Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create “onion-like” multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became “hot” within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Systemic inflammation includes a widespread immune response to a harmful stimulus that results in extensive systemic damage. One common example of systemic inflammation is sepsis, which is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Under the pro-inflammatory environment of sepsis, oxidative stress contributes to tissue damage due to dysfunctional microcirculation that progressively causes the failure of multiple organs that ultimately triggers death. To address the underlying inflammatory condition in critically ill patients, progress has been made to assess the beneficial effects of dietary supplements, which include polyphenols, amino acids, fatty acids, vitamins, and minerals that are recognized for their immuno-modulating, anticoagulating, and analgesic properties. Therefore, we aimed to review and discuss the contribution of food-derived supplementation in the regulation of inflammation from gene expression to physiological responses and summarize the precedented potential of current therapeutic approaches during systemic inflammation.

IntroductionGestational hypothyroxinemia (HTX) is a condition that occurs frequently at the beginning of pregnancy, and it correlates with cognitive impairment, autism, and attentional deficit in the offspring. Evidence in animal models suggests that gestational HTX can increase the susceptibility of the offspring to develop strong inflammation in immune-mediated inflammatory diseases. Ulcerative colitis (UC) is a frequent inflammatory bowel disease with unknown causes. Therefore, the intensity of ulcerative colitis-like disorder (UCLD) and the cellular and molecular factors involved in proinflammatory or anti-inflammatory responses were analyzed in the offspring gestated in HTX (HTX-offspring) and compared with the offspring gestated in euthyroidism (Control-offspring).MethodsGestational HTX was induced by the administration of 2-mercapto-1-methylimidazole in drinking water to pregnant mice during E10–E14. The HTX-offspring were induced with UCLD by the acute administration of dextran sodium sulfate (DSS). The score of UCLD symptomatology was registered every day, and colon histopathology, immune cells, and molecular factors involved in the inflammatory or anti-inflammatory response were analyzed on day 6 of DSS treatment.ResultsThe HTX-offspring displayed earlier UCLD pathological symptoms compared with the Control-offspring. After 6 days of DSS treatment, the HTX-offspring almost doubled the score of the Control-offspring. The histopathological analyses of the colon samples showed signs of inflammation at the distal and medial colon for both the HTX-offspring and Control-offspring. However, significantly more inflammatory features were detected in the proximal colon of the HTX-offspring induced with UCLD compared with the Control-offspring induced with UCLD. Significantly reduced mRNA contents encoding for protective molecules like glutamate-cysteine ligase catalytic subunit (GCLC) and mucin-2 (MUC-2) were found in the colon of the HTX-offspring as compared with the Control-offspring. Higher percentages of Th17 lymphocytes were detected in the colon tissues of the HTX-offspring induced or not with UCLD as compared with the Control-offspring.DiscussionGestational HTX accelerates the onset and increases the intensity of UCLD in the offspring. The low expression of MUC-2 and GCLC together with high levels of Th17 Lymphocytes in the colon tissue suggests that the HTX-offspring has molecular and cellular features that favor inflammation and tissue damage. These results are important evidence to be aware of the impact of gestational HTX as a risk factor for UCLD development in offspring.

Abstract BACKGROUND Glioblastoma immunotherapy trials remain limited by heterogeneity and the immunosuppressive tumor microenvironment (TME). To overcome these challenges, we developed a novel cancer immunotherapy that leverages use of mRNA lamellar aggregates (RNA-LPA) encoding for personalized glioblastoma antigens to simultaneously reprogram the GBM TME while inducing tumor specific immunity in the periphery. METHODS In a Phase I trial (PNOC020) with an embedded acceleration titration design (ATD) for patients with newly-diagnosed MGMT unmethylated glioblastoma, we sought to assess whether intravenous administration of RNA-LPAs encoding for pp65 mRNA (tumor associated antigen) mixed with personalized tumor mRNA (extracted and amplified from patient specific biopsies) could activate peripheral immunity while simultaneously reprogramming the GBM TME. All patients received surgical resection with adjuvant chemoradiation followed by escalating doses of RNA-LPA (0.625-1.5 µg/kg). RESULTS We have treated 3 patients on the ATD and one patient on the expanded Phase I trial. In all patients treated to date, RNA-LPAs elicited a rapid response (within hours) characterized by release of cytokines (IL-12, TNF-α, IFN-α), chemokines (CCL2, CCL4, CXCL9-10), increase in plasmacytoid dendritic cells and recruitment of peripheral blood mononuclear cells. Over time there was expansion of antigen specific T cells; T cell receptor (TCR) sequencing pre- and post-infusion demonstrated changes to the most prevalent clonotypes by ~10-20%. In the first subject treated on the expanded phase I trial, we observed significant immunologic response after the fourth vaccine, including 20-fold increase in IFN-γ inducible protein-10. One month after vaccine administration, there was marked increase in the enhancing areas on MRI, which on biopsy demonstrated no viable tumor cells and only reactive gliosis, necrosis, and lymphocytic infiltrates. CONCLUSION RNA-LPAs elicit rapid immune activation in the periphery and reprogram the GBM TME into a proinflammatory milieu as evidenced by tissue confirmed pseudoprogression.

Numerous studies relate the onset and severity of multiple sclerosis (MS) with viral infections. Herpes simplex virus type 1 (HSV-1), which is neurotropic and highly prevalent in the brain of healthy individuals, has been proposed to relate to MS. Here, we review and discuss the reported connections between HSV-1 and MS.

Hemostasis preserves blood fluidity and prevents its loss after vessel injury. The maintenance of blood fluidity requires a delicate balance between pro-coagulant and fibrinolytic status. Endothelial cells (ECs) in the inner face of blood vessels maintain hemostasis through balancing anti-thrombotic and pro-fibrinolytic activities. Dyslipidemias are linked to hemostatic alterations. Thus, it is necessary a better understanding of the underlying mechanisms linking hemostasis with dyslipidemia. Statins are drugs that decrease cholesterol levels in the blood and are the gold standard for treating hyperlipidemias. Statins can be classified into natural and synthetic molecules, approved for the treatment of hypercholesterolemia. The classical mechanism of action of statins is by competitive inhibition of a key enzyme in the synthesis pathway of cholesterol, the HMG-CoA reductase. Statins are frequently administrated by oral ingestion and its interaction with other drugs and food supplements is associated with altered bioavailability. In this review we deeply discuss the actions of statins beyond the control of dyslipidemias, focusing on the actions in thrombotic modulation, vascular and cardiovascular-related diseases, metabolic diseases including metabolic syndrome, diabetes, hyperlipidemia, and hypertension, and chronic diseases such as cancer, chronic obstructive pulmonary disease, and chronic kidney disease. Furthermore, we were prompted to delved deeper in the molecular mechanisms by means statins regulate coagulation acting on liver, platelets, and endothelium. Clinical evidence show that statins are effective regulators of dyslipidemia with a high impact in hemostasis regulation and its deleterious consequences. However, studies are required to elucidate its underlying molecular mechanism and improving their therapeutical actions.

Messenger RNA (mRNA) has emerged as a remarkable tool for COVID-19 prevention but its use for induction of therapeutic cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Herein, we develop a facile approach for substantially enhancing immunogenicity of tumor-derived mRNA in lipid-particle (LP) delivery systems. By using mRNA as a molecular bridge with ultrapure liposomes and foregoing helper lipids, we promote the formation of ‘onion-like’ multi-lamellar RNA-LP aggregates (LPA). Intravenous administration of RNA-LPAs mimics infectious emboli and elicits massive DC/T cell mobilization into lymphoid tissues provoking cancer immunogenicity and mediating rejection of both early and late-stage murine tumor models. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for toll-like receptor engagement, RNA-LPAs stimulate intracellular pathogen recognition receptors (RIG-I) and reprogram the TME thus enabling therapeutic T cell activity. RNA-LPAs were safe in acute/chronic murine GLP toxicology studies and immunologically active in client-owned canines with terminal gliomas. In an early phase first-in-human trial for patients with glioblastoma, we show that RNA-LPAs encoding for tumor-associated antigens elicit rapid induction of pro-inflammatory cytokines, mobilization/activation of monocytes and lymphocytes, and expansion of antigen-specific T cell immunity. These data support the use of RNA-LPAs as novel tools to elicit and sustain immune responses against poorly immunogenic tumors.

Stimulation of a1-adrenergic nervous system is increased during systemic inflammation and other pathological conditions with the consequent adrenergic receptors (ARs) activation. It has been reported that a1-stimulation contributes to coagulation since a1-AR blockers inhibit coagulation and its organic consequences. Also, coagulation induced by a1-AR stimulation can be greatly decreased using a1-AR blockers. In health, endothelial cells (ECs) perform anticoagulant actions at cellular and molecular level. However, during inflammation, ECs turn dysfunctional promoting a procoagulant state. Endothelium-dependent coagulation progresses at cellular and molecular levels, promoting endothelial acquisition of procoagulant properties to potentiate coagulation by means of prothrombotic and antifibrinolytic proteins expression increase in ECs releasing them to circulation, the thrombus formation is strengthened. Calcium signaling is a main feature of coagulation. Inhibition of ion channels involved in Ca2+ entry severely decreases coagulation. The transient receptor potential canonical 6 (TRPC6) is a non-selective Ca2+-permeable ion channel. TRPC6 activity is induced by diacylglycerol, suggesting that is regulated by a1-ARs. Furthermore, a1-ARs stimulation elicits a TRPC-like current in rat mesenteric artery smooth muscle and mesangial cells. However, whether TRPC6 could promote an ECs-mediated platelet adhesion induced by a1-adrenergic stimulation is currently not known. Therefore, the aim of this study was to examine if the TRPC6 calcium channel mediates platelet adhesion induced by a1-adrenergic stimulation. Our results suggest that platelet adhesion to ECs is enhanced by the a1-adrenergic stimulation evoked by phenylephrine mediated by TRPC6 activity. We conclude that TRPC6 is a molecular determinant in platelet adhesion to ECs with implications in systemic inflammatory diseases treatment.

Sepsis is a life-threatening condition and a significant cause of preventable morbidity and mortality globally. Among the leading causative agents of sepsis are bacterial pathogens Escherichia coli , Klebsiella pneumoniae , Staphylococcus aureus , Pseudomonas aeruginosa , and Streptococcus pyogenes , along with fungal pathogens of the Candida species. Here, we focus on evidence from human studies but also include in vitro and in vivo cellular and molecular evidence, exploring how bacterial and fungal pathogens are associated with bloodstream infection and sepsis. This review presents a narrative update on pathogen epidemiology, virulence factors, host factors of susceptibility, mechanisms of immunomodulation, current therapies, antibiotic resistance, and opportunities for diagnosis, prognosis, and therapeutics, through the perspective of bloodstream infection and sepsis. A list of curated novel host and pathogen factors, diagnostic and prognostic markers, and potential therapeutical targets to tackle sepsis from the research laboratory is presented. Further, we discuss the complex nature of sepsis depending on the sepsis-inducing pathogen and host susceptibility, the more common strains associated with severe pathology and how these aspects may impact in the management of the clinical presentation of sepsis.

Sepsis is an uncontrolled inflammatory response against a systemic infection that results in elevated mortality, mainly induced by bacterial products known as endotoxins, producing endotoxemia. Disseminated intravascular coagulation (DIC) is frequently observed in septic patients and is associated with organ failure and death. Sepsis activates endothelial cells (ECs), promoting a prothrombotic phenotype contributing to DIC. Ion channel-mediated calcium permeability participates in coagulation. The transient reception potential melastatin 7 (TRPM7) non-selective divalent cation channel that also contains an α-kinase domain, which is permeable to divalent cations including Ca2+, regulates endotoxin-stimulated calcium permeability in ECs and is associated with increased mortality in septic patients. However, whether endothelial TRPM7 mediates endotoxemia-induced coagulation is not known. Therefore, our aim was to examine if TRPM7 mediates coagulation during endotoxemia. The results showed that TRPM7 regulated endotoxin-induced platelet and neutrophil adhesion to ECs, dependent on the TRPM7 ion channel activity and by the α-kinase function. Endotoxic animals showed that TRPM7 mediated neutrophil rolling on blood vessels and intravascular coagulation. TRPM7 mediated the increased expression of the adhesion proteins, von Willebrand factor (vWF), intercellular adhesion molecule 1 (ICAM-1), and P-selectin, which were also mediated by the TRPM7 α-kinase function. Notably, endotoxin-induced expression of vWF, ICAM-1 and P-selectin were required for endotoxin-induced platelet and neutrophil adhesion to ECs. Endotoxemic rats showed increased endothelial TRPM7 expression associated with a procoagulant phenotype, liver and kidney dysfunction, increased death events and an increased relative risk of death. Interestingly, circulating ECs (CECs) from septic shock patients (SSPs) showed increased TRPM7 expression associated with increased DIC scores and decreased survival times. Additionally, SSPs with a high expression of TRPM7 in CECs showed increased mortality and relative risk of death. Notably, CECs from SSPs showed significant results from the AUROC analyses for predicting mortality in SSPs that were better than the Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scores. Our study demonstrates that sepsis-induced DIC is mediated by TRPM7 in ECs. TRPM7 ion channel activity and α-kinase function are required by DIC-mediated sepsis-induced organ dysfunction and its expression are associated with increased mortality during sepsis. TRPM7 appears as a new prognostic biomarker to predict mortality associated to DIC in SSPs, and as a novel target for drug development against DIC during infectious inflammatory diseases.

The immune system is the first defense against potentially dangerous chemicals, infections, and damaged cells. Interactions between immune cells and inflammatory mediators increase the coordinated activation of cross-talking signaling pathways, resulting in an acute response necessary to restore homeostasis but potentially detrimental if uncontrolled and prolonged. Plastic production exceeds million tons per year, becoming a global concern due to the stability of its constituent polymers, low density, which allows them to spread easily, and small size, which prevents proper removal by wastewater treatment plants, promoting environmental accumulation and increasing health threats. The interaction between plastic particles and the immune system is still being investigated, owing to growing evidence of increased risk not only for dietary intake due to its presence in food packaging, drinking water, and even fruits and vegetables, but also to emerging evidence of new intake pathways such as respiratory and cutaneous. We discuss in depth the impact of small plastic particles on the immune response across the body, with a focus on the nervous system and peripheral organs and tissues such as the gastrointestinal, respiratory, lymphatic, cardiovascular, and reproductive systems, as well as the involvement in increased susceptibility to worsening concomitant diseases and future perspectives in the exploration of potential therapeutics.

Catecholamine stimulation over adrenergic receptors results in a state of hypercoagulability. Chronic stress involves the release and increase in circulation of catecholamines and other stress related hormones. Numerous observational studies in human have related stressful scenarios to several coagulation variables, but controlled stimulation with agonists or antagonists to adrenergic receptors are scarce. This systematic review is aimed at presenting an updated appraisal of the effect of adrenergic receptor modulation on variables related to human hemostasis by systematically reviewing the effect of adrenergic receptor-targeting drugs on scale variables related to hemostasis. By searching 3 databases for articles published between January 1st 2011 and February 16th, 2022 reporting effects on coagulation parameters from stimulation with α- or β-adrenergic receptor targeting drugs in humans regardless of baseline condition, excluding records different from original research and those not addressing the main aim of this systematic review. Risk of bias assessed using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). Tables describing a pro-thrombotic anti-fibrinolytic state induced after β-adrenergic receptor agonist stimulation and the opposite after α1-, β-adrenergic receptor antagonist stimulation were synthesized from 4 eligible records by comparing hemostasis-related variables to their baseline. Notwithstanding this low number of records, experimental interventions included were sound and mostly unbiased, results were coherent, and outcomes were biologically plausible. In summary, this systematic review provides a critical systematic assessment and an updated elaboration, and its shortcomings highlight the need for further investigation in the field of hematology.

Dexmedetomidine is an adrenergic receptor agonist that has been regarded as neuroprotective in several studies without an objective measure to it. Thus, the aim of this meta-analysis was to analyze and quantify the current evidence for the neuroprotective effects of dexmedetomidine in animals. The search was performed by querying the National Library of Medicine. Studies were included based on their language, significancy of their results, and complete availability of data on animal characteristics and interventions. Risk of bias was assessed using SYRCLE's risk of bias tool and certainty was assessed using the ARRIVE Guidelines 2.0. Synthesis was performed by calculating pooled standardized mean difference and presented in forest plots and tables. The number of eligible records included per outcome is the following: 22 for IL-1β, 13 for IL-6, 19 for apoptosis, 7 for oxidative stress, 7 for Escape Latency, and 4 for Platform Crossings. At the cellular level, dexmedetomidine was found protective against production of IL-1β (standardized mean difference (SMD) =  - 4.3 [- 4.8; - 3.7]) and IL-6 (SMD =  - 5.6 [- 6.7; - 4.6]), apoptosis (measured through TUNEL, SMD =  - 6.0 [- 6.8; - 4.6]), and oxidative stress (measured as MDA production, SMD =  - 2.0 [- 2.4; - 1.4]) exclusively in the central nervous system. At the organism level, dexmedetomidine improved behavioral outcomes measuring escape latency (SMD = - 2.4 [- 3.3; - 1.6]) and number of platform crossings (SMD = 9.1 [- 6.8; - 11.5]). No eligible study had high risk of bias and certainty was satisfactory for reproducibility in all cases. This meta-analysis highlights the complexity of adrenergic stimulation and sheds light into the mechanisms potentiated by dexmedetomidine, which could be exploited for improving current neuroprotective formulations.

Background There are no evidence-based resources guiding the perioperative management of patients with moyamoya syndrome who are undergoing revascularization surgery. We investigated practice patterns among a transdisciplinary group aiming at identifying possible heterogeneity of practices on key components of care that warrant prospective studies.Methods We disseminated a web-based Qualtrics survey internationally to physician members of the following: Neurocritical Care Society, Society of Critical Care Medicine, American Academy of Neurology, Society for Neuroscience in Anesthesiology and Critical Care, American Association of Neurological Surgeons, Asian Society of Neuroanesthesia and Critical Care, Indian Society of Neuroanesthesia and Critical Care, Japanese Society for Neuroscience in Anesthesiology and Critical Care, and World Federation of Neurosurgical Societies. The survey contained questions on demographics and aspects of preoperative, intraoperative, and postoperative care.Results Among the 175 physicians who managed at least 1 adult (aged >= 18 years) undergoing moyamoya revascularization in the preceding 24 months, 18 countries (United States, 84.6%) and 4 disciplines (anesthesiology [44.7%, 76/170], critical care medicine [30.6%, 52/170], neurology [32.4%, 55/170], and neurosurgery [15.3%, 26/170]) were represented. Anesthesiologists preferred total intravenous over volatile anesthesia (56.3%, 40/71 versus 42.3%, 30/71) and arterial line zeroing at the circle of Willis/tragus over the phlebostatic axis/right atrium intraoperatively (84.3%, 59/70 versus 11.4%, 8/70) and postoperatively (68.9%, 42/61 versus 24.6%, 15/61). Intraoperative blood pressure goals were primarily targeted to baseline blood pressure (34.8%, 48/138), whereas postoperative blood pressure goals were mainly determined by neurosurgeon preference (48.9%, 65/133). The predominant hemodynamic target was mean arterial pressure intraoperatively (50.4%, 68/135) and systolic blood pressure postoperatively (48.5%, 63/130). Crystalloid infusion was the preferred method to achieve perioperative hemodynamic goals (median rank, 1.0), followed by colloid infusion (median rank, 2.0) and phenylephrine (median rank, 2.0); however, colloid infusion and phenylephrine were considered contraindicated by 18.2% (10/55) and 20.0% (11/55), respectively.Conclusions We demonstrate perioperative practice heterogeneity for moyamoya syndrome revascularization among physicians for both methods and targets of hemodynamic management, constituting equipoise for prospective studies targeting optimal management strategies.

Background: Strong social distancing measures were quickly implemented in Chile during the SARS-CoV-2 outbreak. One of the aims of non-pharmaceutical interventions (NPI) mandates was to decrease overcrowding, thus is usually measured as mobility changes. Methods: we gather data from national health statistics for pediatric emergency (PED) visits for acute respiratory infection (ARI) in children younger than 15. We defined a historical cohort, including data from 2016 to 2019, and compared them with 2020 and 2021 pandemic years. Also, Chile's national mobility reports from the online google database were downloaded. We tested the correlation between changes in mobility and relative reduction in PED-ARI by Spearman's Rank Test. Results: Historical data showed a mean of 46863, (SD 3071) PED-ARI weekly visits with a high seasonal variation, with two peaks in weeks 20 and 28 and weeks 32 to 36. This transient drop was temporally associated with the mid-winter 2-week holiday of schools. The usual PED visits peaks did not occur in 2020 and 2021. Mobility declined from week 9, reaching lower than historical data from week 12 and a minimum of 43% in week 15 of 2020. The correlation between mobility and PED-ARI visits showed a strong monotonic relationship (quadratic) with a Spearman's rho of 0.80 (95% CI 0.75 to 0.86). Conclusion: NPI resulting in a decrease in mobility should be considered a robust public health measure to relieve the winter's collapse of the national health system, decreasing morbimortality in children due to PED-ARI.

This article seeks to analyze how social innovation in Latin America has evolved as our societal problems have changed in nature, depth, and scale. Today, social innovation in Latin America reflects the current social territorial transformation at the local level. As a response to the climate emergency and the political, economic, humanitarian, and health crisis, the region has made progress in articulating its innovation ecosystem and equipping actors with the essential knowledge to create a common understanding of our problems. Despite that, the challenge of making significant inroads in addressing the region’s pressing socio-environmental problems is greater. In the coming years, the acceleration of our understanding of the processes and impact we generate will be more crucial than ever before. On the one hand, this article offers a historical analysis of social innovation in the region and of its ecosystem of actors. On the other hand, it analyzes several recent experiences that illustrate three core principles that are emerging in response to the socio-environmental crisis. These core principles include interdependence, co-creation, and democratization of the change agenda. The analysis contributes to a theoretical-practical reflection in the current global context and points to a paradigm shift in social innovation. This, in turn, gives us a new perspective through which we can analyze future changes and proposals that are emerging from local innovation ecosystems towards creating a sustainable future for the region.

We investigated practice patterns among a transdisciplinary group aiming at identifying possible heterogeneity of practices on key components of care that warrant prospective studies.

OBJECTIVES:. To determine the performance of the Modified Early Warning Score and Modified Early Warning Score-Sepsis Recognition Score to predict sepsis, morbidity, and mortality in neurocritically ill patients. DESIGN:. Retrospective cohort study. SETTING:. Single tertiary-care academic medical center. PATIENTS:. Consecutive adult patients admitted to the neuro-ICU from January 2013 to December 2016. INTERVENTIONS:. Observational study. MEASUREMENTS AND MAIN RESULTS:. Baseline and clinical characteristics, infections/sepsis, neurologic worsening, and mortality were abstracted. Primary outcomes included new infection/sepsis, escalation of care, and mortality. Patients with Modified Early Warning Score-Sepsis Recognition Score/Modified Early Warning Score greater than or equal to 5 were compared with those with scores less than 5. 5. Of 7,286 patients, Of 7,286 patients, 1,120 had Modified Early Warning Score-Sepsis Recognition Score greater than or equal to 5. Of those, mean age was 58.9 years; 50.2% were male. Inhospitality mortality was 22.1% for patients (248/1,120) with Modified Early Warning Score-Sepsis Recognition Score greater than or equal to 5, compared with 6.1% (379/6,166) with Modified Early Warning Score-Sepsis Recognition Score less than 5. Sepsis was present in 5.6% (345/6,166) when Modified Early Warning Score-Sepsis Recognition Score less than 5 versus 14.3% (160/1,120) when greater than or equal to 5, and Modified Early Warning Score elevation led to a new sepsis diagnosis in 5.5% (62/1,120). Three-hundred forty-three patients (30.6%) had neurologic worsening at the time of Modified Early Warning Score-Sepsis Recognition Score elevation. Utilizing the original Modified Early Warning Score, results were similar, with less score thresholds met (836/7,286) and slightly weaker associations. CONCLUSIONS:. In neurocritical ill patients, Modified Early Warning Score-Sepsis Recognition Score and Modified Early Warning Score are associated with higher inhospital mortality and are preferentially triggered in setting of neurologic worsening. They are less reliable in identifying new infection or sepsis in this patient population. Population-specific adjustment of early warning scores may be necessary for the neurocritically ill patient population.

In recent years, the vascular endothelium has gained attention as a key player in the initiation and development of pregnancy disorders. Endothelium acts as an endocrine organ that preserves the homeostatic balance by responding to changes in metabolic status. However, in metabolic disorders, endothelial cells adopt a dysfunctional function, losing their normal responsiveness. During pregnancy, several metabolic changes occur, in which endothelial function decisively participates. Similarly, when pregnancy metabolic disorders occur, endothelial dysfunction plays a key role in pathogenesis. This review outlines the main findings regarding endothelial dysfunction in three main metabolic pathological conditions observed during pregnancy: gestational diabetes, hypertensive disorders, and obesity and hyperlipidemia. Organ, histological and cellular characteristics were thoroughly described. Also, we focused in discussing the underlying molecular mechanisms involved in the cellular signaling pathways that mediate responses in these pathological conditions.