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.

Intensive care unit-acquired weakness.

When critically ill, a severe weakness of the limbs and respiratory muscles often develops with a prolonged stay in the intensive care unit (ICU), a condition vaguely termed intensive care unit-acquired weakness (ICUAW). Many of these patients have serious nerve and muscle injury. This syndrome is most often seen in surviving critically ill patients with sepsis or extensive inflammatory response which results in increased duration of mechanical ventilation and hospital length of stay. Patients with ICUAW often do not fully recover and the disability will seriously impact on their quality of life. In this chapter we discuss the current knowledge on the pathophysiology and risk factors of ICUAW. Tools to diagnose ICUAW, how to separate ICUAW from other disorders, and which possible treatment strategies can be employed are also described. ICUAW is finally receiving the attention it deserves and the expectation is that it can be better understood and prevented.

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill.

Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca(2+) dysregulation is present through altered Ca(2+) homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

Retinitis pigmentosa and bronchiectasis: a case report on a rare association suggestive of a common underlying primary ciliary dyskinesia (PCD).

We describe a case of retinitis pigmentosa, associated with bronchiectasis, as the first sign of primary ciliary dyskinesia (PCD). Only a few cases were described in the literature and the association of both diseases is not obvious at first sight, although a common ciliary dysfunction of both respiratory epithelium and photoreceptors of the retina seems to be the common factor. It is important to recognize the association and to question patients with retinitis pigmentosa about their respiratory functions, because an early diagnosis of PCD can prevent recurrent infections and development of bronchiectasis with daily physiotherapy.

[An unusual interstitial pneumonitis]. / Une pneumopathie interstitielle inhabituelle.

We report the case of a twenty-six-years-old patient who developed acute silicosis after only five years of professional exposure. He also succeedingly presented in the course of the disease progressive massive fibrosis, rest hypoxia, and eventually spontaneous pneumothorax. Monopulmonary transplantation was finally successfully performed.

Usefulness of FDG-PET to diagnose intravascular lymphoma with encephalopathy and renal involvement.

Intravascular lymphoma (IVL) is a rare subtype of extranodal diffuse large B-cell lymphoma. It is characterized by proliferation of neoplastic Lymphoid cells almost exclusively within the lumina of small blood vessels. It can affect virtually every organ system. Due to its rarity and its diverse and heterogeneous clinical presentation, diagnosis is difficult and often made post-mortem. When diagnosed early, it is, however, potentially treatable. We present a young woman with longstanding constitutional symptoms, positive antinuclear antibody, elevated LDH levels and rapidly progressive encephalopathy. FDG-PET scan showed intense uptake in the renal cortex, which prompted us to perform a kidney biopsy which was compatible with IVL. The value of PET in establishing the diagnosis of this rare disease will be discussed.

[Ground-glass opacity and mixed pulmonary nodules: a new computed tomography semiology of the pulmonary adenocarcinoma]. / Comment j'explore... les nodules pulmonaires de types verre dépoli et mixte: une nouvelle sémiologie tomodensitométrique de l'adénocarcinome pulmonaire.

Recently a new computed tomography semiology of the pulmonary adenocarcinoma was highlighted. Studies on ground-glass nodule and on mixed nodule showed the relation between these radiological images and the different anatomopathological forms of lung adenocarcinoma. Ground-glass opacity can correspond to precancerous lesions and morphological characteristics of nodules are correlated with the prognosis. The presence of spiculation, pleural retraction and air bronchogram is significantly more important in neoplasic lesions. The presence or the apparition of a solid component inside the nodule or the presence of indentation is highly suggestive of adenocarcinoma. A lesion smaller than 20 mm and persistant after 1 month must be, either followed up, or removed by a limited surgical resection. Lesions larger than 20 mm or associated with a solid component must be treated by conventional surgery.

Extracorporeal membrane oxygenation: experience in an adult medical ICU.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a technology that can provide extracorporeal gas exchange to patients with severe pulmonary or cardiac dysfunction. We report on our clinical experience with ECMO in critically ill patients. METHODS: We performed a retrospective analysis of 23 patients treated with ECMO in a medical intensive care unit in a tertiary referral academic centre. RESULTS: 13 patients were considered immunocompetent and 10 were immunocompromised when extracorporeal membrane oxygenation was started. 16 patients presented with acute respiratory distress syndrome (ARDS), 2 patients had intractable cardiac failure, and 5 patients had combined respiratory and cardiac failure. In 16 patients, a veno-venous bypass was constructed; in 7 patients, the initial bypass was venoarterial. 11 patients survived. In 2 patients technical complications were fatal. CONCLUSIONS: Our data indicate that patients with community-acquired pneumonia and no underlying disease will benefit most from this technique. However, long-term survival is possible in immunocompromised patients. Venoarterial bypass can carry a higher risk for technical complications. Increasing experience apparently also reduces the risk of technical complications.

Evolution and diversification of the forest and hypogean ground-beetle genus Trechus in the Canary Islands.

The beetle genus Trechus (Carabidae) is represented in the Macaronesian Islands by 43 endemic species. The Canary Islands have 16 endemic species, with two adapted to hypogean life. Phylogenetic relationships among 177 individuals of 38 Canarian, Madeiran, Azorean and continental Trechus species were examined using mitochondrial DNA and nuclear internal transcribed spacer 2 (ITS2) sequence data. Results show two main lineages in the Canaries: one comprising two sister groups with species from the laurel forest of La Gomera and Tenerife, and the other containing the single species from Gran Canaria and a species complex in the four western islands including two troglobites. Calibrations were applied to a linearized tree using a relaxed molecular clock method to estimate the major evolutionary divergence times of the Canarian Trechus species. Although the species assemblage in this archipelago is relatively ancient (7-8 million years), much of the species diversity is recent. Transition to the hypogean environment is more consistent with the "adaptive shift" rather than with the competing "climatic relict" hypothesis.

[Anatomo-clinical confrontation: idiopathic pulmonary fibrosis]. / Confrontation anatomo-clinique. Dyspnée progressive chez un homme de 58 ans.

Idiopathic pulmonary fibrosis and pulmonary fibrosis associated with systemic diseases are the most frequent diffuse interstitial pulmonary diseases. They slowly but irrevocably progress towards terminal respiratory failure. They can also be complicated by severe acute respiratory failure and admission in the intensive care unit can be discussed. Despite invasive mechanical ventilation, anti-infectious and immunosuppressive treatments, the disease carries a high mortality rate. We report and discuss the case of a patient with idiopathic, pulmonary fibrosis (UIP) who underwent rapid clinical deterioration.

Genetic structure, phylogeography and demography of two ground-beetle species endemic to the Tenerife laurel forest (Canary Islands).

The volcanic island of Tenerife (Canary archipelago) was formerly covered at 600-1200 m above sea level on most of its northern side by a cloud forest holding much of the endemic insect fauna. In the most significant surviving patches of this laurel forest at the eastern and western tips of the island occur two forest-specialist, closely related species of Eutrichopus (Coleoptera, Carabidae); here we present data on mitochondrial DNA variation among populations of these species. In total, 116 individuals from 16 localities were sampled and a 638 bp fragment of the cytochrome oxidase subunit II gene was sequenced, obtaining evidence for two distinct evolutionary lineages, in accordance with morphological and biogeographical data. Volcanic events at approximately 0.7 Ma might be responsible for vicariance and the fragmentation of the geographical range of an ancestral species, causing the establishment of two matrilineal lineages. Using nested clade and historical demography analyses we infer past cycles of demographic bottlenecks followed by population expansion, mostly in agreement with the geological time scale of volcanic events. Recent trends, however, refer to fragmentation of the cloud forest due to human intervention.

[Work with visual demands. Assumption of responsibility for optical correction by the employer]. / Travail avec un écran de visualisation. Prise en charge de la correction optique par l'employeur.

Comparison of visual demands of work in a traditional office to those of work in an office equiped with a screen. Description of problems of vision when focusing the eye to various distances and fixing it in various directions. Range of possibilities for optical correction for work with a screen (monofocal, bifocal, progressive or for reading), specifying among the optical corrections those which are exclusively reserved for this activity and should become the employer's responsibility.

[Information for the patient regarding consent clarification both before and after...]. / De l'information du patient au consentement éclairé et après ....

The provision of information to the patient begins before the consultation. The doctor's duty to inform the patient starts with the consultation and continues until after the medical act. The person responsible to provide information, the kind of information that needs to be provided, the moment when such information needs to be given and proofs that information has been given are all discussed. Valuable information is the basis of informed consent.

[Patient access to the medical file]. / L'accès du patient au dossier médical.

A new law regulates the access of the patients to their medical files in Belgium. The authors discuss the implications of this law for everyday medical practice.

Phylogeography of the endangered darkling beetle species of Pimelia endemic to Gran Canaria (Canary Islands).

Phylogenetic and geographical nested clade analysis (NCA) methods were applied to mitochondrial DNA sequences of Pimelia darkling beetles (Coleoptera, Tenebrionidae) endemic to Gran Canaria, an island in the Canary archipelago. The three species P. granulicollis, P. estevezi and P. sparsa occur on the island, the latter with three recognized subspecies. Another species, P. fernandezlopezi (endemic to the island of La Gomera) is a close relative of P. granulicollis based on partial Cytochrome Oxidase I mtDNA sequences obtained in a previous study. Some of these beetles are endangered, so phylogeographical structure within species and populations can help to define conservation priorities. A total of about 700 bp of Cytochrome Oxidase II were examined in 18 populations and up to 75 individuals excluding outgroups. Among them, 22 haplotypes were exclusive to P. granulicollis and P. estevezi and 31 were from P. sparsa. Phylogenetic analysis points to the paraphyly of Gran Canarian Pimelia, as the La Gomera P. fernandezlopezi haplotypes are included in them, and reciprocal monophyly of two species groups: one constituted by P. granulicollis, P. estevezi and P. fernandezlopezi (subgenus Aphanaspis), and the other by P. sparsa'sensu lato'. The two species groups show a remarkably high mtDNA divergence. Within P. sparsa, different analyses all reveal a common result, i.e. conflict between current subspecific taxonomic designations and evolutionary units, while P. estevezi and P. fernandezlopezi are very close to P. granulicollis measured at the mtDNA level. Geographical NCA identifies several cases of nonrandom associations between haplotypes and geography that may be caused by allopatric fragmentation of populations with some cases of restriction of gene flow or range expansion. Analyses of molecular variance and geographical NCA allow definition of evolutionary units for conservation purposes in both species-groups and suggest scenarios in which vicariance caused by geological history of the island may have shaped the pattern of the mitochondrial genetic diversity of these beetles.

The effect of two traffic situations on the behavior and performance of cows in an automatic milking system.

Two cow traffic situations were tested sequentially in an automatic milking system (AMS) for effects on cow behavior, effective use of the barn, and milking capacity. The first situation was forced cow traffic: 63 cows had to pass through the AMS to go from the lying area to the feeding area. The second was semiforced cow traffic: 67 cows (60 cows from before) had free access to a forage feeding area at one end of the barn but could only access an area with concentrate feeders by passing through the AMS. Behavior of all cows was monitored as well as for two subsets of cows present in both situations: 8 cows with low frequency vs. 7 cows with high frequency of visits to the AMS. In each situation, cows were observed for 72 h. Cow locations and behavior were noted at 10-min intervals for all cows and individually for the selected cows. In semiforced traffic, the herd readily used the freely accessible forage feeding area, ate longer (17.4% of the day vs. 15.1 +/- 0.59%), and stood less in freestalls (9.0 vs. 11.8 +/- 0.30%) than when cow traffic was forced. Nonmilking visits to the AMS tended to decrease, whereas milking visits remained unchanged in the semiforced situation. The subset of cows that visited the AMS more often had fewer nonmilking visits (1.8 vs. 4.2 +/- 0.7) in the semiforced traffic situation whereas cows with low frequency of visits to the AMS had a nonsignificant increase (1.5 vs. 1.0) in nonmilking visits. Cows that visited the AMS frequently used the forage feeding area and the lying area next to it more than low frequency cows and use of those areas increased further during the semiforced situation. The semiforced cow traffic was deemed more desirable than forced cow traffic both for cows and for the capacity of the automatic milking system.