Inflammation-Induced Coagulopathy Substantially Differs Between COVID-19 and Septic Shock: A Prospective Observational Study

Critical COVID-19, like septic shock, is related to a dysregulated systemic inflammatory reaction and is associated with a high incidence of thrombosis and microthrombosis. Improving the understanding of the underlying pathophysiology of critical COVID-19 could help in finding new therapeutic targets already explored in the treatment of septic shock. The current study prospectively compared 48 patients with septic shock and 22 patients with critical COVID-19 regarding their clinical characteristics and outcomes, as well as key plasmatic soluble biomarkers of inflammation, coagulation, endothelial activation, platelet activation, and NETosis. Forty-eight patients with matched age, gender, and co-morbidities were used as controls. Critical COVID-19 patients exhibited less organ failure but a prolonged ICU length-of-stay due to a prolonged respiratory failure. Inflammatory reaction of critical COVID-19 was distinguished by very high levels of interleukin (IL)-1β and T lymphocyte activation (including IL-7 and CD40L), whereas septic shock displays higher levels of IL-6, IL-8, and a more significant elevation of myeloid response biomarkers, including Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) and IL-1ra. Subsequent inflammation-induced coagulopathy of COVID-19 also differed from sepsis-induced coagulopathy (SIC) and was characterized by a marked increase in soluble tissue factor (TF) but less platelets, antithrombin, and fibrinogen consumption, and less fibrinolysis alteration. In conclusion, COVID-19 inflammation-induced coagulopathy substantially differs from SIC. Modulating TF release and activity should be evaluated in critical COVID-19 patients.

RNA profiles reveal signatures of future health and disease in pregnancy

Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden1. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method2. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.

THE UNDERLYING PATHOPHYSIOLOGY AND CLINICAL APPEARANCE OF LSS, AND THE AVAILABLE DIAGNOSTIC AND THERAPEUTIC OPTIONS

The term lumbar spinal stenosis (LSS) refers to the narrowing of the spinal canal due to anatomical reasons, and it is linked to a variety of clinical symptoms.The onset of stenosis LSS can be unilateral or bilateral, monosegmental or multisegmental. The stenosis can be characterized as central, lateral, or foraminal anatomically.Neurogenic claudication is the most prevalent symptom of LSS, which is defined as limping or cramping lumbar pain that spreads into the legs primarily during walking.Typical patient symptoms include unilateral or bilateral (exertional) back and leg discomfort that develops over months, if not years.As people live longer and seek a better quality of life, as well as increased knowledge of the condition and the availability of improved imaging techniques, the number of people diagnosed with degenerative LSS has increased.

Cerebral Venous Sinus Thrombosis due to Thrombosis with Thrombocytopenia Syndrome Following Ad26.COV2.S: A First Real-World Case Report of a Male Subject

Thrombosis with Thrombocytopenia Syndrome (TTS) or Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT) had been reported in patients receiving the Ad26.COV2.S vaccination (Johnson & Johnson [J&J]/Janssen) vaccine. They frequently presented with cerebral venous sinus thrombosis (CVST), but venous or arterial thrombosis at other locations can be present. The majority of those affected are younger adult females. Therefore, after a brief pause from April 13–23, 2021, the Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) recommended caution in using this vaccine in females under 50 years. Based on the reported 28 cases of TTS after this vaccination (data till April 21, 2021) by CDC, 22 were females (78%), and 6 were male. None of those males had CVST but had thrombosis at other locations. We report the first case of a young male with TTS and CVST following Ad26.COV2.S vaccine presented with severe headache and diagnosed with acute right transverse and sigmoid cerebral venous sinus thrombosis, multiple right-sided pulmonary emboli, and right hepatic vein thrombosis. He was treated with parenteral anticoagulation with argatroban and intravenous immune globulin with the improvement of his symptoms. A heparin-induced thrombocytopenia with thrombosis (HITT) like syndrome caused by the genesis of a platelet-activating autoantibody against platelet factor 4 (PF4) triggered by adenoviral vector-based COVID-19 vaccinations is understood to be the underlying pathophysiology. TTS with CVST should be considered when patients present with headaches, stroke-like neurological symptoms, thrombocytopenia, and symptom onset 6–15 days after Ad26.COV2.S vaccination.

Endometriosis related sex steroid hormones, hypothalamic pituitary gonadal axis hormones and related animal modeling: A comprehensive review of published articles and endometriosis induction methods from 2010 to 2021 with scoring based approach

Endometriosis is an enigmatic gynecological disease initiated by the ectopic growth of endometrial tissue and causes critical symptoms such as chronic pelvic pain, cyclic menstrual pain, subfertility or infertility. Considering extensive investigations for explaining the underlying pathophysiology of endometriosis, origin and distinctive processes which lead to endometritic state are not completely understood. In this comprehensive review, studies published from 2010 to 2021 are reviewed in order to provide a bright insight through the applications of translational animal models and endometriosis induction methods for evaluation of endometriosis pathogenesis and treatment. We provided method based inclusion criteria and reviewed all hormone-based studies with concentration on animal models. Additionally, studies with novel induction methods and approaches are categorized separately and analyzed by a novel scoring table for suitability of further investigations. Eventually, our scoring system suggested that the best-evaluated animal model for hormone related endometriosis studies is an “unopposed estrogenicity baboon model of endometriosis”.

Emerging Roles of Non-Coding RNA in Neuronal Function and Dysfunction

Advancements in RNA sequencing technologies in recent years have contributed greatly to our understanding of the transcriptome and the now widely recognized multifaceted functions of RNA. The discovery and functional analysis of an increasing number of novel small non-coding RNAs (ncRNAs) has highlighted their importance as critical regulators of gene expression and brain function. In particular, two diverse classes of ncRNAs, microRNAs (miRNAs) and tRNA-derived small RNAs (tsRNAs), are especially abundant in the nervous system and play roles in regulation of gene expression and protein translation, cellular stress responses and complex underlying pathophysiology of neurological diseases. This chapter will discuss the most recent findings highlighting the dysregulation, functions and regulatory roles of ncRNAs in the pathophysiological mechanisms of neurological disorders and their relevance as novel biomarkers of injury and therapeutic agents.

Association of circulating let-7b-5p with major depressive disorder: a nested case-control study

Background Major depressive disorder (MDD) is one of the most common psychiatric disorders and is a great disease burden. However, its underlying pathophysiology and aetiology remain poorly understood. Available evidence suggests that circulating microRNAs (miRNAs) are associated with MDD, but it is still unknown whether miRNAs can predict subsequent incident MDD. Methods In this nested case-control study, a total of 104 individuals, who were free of MDD at baseline, from the Women’s Health in Lund Area (WHILA) cohort were included. Among them, 52 individuals developed MDD (cases) during the 5 years follow-up and 52 individuals did not develop MDD (controls). Plasma expression levels of miR-17-5p, miR-134-5p, miR-144-5p, let-7b-5p and let-7c-5p at baseline were assessed using qRT-PCR. Logistic regression was used to estimate the odds of developing MDD among individuals with different levels of miRNA expression. Results Plasma expression levels of let-7b-5p were significantly lower (p = 0.02) at baseline in cases compared to controls. After adjustment for age and BMI, let-7b-5p was negatively associated with odds for developing MDD (OR = 0.33, p = 0.03, 95% CI = 0.12–0.91). Moreover, let-7b-5p expression levels showed a trend over time with larger differences between cases and controls for the earlier cases (MDD diagnosis <2 years from baseline) than MDD cases developed later (MDD diagnosis 2–5 years from baseline). Conclusions These findings show that lower plasma levels of let-7b-5p are associated with a higher future risk of MDD. Results need to be validated in a large cohort to examine its potential as a peripheral biomarker for MDD.

Infarct Progression in the Early and Late Phases of Acute Ischemic Stroke

Purpose of ReviewTo explore factors associated with infarct progression in the early and late phase of acute ischemic stroke in patients undergoing endovascular therapy.Recent FindingsFollowing ischemic stroke, brain injury can progress at a variable rate, at the expense of “penumbral tissue,” which is the ischemic tissue at risk of infarction. Despite dramatic advances in endovascular stroke therapies with early revascularization in more than 80% of cases, nearly half of patients do not achieve functional independence despite successful recanalization. This is largely attributed to the irreversible damage that is already extensive at the time of revascularization.SummaryThe underlying pathophysiology and determinants of the core infarct progression are complex and multifactorial, depending on a balance between brain energy consumption and collateral perfusion supply. It is crucial to develop creative and individualized theranostics to predict infarct progression and to “freeze” the tissue at risk prior to recanalization.

Oligodendrocyte Development and Implication in Perinatal White Matter Injury

Perinatal white matter injury (WMI) is the most common brain injury in premature infants and can lead to life-long neurological deficits such as cerebral palsy. Preterm birth is typically accompanied by inflammation and hypoxic-ischemic events. Such perinatal insults negatively impact maturation of oligodendrocytes (OLs) and cause myelination failure. At present, no treatment options are clinically available to prevent or cure WMI. Given that arrested OL maturation plays a central role in the etiology of perinatal WMI, an increased interest has emerged regarding the functional restoration of these cells as potential therapeutic strategy. Cell transplantation and promoting endogenous oligodendrocyte function are two potential options to address this major unmet need. In this review, we highlight the underlying pathophysiology of WMI with a specific focus on OL biology and their implication for the development of new therapeutic targets.

dynaPhenoM: Dynamic Phenotype Modeling from Longitudinal Patient Records Using Machine Learning

Identification of clinically meaningful subphenotypes of disease progression can facilitate better understanding of disease heterogeneity and underlying pathophysiology. We propose a machine learning algorithm, termed dynaPhenoM, to achieve this goal based on longitudinal patient records such as electronic health records (EHR) or insurance claims. Specifically, dynaPhenoM first learns a set of coherent clinical topics from the events across different patient visits within the records along with the topic transition probability matrix, and then employs the time-aware latent class analysis (T-LCA) procedure to characterize each subphenotype as the evolution of these learned topics over time. The patients in the same subphenotype have similar such topic evolution patterns. We demonstrate the effectiveness and robustness of dynaPhenoM on the case of mild cognitive impairment (MCI) to Alzheimer's disease (AD) progression on three patient cohorts, and five informative subphenotypes were identified which suggest the different clinical trajectories for disease progression from MCI to AD.