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Severe COVID-19 infections present with cytokine storms, hypercoagulation, and acute respiratory distress syndrome, with extracellular vesicles (EVs) being involved in coagulation and inflammation. This study aimed to determine whether coagulation profiles and EVs reflect COVID-19 disease severity. Thirty-six patients with symptomatic COVID-19 infection with mild/moderate/severe disease (12 in each group) were analyzed. Sixteen healthy individuals served as controls. Coagulation profiles and EV characteristics were tested by nanoparticle tracking analysis (NTA), flow cytometry, and Western blot. While coagulation factors VII, V, VIII, and vWF were comparable, significant differences were found in patients’ D-Dimer/fibrinogen/free protein S levels compared to controls. Severe patients’ EVs displayed higher percentages of small EVs (<150 nm) with increased expression of exosome marker CD63. Severe patients’ EVs displayed high levels of platelet markers (CD41) and coagulation factors (tissue factor activity, endothelial protein C receptor). EVs of patients with moderate/severe disease expressed significantly higher levels of immune cell markers (CD4/CD8/CD14) and contained higher levels of IL-6. We demonstrated that EVs, but not the coagulation profile, may serve as biomarkers for COVID-19 severity. EVs demonstrated elevated levels of immune- and vascular-related markers in patients with moderate/severe disease, and may play a role in disease pathogenesis.

The resurgence of COVID-19 cases since June 2021, referred to as the fourth COVID-19 wave, has led to the approval and administration of booster vaccines. Our study aims to identify any associations between vaccine status with the characteristics and outcomes of patients hospitalized with severe COVID-19 disease. We retrospectively reviewed all COVID-19 patients admitted to a large tertiary center between July 25 and October 25, 2021 (fourth wave in Israel). Univariant and multivariant analyses of variables associated with vaccine status were performed. Overall, 349 patients with severe or critical disease were included. Patients were either not vaccinated (58%), had the first two vaccine doses (35%) or had the booster vaccine (7%). Vaccinated patients were significantly older, male predominant, and with a higher number of comorbidities including diabetes, hyperlipidemia, ischemic heart disease, heart failure, immunodeficient state, kidney disease and cognitive decline. Time from the first symptom to hospital admission was longer among non-vaccinated patients (7.2 ± 4.4 days, p = 0.002). Critical disease (p<0.05), admissions to the intensive care unit (p = 0.01) and advanced oxygen support (p = 0.004) were inversely proportional to the number of vaccines given, lowest among the booster vaccine group. Death (20%, p = 0.83) and hospital stay duration (8.05± 8.47, p = 0.19) were similar between the groups. Hospitalized vaccinated patients with severe COVID-19 had significantly higher rates of most known risk factors for COVID-19 adverse outcomes. Still, all disease outcomes were similar or better compared with the non-vaccinated patients.

Background: Hepatic injury secondary to congestive heart failure is well described, however, only limited data exist about the possible impact of acute cardiac dysfunction on the liver. We aimed to explore the possible cardio-hepatic interaction in patients with myocardial infarction. Material and methods: A single-center retrospective cohort study of 1339 ST elevation myocardial infarction (STEMI) patients who underwent primary coronary intervention between June 2012 to June 2019. Echocardiographic examinations were performed to assess left ventricular ejection fraction (LVEF) and central venous pressure (CVP). Patients were stratified into four groups by their LVEF and CVP levels: LVEF ≥ 45%, and CVP ≤ 10 mm/Hg (n = 853), LVEF < 45% with CVP ≤ 10 mm/Hg (n = 364), EF ≥ 45%, with CVP > 10 mm/Hg (n = 61), and LVEF < 45% with CVP > 10 mm/Hg (n = 61). Patients were evaluated for baseline and peak liver enzymes including alanine transaminase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and bilirubin. Results: Greater severity of cardiac dysfunction was associated with worse elevation of liver enzymes. We found a graded increase in mean levels of maximal ALT, first and maximal ALP, and first and maximal GGT values. Using propensity score matching to estimate the impact of cardiac dysfunction on liver injury, we chose patients with the worst cardiac function parameters: (LVEF < 45% and CVP >10 mm/Hg; n = 61) and compared them to matched patients with better cardiac function (n = 45). We found a significantly higher level of maximal ALT, first and maximal ALP, and GGT values in the group with the worst cardiac function parameters (p < 0.05). Conclusions: Among patients with STEMI, the combination of decreased LVEF and venous congestion was associated with liver enzymes elevation suggesting a possible cardio-hepatic syndrome.

Background Tetrahydrocannabinol (THC) has shown efficacy in alleviating chronic pain, particularly in disorders characterized by central sensitization. Offset analgesia (OA) and conditioned pain modulation (CPM) are key biomarkers used to evaluate central pain modulation. This study aimed to compare the effects of THC on OA and CPM in fibromyalgia syndrome (FMS), a prototypical condition of central sensitization. Methods In a randomized, double-blind, placebo-controlled crossover design, 23 FMS patients participated in two experimental sessions. Each session included the McGill Pain Questionnaire, visual analogue scale (VAS) assessments, and evaluations of OA and CPM, conducted both before and after sublingual administration of either THC (0.2 mg/kg) or placebo. Results THC significantly reduced spontaneous pain ratings on the McGill scale compared to both baseline and placebo ( P  = 0.01 and P  = 0.02, respectively). THC also significantly enhanced OA relative to baseline and placebo ( P  = 0.04 and P  = 0.008), while no effect was observed on CPM ( P  = 0.27). Notably, baseline OA magnitude significantly predicted THC-induced pain relief (R² = 0.404, P  = 0.003), whereas CPM did not show a significant association ( P  = 0.121). Conclusions This is the first study to evaluate THC’s distinct effects on central pain modulation using both OA and CPM. THC selectively enhanced OA without influencing CPM, highlighting differential neural mechanisms underlying these paradigms. Furthermore, OA predicted treatment response, suggesting its potential as a biomarker for personalized cannabinoid-based therapies in FMS and other central sensitization disorders. Trial registration The study was prospectively registered on ClinicalTrials.gov (ID: NCT05644054) at 1.1.2023. Further details can be found at: https://clinicaltrials.gov/study/NCT05644054?locStr=Israel&country=Israel&cond=fibromyalgi215a%20&intr=THC&aggFilters=status:not%20rec&rank=1 .

Background. Fibromyalgia syndrome (FMS), a chronic widespread pain disorder, has been associated with various models of stress, including those that are workplace-related. In a previous study, we have documented the significantly increased prevalence of FMS among schoolteachers, as well as correlating symptoms with stressful workplace-related factors. In the current study, we have focused on the specific population of kindergarten teachers and attempted to document both the prevalence of FMS symptoms among this group and the association with stress and symptoms of posttrauma. Methods. All participants in the study were working as kindergarten teachers in Israel at the time of the study. Participants responded to a questionnaire documenting FMS symptom, which included the widespread pain index (WPI) and symptom severity scale (SSS), which together constitute the suggested American College of Rheumatology (ACR) FMS diagnostic criteria. Additional items on the questionnaire documented work motivation and performance, the occurrence of workplace-related stressful events, and the presence of posttraumatic symptoms. Results. 242 participants were recruited to the current study, including 239 (98.8%) females and 3 (1.2%) males. 62 individuals (25.6%) were found to fulfill ACR FMS criteria. Significant differences in work performance were found between teachers fulfilling FMS criteria compared with those not fulfilling criteria. Thus, FMS-positive teachers reported significantly higher rates of missing workdays, leaving work early, and a lower quality of interaction with children in the kindergarten and with peers and supervisors. Motivation to work was also significantly lower among these individuals. The widespread pain index (WPI) and symptom severity scale (SSS), which together constitute the components of the FMS diagnostic criteria, were positively correlated with both stress and posttraumatic symptoms. In addition, widespread pain, disordered sleep, difficulty with concentration, and other FMS symptoms were strongly correlated with many specific stressful factors at the workplace, including the number of children in the kindergarten, interaction with parents, lack of optimal physical conditions in the classrooms, and various demands on behalf of the educational system. Conclusion. FMS symptoms were found to be highly prevalent among Israeli kindergarten teachers, at a rate that greatly exceeds the prevalence in the general Israeli population. Stressful work-related events appear to be positively associated with the occurrence of FMS symptoms and may serve as triggers for their development. Healthcare professionals treating individuals engaged in this occupation should be vigilant for the occurrence of symptoms that are clinically associated with FMS and overlapping functional disorders.

Objective. The association between Fibromyalgia Syndrome (FMS) and childhood maltreatment and adversity has frequently been proposed but limited data exists regarding the transcultural nature of this association. Methods. 75 Israeli FMS patients and 23 Rheumatoid Arthritis (RA) patients were compared. Childhood maltreatment was assessed by the Childhood Trauma Questionnaire (CTQ) and potential depressive and anxiety disorders were assessed by the Patient Health Questionnaire-4. FMS severity was assessed by the Widespread Pain Index (WPI), the Symptom Severity Score (SSS), and the FIQ. PTSD was diagnosed according to the DSM IV. RA severity was assessed by the RA Disease Activity Index. Health status was assessed by the SF-36. Results. Similar to reports in other countries, high levels of self-reported childhood adversity were reported by Israeli FMS patients. PTSD was significantly more common among FMS patients compared with RA patients, as well as childhood emotional abuse and physical and emotional neglect. Levels of depression and anxiety were significantly higher among FMS patients. Conclusion. The study demonstrated the cross cultural association between FMS and childhood maltreatment, including neglect, emotional abuse, and PTSD. Significant differences were demonstrated between FMS patients and patients suffering from RA, a model of an inflammatory chronic rheumatic disease.

Catecholamine infusion elicits an increase in clotting factors and this increase has been attributed to stimulation of β2-adrenorecptors (β2AR). Accordingly, we tested the hypothesis that inhalation of a short-acting selective β2AR agonist can induce a procoagulant state in healthy individuals. We recruited 23 healthy volunteers (nine females; mean age: 26±0.8 years; body mass index: 24.7±0.5 kg/m2) and randomly allocated them into two groups, the β2AR arm (seventeen subjects) and the saline arm (six subjects). Hemodynamics, plasma norepinephrine concentration, and procoagulant, anticoagulant, and fibrinolytic profiles of each participant were determined using specific assays before and after inhalation of either 2 mL nebulized normal saline or a mixture of 1 mL saline and 1 mL of salbutamol (5 mg salbutamol sulfate), a selective β2AR agonist, which were delivered by a nebulizer over ten minutes. Saline inhalation had no effect on the procoagulant, anticoagulant and fibrinolytic profiles of the six healthy volunteer in the study's saline arm. Salbutamol inhalation caused (a) a significant increase in the activity or levels of the procoagulant factors; FVIII increased by 11±3% (p = 0.04), von Willebrand factor increased by 7±1% (p = 0.03), and (b) a significant decrease in the activated partial prothrombin time from 27.4±0.4 seconds to 25.5 ±0.5 seconds (p<0.001) in the 17 volunteers in the study's β2AR arm. D-dimer and prothrombin fragments F1+2 were elevated by 200 ±90% and 505.0 ±300.0%, respectively. In addition, the activity of the anticoagulant protein C pathway (demonstrated by the protein C Global assay) decreased from 1.0±0.08 to 0.82±0.06 (p<0.001). Although plasma levels of tissue plasminogen activator decreased, all other indices of the fibrinolytic system did not change following salbutamol inhalation. We found that a single inhalation of salbutamol, a short-acting β2AR agonist, activates the clotting system without affecting the fibrinolytic system. This induction of a procoagulant state in healthy subjects warrants further investigation in patients treated with these agents.

Abstract Objective. The α2-agonist clonidine is an analgesic agent, whose yet uncertain action may involve either increase in pain modulation efficiency, change in autonomic function, and/or decrease in anxiety level. The present study aimed to examine the effect of oral clonidine on pain perception in healthy subjects in order to reveal its mode of action. Design. Randomized, double-blind, placebo-controlled study. Subjects. Forty healthy subjects. Methods. Subjects received either 0.15 mg oral clonidine or placebo. We measured pain parameters of heat pain thresholds, tonic heat stimulus, mechanical temporal summation, offset analgesia (OA) and conditioned pain modulation (CPM); autonomic parameters of deep breathing ratio and heart rate variability indices obtained before, during, and after tonic heat stimulus; and psychological parameters of anxiety and pain catastrophizing. Results. Clonidine decreased systolic blood pressure (P = 0.022) and heart rate (P = 0.004) and increased rMSSD (P = 0.020), though no effect was observed on pain perception, pain modulation, and psychological parameters. Autonomic changes were correlated with pain modulation capacity; for OA, the separate slope model was significant (P = 0.008); in the clonidine group, more efficient OA was associated with lower heart rate (r = 0.633, P = 0.005), unlike in the placebo group. Conclusions. The change in autonomic function that was related to the increase in pain modulation capacity, and the lack of change in anxiety, suggest a combined modulatory-autonomic mode of analgesic action for clonidine.

The postural tachycardia syndrome is a chronic form of orthostatic intolerance that primarily affects young women. This disorder is characterized by symptoms (such as lightheadedness, dimming of vision, confusion, and anxiety) and signs (such as bluish-red skin in dependent limbs) that occur on standing and that are relieved by lying down or sitting. 1 , 2 A remarkable physical finding is a dramatic increase in the heart rate that occurs on standing and that is not associated with a decrease in blood pressure. 3 Patients with this syndrome frequently have high plasma catecholamine concentrations, a finding that suggests that the disorder is a . . .