lacticaseibacillus paracasei and Lactiplantibacillus plantarum impairs in vitro migration by a mechanism likely involving attenuation of focal adhesion kinase (FAK) tyrosine phosphorylation. Cell treatment with the Orai1 inhibitor synta-66 attenuates SOCE and prevents any further effect of Lacticaseibacillus paracasei and Lactiplantibacillus plantarum postbiotics. Together, our results indicate for the first time that Lacticaseibacillus paracasei and Lactiplantibacillus plantarum postbiotics selectively exert negative effects on Ca2+ influx through SOCE in colorectal adenocarcinoma cell lines, providing evidence for an attractive strategy against CRC.

Estimated population-level impact of pneumococcal conjugate vaccines against all-cause pneumonia mortality among unvaccinated age groups in five Latin American countries.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) provide strong direct protection in children, while limited data are available on their indirect effect on mortality among older age groups. This multi-country study aimed to assess the population-level impact of pediatric PCVs on all-cause pneumonia mortality among ≥5 years of age, and invasive pneumococcal disease (IPD) cases in Chile. METHODS: Demographic and mortality data from Argentina, Brazil, Chile, Colombia, and Mexico were collected considering the ≥ 5-year-old population, from 2000-2019, with 1,795,789 deaths due to all-cause pneumonia. IPD cases in Chile were also evaluated. Time series models were employed to evaluate changes in all-cause pneumonia deaths during the post-vaccination period, with other causes of death used as synthetic controls for unrelated temporal trends. RESULTS: No significant change in death rates due to all-cause pneumonia was detected following PCV introduction among most age groups and countries. The proportion of IPD cases caused by vaccine serotypes decreased from 29% (2012) to 6% (2022) among ≥65 years in Chile. DISCUSSION: While an effect of PCV against pneumonia deaths (a broad clinical definition that may not be specific enough to measure indirect effects) was not detected, evidence of indirect PCV impact was observed among vaccine-type-specific IPD cases.

An Insertion Within SIRPß1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response.

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPß1, a surface receptor that triggers amyloid-ß(Aß) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPß1 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. SIRPß1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPß1 protein isoform landscape compromising its ability to bind oligomeric Aß and its affinity for TYROBP. SIRPß1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aß 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 SIRPß1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPß1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aß. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPß1 structural variant might be considered as a potential modulator of this causative pathway.

Synergistic Activity of Ingulados Bacteria with Antibiotics against Multidrug-Resistant Pathogens.

Antimicrobial resistance is a critical challenge due to the overuse of conventional antimicrobials, and alternative solutions are urgently needed. This study investigates the efficacy of compounds derived from lactic acid bacteria (LAB) fermentation combined with antibiotics against multidrug-resistant pathogens isolated from clinical cases in a hospital setting. Strains of Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecium and faecalis were isolated and selected from blood, respiratory, and urine samples. They were tested against the fermentation products from the Ingulados LAB collection (BAL5, BAL6, BAL8, BAL13, and BAL16), recognized for their antimicrobial efficacy against veterinary pathogens. The activity against multidrug-resistant (MDR) pathogens was evaluated initially, followed by synergy tests using checkerboard assays and subsequent analysis. Bioinformatic assessments and supernatant treatments were performed to characterize the nature of the compounds responsible for the antimicrobial activity. Notably, BAL16 exhibited significant growth inhibition against multidrug-resistant E. faecium. Synergy tests highlighted its combined activity with tetracycline through FICI and surface analysis and bioinformatic analysis unveiled the protein fraction containing bacteriocins as the underlying mechanism. This study highlights BAL16 fermentation products potential as valuable antimicrobial agents against MDR E. faecium infections, attributed to bacteriocins. Further in-depth studies are necessary for complete bacteriocin characterization.

Plasma Phosphorylated Tau 231 Increases at One-Year Intervals in Cognitively Unimpaired Subjects.

Background: Plasma biomarkers of Alzheimer's disease (AD) constitute a non-invasive tool for diagnosing and classifying subjects. They change even in preclinical stages, but it is necessary to understand their properties so they can be helpful in a clinical context. Objective: With this work we want to study the evolution of p-tau231 plasma levels in the preclinical stages of AD and its relationship with both cognitive and imaging parameters. Methods: We evaluated plasma phosphorylated (p)-tau231 levels in 146 cognitively unimpaired subjects in sequential visits. We performed a Linear Mixed-effects Model to analyze their rate of change. We also correlated their baseline levels with cognitive tests and structural and functional image values. ATN status was defined based on cerebrospinal fluid biomarkers. Results: Plasma p-tau231 showed a significant rate of change over time. It correlated negatively with memory tests only in amyloid-positive subjects. No significant correlations were found with any imaging measures. Conclusions: Increases in plasma p-tau231 can be detected at one-year intervals in cognitively healthy subjects. It could constitute a sensitive marker for detecting early signs of neuronal network impairment by amyloid.