Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study.

BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

Stem cell therapy for the treatment of myocardial infarction.

Despite timely reperfusion and subsequent optimal postinfarct pharmacotherapy and device-based treatment, the outcome in patients with severe myocardial infarction remains unfavourable. Myocardial salvage is incomplete, resulting in adverse left ventricular remodeling with concomitant morbidity and mortality. The combined risk of recurrent myocardial infarction, death or readmission for heart failure amounts to 25 % within the first year, highlighting the need for additional treatment strategies. Recent and rapidly evolving insights in cardiac biology, recognizing endogenous repair capabilities of the adult human heart, paved the path towards progenitor or stem cell based cardiac protection and repair strategies following ischemic injury. We critically report on the major randomized controlled clinical trials published so far concerning intracoronary transfer of autologous bone marrow cells in the setting of acute myocardial infarction. Moreover, underlying mechanisms, practical aspects, remaining questions and future challenges are highlighted. Taken together, these trials confirm the safety and feasibility of intracoronary progenitor cell transfer in the setting of myocardial infarction. Efficacy data suggests its potential to improve left ventricular function recovery beyond current state of the art therapy, but results are mixed, modest at best and do not support true cardiomyogenesis. Hence, due to its complexity, costs and remaining uncertainties, it is still too early to implement progenitor cell therapy in its current form in standard treatment strategies for ischemic heart disease. Future studies on strategies for cardiomyocyte regeneration in combination with myocardial protection are needed.

Role of stem and progenitor cells in postmyocardial infarction patients.

Despite state-of-the-art therapy, clinical outcome remains poor in myocardial infarction (MI) patients with reduced left ventricular (LV) function. Stem cell-mediated repair of the damaged heart is a promising new development in cardiovascular medicine. Embryonic stem cells and adult progenitor cells have been extensively studied for their capacity to improve LV function recovery in preclinical MI models but underlying mechanisms remain incompletely understood. Recent placebo-controlled, randomized bone marrow cell transfer trials in MI patients have shown mixed results with cell-mediated effects on global or regional LV function recovery of variable magnitude and duration. There is now growing consensus that the observed effects of bone marrow-(BM)-derived progenitor cell transfer, as applied in post-MI patients thus far, occur independently of cardiomyocyte formation. Subgroup and meta-analysis of currently available randomized and observational pilot trials have highlighted limitations of current cell-based cardiac repair and provided suggestions for future focused clinical trial design. However, the two most recently reported randomized clinical trials failed to confirm a significant biological effect. A better understanding of underlying molecular mechanisms and modalities of cell-based repair is therefore mandatory to facilitate translation of innovative cell-mediated therapies for functional recovery after MI in the years to come. Rapidly growing insights in the biology of cardiac resident cells and technological advances in generation of patient-specific induced pluripotent stem cells may hold great promise to accomplish cardio-myogenesis and directly restore contractile force generation capacity.

The value of wrist arthroscopy. An evaluation of 129 cases.

In order to evaluate diagnostic and therapeutic wrist arthroscopy we analyzed 129 arthroscopies with a follow-up of at least 6 months. Seventy-seven arthroscopies were performed for therapeutic purposes; 52 arthroscopies were diagnostic. There were diagnostic benefits in 55 arthroscopies (42.5%), therapeutic benefits in 29 arthroscopies (22.5%), combined diagnostic and therapeutic benefits in 39 (30%) and no benefits in six (5%). In 65 cases of the therapeutic group (with preoperative diagnosis) the authors found that the arthroscopy had been worthwhile. For the diagnostic group without a preoperative diagnosis, an arthroscopic diagnosis was made in 44 cases. Complications occurred in two patients: one tendon incision over a Kirschner wire in the therapeutic group and one superficial infection in the diagnostic group.

Arthroscopic treatment of triangular fibrocartilage complex lesions of the wrist.

The arthroscopic treatments (suture, debridement and "wafer" resection of the distal ulna) performed for TFCC lesions in 42 patients were retrospectively reviewed. Overall results were disappointing, with a better outcome for isolated lesions, for sutured TFCC's and degenerative lesions.

Septic arthritis of a lumbar facet joint and a sternoclavicular joint.

STUDY DESIGN: This is a case report. OBJECTIVES: To the authors' knowledge, simultaneous septic arthritis of a lumbar facet joint and another joint has not been described as yet. Therefore, a patient is presented in whom both a lumbar facet joint (L4-L5 on the right) and a sternoclavicular joint were involved. SUMMARY OF BACKGROUND DATA: Septic arthritis of a lumbar facet joint is a rare condition, and only a few cases have been reported in the literature. METHODS: The etiology, clinical presentation, technical examinations, and treatment are reviewed. RESULTS: Antibiotic treatment was sufficient to heal these lesions. CONCLUSION: Antibiotic treatment was sufficient to heal these lesions.

Incidence of cartilaginous and ligamentous lesions of the radio-carpal and distal radio-ulnar joint in an elderly population.

51 wrists of 30 embalmed cadavers have been used to perform an anatomical and radiological study relating cartilaginous and ligamentous lesions of the wrist with sex, age, ulnar variance (UV) and the state of the triangular fibrocartilage complex (TFCC) in an elderly population (mean 76.6 years). Two-thirds of all wrists (66%) showed cartilaginous lesions, mainly on the lunate (22, or 44%). The TFCC was perforated in 23 wrists (46%), and most were central degenerative perforations. Correlations were found between ulnar variance and TFCC thickness (P < 0.05) and ulnar variance and TFCC perforations (P < 0.05). A significant relation was observed between age and proximal row intercarpal ligamentous ruptures (P < 0.05) and between age and ulnar variance (P < 0.05). No statistical correlation was seen between ulnar variance and cartilaginous lesions on the lunate (P < 0.05) in this slightly ulnar negative population (mean-0.37 mm).

Spontaneous ruptures of the flexor carpi radialis tendon secondary to STT osteoarthritis.

Two cases of closed ruptures of the flexor carpi radialis which resulted from attrition of the tendon caused by bony spurs secondary to Scapho Trapezo Trapezoidal (STT) osteoarthritis are described. Treatment is conservative.

An advanced abdominal twin gestation after primary infertility and after tubal pregnancy.

A developing extra-uterine intra-abdominal gestation is very rare. In the literature the incidence varies from 1 : 6389 to 1 : 10,200. Our case concerns an abdominal ectopic twin gestation, exclusively in relation with the peritoneal surface, which developed normally until 13 weeks and then died.