The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity.

The thrombolytic protease tissue plasminogen activator (tPA) is expressed in the CNS, where it regulates diverse functions including neuronal plasticity, neuroinflammation, and blood-brain-barrier integrity. However, its role in different brain regions such as the substantia nigra (SN) is largely unexplored. In this study, we characterize tPA expression, activity, and localization in the SN using a combination of retrograde tracing and β-galactosidase tPA reporter mice.

PAI-1 Interaction with Sortilin Related Receptor-1 is Required for Lung Fibrosis.

Plasminogen activator inhibitor-1 (PAI-1) has been previously shown to promote lung fibrosis via a mechanism that requires an intact vitronectin (VTN) binding site. In the present study, employing two distinct murine fibrosis models, we find that VTN is not required for PAI-1 to drive lung scarring. This result suggested the existence of a previously unrecognized profibrotic PAI-1-protein interaction involving the VTN-binding site for PAI-1.

Magnetically powered microwheel thrombolysis of occlusive thrombi in zebrafish.

Tissue plasminogen activator (tPA) is the only FDA-approved treatment for ischemic stroke but carries significant risks, including major hemorrhage. Additional options are needed, especially in small vessel thrombi which account for ~25% of ischemic strokes. We have previously shown that tPA-functionalized colloidal microparticles can be assembled into microwheels (µwheels) and manipulated under the control of applied magnetic fields to enable rapid thrombolysis of fibrin gels in microfluidic models of thrombosis.

The painful truth of waiting for hip and knee arthroplasty in Northern Ireland.

Aims: The aim of this study was to report health-related quality of life (HRQoL) and joint-specific function in patients waiting for total hip or knee arthroplasty surgery (THA or TKA) in Northern Ireland, compared to published literature and a matched normal population. Secondary aims were to report emergency department (ED) and out-of-hours general practitioner (OOH GP) visits, new prescriptions of strong opioids, and new prescriptions of antidepressants while waiting.

Methods: This was a cohort study of 991 patients on the waiting list for arthroplasty in a single Northern Ireland NHS trust: 497 on the waiting list for ≤ three months; and 494 waiting ≥ three years.

Opposing effects of β-2 and β-1 adrenergic receptor signaling on neuroinflammation and dopaminergic neuron survival in α-synuclein-mediated neurotoxicity.

Background: Noradrenergic neurons in the locus coeruleus (LC) are the primary source of norepinephrine (NE) in the brain and degeneration of these neurons is reported in the early stages of Parkinson's disease (PD), even prior to dopaminergic neuron degeneration in the substantia nigra (SN), which is a hallmark of PD pathology. NE depletion is generally associated with increased PD pathology in neurotoxin-based PD models. The effect of NE depletion in other models of PD-like α-synuclein-based models is largely unexplored.

Index60 Is Superior to HbA1c for Identifying Individuals at High Risk for Type 1 Diabetes.

Context: HbA1c from ≥ 5.7% to < 6.5% (39-46 mmol/mol) indicates prediabetes according to American Diabetes Association guidelines, yet its identification of prediabetes specific for type 1 diabetes has not been assessed.

Oral Glucose Tolerance Test Measures of First-phase Insulin Response and Their Predictive Ability for Type 1 Diabetes.

Context: Decreased first-phase insulin response (FPIR) during intravenous glucose tolerance testing (IVGTT) is an early indicator of β-cell dysfunction and predictor of type 1 diabetes (T1D).

Objective: Assess whether oral glucose tolerance test (OGTT) measures could serve as FPIR alternatives in their ability to predict T1D in autoantibody positive (Aab+) subjects.

Design: OGTT and IVGTT were performed within 30 days of each other.

Compartmentalized Actions of the Plasminogen Activator Inhibitors, PAI-1 and Nsp, in Ischemic Stroke.

Tissue plasminogen activator (tPA) is a multifunctional protease. In blood tPA is best understood for its role in fibrinolysis, whereas in the brain tPA is reported to regulate blood-brain barrier (BBB) function and to promote neurodegeneration. Thrombolytic tPA is used for the treatment of ischemic stroke.

HOMA2-B enhances assessment of type 1 diabetes risk among TrialNet Pathway to Prevention participants.

Aims/hypothesis: Methods to identify individuals at highest risk for type 1 diabetes are essential for the successful implementation of disease-modifying interventions. Simple metabolic measures are needed to help stratify autoantibody-positive (Aab+) individuals who are at risk of developing type 1 diabetes. HOMA2-B is a validated mathematical tool commonly used to estimate beta cell function in type 2 diabetes using fasting glucose and insulin.

Genetic Variants Do Not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes.

Objective: We aimed to test whether type 2 diabetes (T2D)-associated genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D).

Research Design And Methods: We studied autoantibody-positive TrialNet Pathway to Prevention study participants ( = 1,061) (mean age 16.3 years) with single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion.

Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients.

Patients with coronavirus disease-19 (COVID-19) are at high risk for thrombotic arterial and venous occlusions. However, bleeding complications have also been observed in some patients. Understanding the balance between coagulation and fibrinolysis will help inform optimal approaches to thrombosis prophylaxis and potential utility of fibrinolytic-targeted therapies.

Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients.

Patients with coronavirus disease-19 ( ) are at high risk for thrombotic arterial and venous occlusions. However, bleeding complications have also been observed in some patients. Understanding the balance between coagulation and fibrinolysis will help inform optimal approaches to thrombosis prophylaxis and potential utility of fibrinolytic-targeted therapies.

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.

Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.

Design, Setting, And Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin.

One-Hour Oral Glucose Tolerance Tests for the Prediction and Diagnostic Surveillance of Type 1 Diabetes.

Context: Once islet autoantibody-positive individuals are identified, predicting which individuals are at highest risk for type 1 diabetes (T1D) is important. A metabolic risk score derived from 2-hour oral glucose tolerance test (OGTT) data, the Diabetes Prevention Trial-Type 1 risk score (DPTRS), can accurately predict T1D. However, 2-hour OGTTs are time-consuming and costly.

Obstructive Lung Disease and Obstructive Sleep Apnea (OLDOSA) cohort study: 10-year assessment.

Study Objectives: Asthma, chronic obstructive pulmonary disease (COPD), and obstructive sleep apnea (OSA) are very prevalent disorders. Their coexistence in the same individual has an unclear effect on natural history and long-term outcomes.

Methods: The OLDOSA (Obstructive Lung Disease and Obstructive Sleep Apnea) cohort enrolled 4,980 veterans with an acute hospitalization and in whom asthma, COPD, OSA, overlapping conditions, or none of these disorders at baseline had been diagnosed.

Outcomes of conservatively managed complex acetabular fractures in the frail and elderly one year post injury.

Background: Acetabular fractures in the elderly are associated with high levels of morbidity and mortality. Despite advances in operative techniques, there remains a cohort of elderly, extremely frail patients with comminuted fractures who are considered unfit for surgery and are treated conservatively. We aim to assess mortality, mobility and radiological outcomes one-year post injury in this challenging cohort.

Antibiotic Prophylaxis Protocols and Surgical Site Infection Rates in Trauma Surgery: A Prospective Regional Study of 26,849 Procedures.

Introduction: Prophylactic antibiotics have been shown to reduce the rate of surgical site infection (SSI) 1, however there is little evidence supporting the effectiveness of one antibiotic over another. We have studied SSI rates and antibiotic prophylaxis protocols in Northern Ireland trauma surgery over a 10-year period to Identify the most effective antibiotic protocol associated with lowest rate of SSI.

Method: Antibiotic prophylaxis protocols from 2004-2014 were sought from each of the region's 4 trauma hospitals and their dates of introduction recorded.

Low-Dose Anti-Thymocyte Globulin Preserves C-Peptide, Reduces HbA, and Increases Regulatory to Conventional T-Cell Ratios in New-Onset Type 1 Diabetes: Two-Year Clinical Trial Data.

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA for 1 year in new-onset type 1 diabetes. Subjects ( = 89) were randomized to ) ATG and pegylated granulocyte colony-stimulating factor (GCSF), ) ATG alone, or ) placebo.

CpaA Is a Glycan-Specific Adamalysin-like Protease Secreted by Acinetobacter baumannii That Inactivates Coagulation Factor XII.

Antibiotic-resistant is increasingly recognized as a cause of difficult-to-treat nosocomial infections, including pneumonia, wound infections, and bacteremia. Previous studies have demonstrated that the metalloprotease CpaA contributes to virulence and prolongs clotting time when added to human plasma as measured by the activated partial thromboplastin time (aPTT) assay. Here, we show that CpaA interferes with the intrinsic coagulation pathway, also called the contact activation system, in human as well as murine plasma, but has no discernible effect on the extrinsic pathway.

Dual-reporter high-throughput screen for small-molecule inhibitors of plasminogen activator inhibitor type-1 yields a clinical lead candidate.

Plasminogen activator inhibitor type-1 (PAI-1) is a ine rotease hibitor (serpin) implicated in numerous pathological processes, including coronary heart disease, arterial and venous thrombosis, and chronic fibrotic diseases. These associations have made PAI-1 an attractive pharmaceutical target. However, the complexity of the serpin inhibitory mechanism, the inherent metastability of serpins, and the high-affinity association of PAI-1 with vitronectin have made it difficult to identify pharmacologically effective small-molecule inhibitors.

Does red blood cell irradiation and/or anemia trigger intestinal injury in premature infants with birth weight ≤ 1250 g? An observational birth cohort study.

Background: Necrotizing enterocolitis (NEC) is a leading cause of neonatal morbidity and mortality in premature infants. To date, no effective biomarkers exist to predict which premature infants will develop NEC, limiting targeted prevention strategies. Multiple observational studies have reported an association between the exposure to red blood cell (RBC) transfusion and/or anemia and the subsequent development of NEC; however, the underlying physiologic mechanisms of how these factors are independently associated with NEC remain unknown.

Magnetic resonance imaging safety in nonconditional pacemaker and defibrillator recipients: A meta-analysis and systematic review.

Background: Recommendations regarding performance of magnetic resonance imaging (MRI) in non-MRI conditional pacemaker and defibrillator recipients are evolving. Previous studies have suggested low adverse event rates with MRI in nonconditional cardiac implantable electronic device (CIED) recipients, but low power limits optimal characterization of risk.

Objective: The purpose of this study was to perform a systematic review and meta-analysis to characterize the clinical risk associated with MRI in CIED recipients in order to improve power.

A latent class analysis of PTSD symptoms among inner city primary care patients.

Objectives: Examine evidence for different subclasses of posttraumatic stress disorder (PTSD) symptoms in a sample of trauma exposed, low-income, predominantly African American men and women. Assess the relationship between PTSD subclasses with major depressive disorder (MDD) and types of trauma experienced.

Method: Latent class analysis (LCA) using a multivariate normal mixture model on the 17-item PTSD Symptom Scale (PSS) was used to identify latent subclasses of PTSD symptoms (N = 5063).

Erratum: Revisiting the Warnock rule.

This corrects the article DOI: 10.1038/nbt.4015.