Risk factors for severe and critically ill COVID-19 patients: A review

The pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global social and economic impact, and high numbers of deaths. Many risk factors have been identified in the progression of COVID-19 into a severe and critical stage, including old age, male gender, underlying comorbidities such as hypertension, diabetes, obesity, chronic lung diseases, heart, liver and kidney diseases, tumors, clinically apparent immunodeficiencies, local immunodeficiencies, such as early type I interferon secretion capacity, and pregnancy. Possible complications include acute kidney injury, coagulation disorders, thoromboembolism. The development of lymphopenia and eosinopenia are laboratory indicators of COVID-19. Laboratory parameters to monitor disease progression include lactate dehydrogenase, procalcitonin, high-sensitivity C-reactive protein, proinflammatory cytokines such as interleukin (IL)-6, IL-1β, Krebs von den Lungen-6 (KL-6), and ferritin. The development of a cytokine storm and extensive chest computed tomography imaging patterns are indicators of a severe disease. In addition, socioeconomic status, diet, lifestyle, geographical differences, ethnicity, exposed viral load, day of initiation of treatment, and quality of health care have been reported to influence individual outcomes. In this review, we highlight the scientific evidence on the risk factors of severity of COVID-19.     

Cdc42 is a key regulator of B cell differentiation and is required for antiviral humoral immunity

The small Rho GTPase Cdc42, known to interact with Wiskott–Aldrich syndrome (WAS) protein, is an important regulator of actin remodeling. Here, we show that genetic ablation of Cdc42 exclusively in the B cell lineage is sufficient to render mice unable to mount antibody responses. Indeed Cdc42-deficient mice are incapable of forming germinal centers or generating plasma B cells upon either viral infection or immunization. Such severe immune deficiency is caused by multiple and profound B cell abnormalities, including early blocks during B cell development; impaired antigen-driven BCR signaling and actin remodeling; defective antigen presentation and in vivo interaction with T cells; and a severe B cell–intrinsic block in plasma cell differentiation. Thus, our study presents a new perspective on Cdc42 as key regulator of B cell physiology.B cells provide a critical line of defense from pathogenic infections through the production of highly specific antibodies. The initial stages of B cell development occur in the bone marrow, where hematopoietic stem cells undergo stepwise rearrangements of the genes encoding the B cell receptor (BCR) and changes in the expression of cell surface receptors (Hardy et al., 1991). Immature B cells egress the bone marrow and migrate to the spleen to complete their development, going through transitional stages. Mature follicular B cells then recirculate throughout the body in search for cognate antigen, continually entering secondary lymphoid organs, including the LNs and spleen. Specific recognition of antigen by the BCR provides the first signal required for B cell activation. Typically, a second signal is required for maximal activation and is provided by CD4⁺ helper T cells after the presentation of processed antigen on the B cell surface. These two signals in combination trigger the proliferation and differentiation of B cells, which go on to form antibody-secreting plasma cells and to establish germinal center responses for affinity maturation (Rajewsky, 1996).B cell activation in vivo is predominantly triggered by antigen on the surface of a presenting cell (Batista and Harwood, 2009). The prevalence of this mode of activation has brought about a reevaluation of the importance of the cytoskeleton, given that the recognition of tethered antigen requires considerable alteration in B cell morphology (Fleire et al., 2006). Antigen-induced BCR signaling leads to radical reorganization of the actin cytoskeleton resulting in the modification of the BCR dynamics at the cell surface (Hao and August, 2005; Treanor et al., 2010; Treanor et al., 2011). Moreover the binding of membrane-bound antigen to cognate BCR triggers a cascade of intracellular signaling events that induces actin-dependent spreading of the B cell across the antigen-containing surface (Weber et al., 2008; Sohn et al., 2008; Depoil et al., 2008). However the mediators that link BCR signaling with reorganization of the actin cytoskeleton are currently not well defined.Among actin regulators, the RhoGTPases are a highly conserved family that function as molecular switches by cycling between inactive GDP (guanosine diphosphate) and active GTP (guanosine triphosphate) bound states (Tybulewicz and Henderson, 2009). RhoGTPase activity is modulated by G-nucleotide exchange factors (GEF) that promote the formation of the GTP-bound state and binding to various effectors involved in actin reorganization. Conversely, GTPase-activating proteins (GAP) catalyze the hydrolysis of GTP and thereby switch off RhoGTPase activity. The importance of the RhoGTPases as a whole in the regulation of B cell responses is highlighted by the far-reaching consequences that impaired activity of several GEFs, such as Vav and DOCK8, has on humoral immune responses (Doody et al., 2001; Fujikawa et al., 2003; Randall et al., 2009; Zhang et al., 2009).The importance of Rho GTPases in B cell physiology has been well established. For example, RhoA has been shown to regulate BCR signaling by influencing inositol-3 phosphate synthesis and calcium signaling (Saci and Carpenter, 2005). Moreover, B cell–specific inactivation of both Rac1 and Rac2 leads to virtually complete absence of B cells (Walmsley et al., 2003), and inactivation of Rac1 results in defects in spreading in transitional cells (Brezski and Monroe, 2007). However, although the inactivation of Rac2 leads to defects in B cell adhesion and synapse formation, it is unclear whether these proteins are involved in actin-dependent spreading in mature B cells (Arana et al., 2008).Cdc42 has been little characterized in B cells, in spite of its proven chief role as an essential regulator of cell cycle (Johnson and Pringle, 1990), cell polarity (Etienne-Manneville, 2004), and actin cytoskeleton in other cellular systems. This is likely due, at least in part, to the reported mild phenotype of mice lacking Cdc42 in B cells (Guo et al., 2009) compared with the severe deficiencies observed in animals lacking Rac family members (Walmsley et al., 2003). However, the mild phenotype is somehow surprising given that Cdc42 directly or indirectly associates with Wiskott–Aldrich Syndrome Protein (WASp) and in complex with Arp2/3 regulates cytoskeleton remodeling (Symons et al., 1996; Aspenström et al., 1996; Kolluri et al., 1996). Importantly, mutations in WAS gene lead to a X-linked, recessive disease characterized by recurrent infections, abnormal lymphocyte function, as well as an increased risk for systemic autoimmunity (Derry et al., 1994; Sullivan et al., 1994). WASp deficient B cells play a primary role in driving autoimmunity (Becker-Herman et al., 2011). The Cdc42 effectors WASp and N-WASp have both been implicated the regulation of actin reorganization in response to BCR antigen engagement (Westerberg et al., 2012; Liu et al., 2013). Besides, expression of a dominant negative form of Cdc42 in B cells leads to alterations of the actin cytoskeleton (Westerberg et al., 2001). In addition, Cdc42 has been shown to play a role in the polarization and secretion of lysosomal protein involved in antigen extraction (Yuseff et al., 2011).Here, we used a strategy harnessing the mb1 promoter to generate mice with a selective and very effective deletion of Cdc42 in early B cell progenitors (Hobeika et al., 2006). Using this model, we demonstrated that Cdc42 plays an essential role in many aspects of B cell biology, including the formation of mature B cells and the establishment of antibody responses. We went on to dissect the underlying cause of the severe immunodeficiency of these mice and found that Cdc42-deficient B cells exhibit defects in BCR signaling and presentation of internalized antigen, leading to reduced B–T cell interactions and the absence of germinal center responses in vivo. Moreover, Cdc42-deficient B cells can normally proliferate and class switch when stimulated with CD40 or LPS, but they are completely impaired in their ability to differentiate into plasma cells. Together, these attributes render Cdc42-deficient mice unable to mount antibody responses after immunization with model antigen or viral infection, and highlight a fundamental role for this RhoGTPase in the regulation of B cell responses.     

Placebo use in vaccine trials: Recommendations of a WHO expert panel

Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease.     

Neural mechanisms of empathy in humans: a relay from neural systems for imitation to limbic areas

How do we empathize with others? A mechanism according to which action representation modulates emotional activity may provide an essential functional architecture for empathy. The superior temporal and inferior frontal cortices are critical areas for action representation and are connected to the limbic system via the insula. Thus, the insula may be a critical relay from action representation to emotion. We used functional MRI while subjects were either imitating or simply observing emotional facial expressions. Imitation and observation of emotions activated a largely similar network of brain areas. Within this network, there was greater activity during imitation, compared with observation of emotions, in premotor areas including the inferior frontal cortex, as well as in the superior temporal cortex, insula, and amygdala. We understand what others feel by a mechanism of action representation that allows empathy and modulates our emotional content. The insula plays a fundamental role in this mechanism.     

Modulation of motor and premotor activity during imitation of target-directed actions

Behavioral studies reveal that imitation performance and the motor system are strongly influenced by the goal of the action to be performed. We used functional magnetic resonance imaging (fMRI) to assess the effect of explicit action goals on neural activity during imitation. Subjects imitated index finger movements in the absence and presence of visible goals (red dots that were reached for by the finger movement). Finger movements were either ipsilateral or contralateral. The pars opercularis of the inferior frontal gyrus showed increased blood oxygen level-dependent fMRI signal bilaterally for imitation of goal-oriented actions, compared with imitation of actions with no explicit goal. In addition, bilateral dorsal premotor areas demonstrated greater activity for goal-oriented actions, for contralateral movements and an interaction effect such that goal-oriented contralateral movements yielded the greatest activity. These results support the hypothesis that areas relevant to motor preparation and motor execution are tuned to coding goal-oriented actions and are in keeping with single-cell recordings revealing that neurons in area F5 of the monkey brain represent goal-directed aspects of actions.     

Follicle center lymphoma is associated with significantly elevated levels of BCL-6 expression among lymphoma subtypes, independent of chromosome 3q27 rearrangements.

The BCL-6 gene, located on chromosome 3q27, is implicated in the normal germinal center formation and is frequently rearranged in a wide spectrum of lymphomas. However the links between genetic alterations and expression of the gene are not clearly determined. We established a quantitative RT-PCR assay based on TaqMan technology to quantify BCL-6 mRNA expression in different subtypes of lymphomas and to compare the level of expression in lymphomas characterized by the presence or absence of BCL-6 translocation. Total RNA was extracted from 105 nodes biopsies (35 diffuse large B cell lymphomas (DLBCL); 26 follicle center lymphomas (FCL); 7 marginal zone lymphomas (MZL); 6 mantle cell lymphomas (MCL); 6 chronic lymphocytic leukemia (CLL); 5 T cell lymphomas (TCL); 7 classical Hodgkin diseases (HD); 6 nodal metastasis (NM); and 7 reactive hyperplasia (RH)). BCL-6 gene rearrangement was assessed by Southern blot analysis in 75% of 3q27(+) DLBCL (n = 20) cases and 67% of 3q27(+) cases (n = 10). The highest level of relative BCL-6 expression was observed in FCL (9.12 +/- 7.28) comparatively to the other lymphoma subtypes including DLBCL (2.53 +/- 1.82; P < 0.001), MCL (1.23 +/- 0.73), MZL (1.49 +/- 1.3), HD (1.60 +/- 1.00), TCL (1.75 +/- 1.64), but also RH (3.91 +/- 3.12) or NM (1.95 +/- 2.6). Among the 26 FCL cases, we observed a lower expression in grade 3 (n = 8) than in grade 1/2 (P < 0.001). Conversely, we failed to show any difference between 3q27(+) DLBCL and 3q27(-)DLBCL cases (P = 0.42). Paradoxically BCL-6 expression in 3q27(+) FCL (n = 10) was significantly lower than in 3q27(-) FCL cases (P = 0.035). Finally, this study showed that BCL-6 expression in lymphoma is largely independent of chromosome 3q27 rearrangement and is more related to the histological subtype. Clinical implication and alternative deregulation pathways of BCL-6 expression remain to be determined.     

Modulation of cortical activity during different imitative behaviors

Imitation is a basic form of motor learning during development. We have a preference to imitate the actions of others as if looking in a mirror (specular imitation: i.e., when the actor moves the left hand, the imitator moves the right hand) rather than with the anatomically congruent hand (anatomic imitation: i.e., actor and imitator both moving the right hand). We hypothesized that this preference reflects changes in activity in previously described frontoparietal cortical areas involved in directly matching observed and executed actions (mirror neuron areas). We used functional magnetic resonance imaging to study brain activity in normal volunteers imitating left and right hand movements with their right hand. Bilateral inferior frontal and right posterior parietal cortex were more active during specular imitation compared with anatomic imitation and control motor tasks. Furthermore this same pattern of activity was also observed in the rostral part of the supplementary motor area (SMA-proper) of the right hemisphere. These findings suggest that the degree of involvement of frontoparietal mirror areas in imitation depends on the nature of the imitative behavior, ruling out a linguistic mediation of these areas in imitation. Moreover, activity in the SMA appears to be tightly coupled to frontoparietal mirror areas when subjects copy the actions of others.     

Self-Perception of Quality of Life by Adolescents with Neuromuscular Diseases

PurposeLittle is known about quality of life of adolescents with neuromuscular diseases or the factors that influence it. We searched whether physical impairment, physical disability, and medical complications were predictors of low quality of life.MethodsMotor function, health, orthopedic status, and rehabilitation were assessed in 43 adolescents with neuromuscular diseases (mean age, 13.8 years, standard deviation 1.7 year; sex ratio 2.9/1). Quality of life was measured with the VSP-A (“Vécu Santé Perçu par l'Adolescent”; self-perceived health state in adolescents), a validated health-related quality of life self-perception test. A mixed linear regression related quality of life to impairment, disability, and respiratory status. Comparisons were made with results from an age/sex-matched nondisabled group.ResultsOn the average, the VSP-A scores in physically disabled adolescents were: (1) similar to those of the nondisabled group with regard to vitality, body image, relationships with parents and friends, and physical and psychological well-being; (2) higher with regard to school performance (score 68 vs. 52.8) and relationships with teachers (67.4 vs. 43.2); and (3) lower with regard to leisure activities (43.9 vs. 60.9). Physical disability and physical impairment were not negatively associated with seven of the nine VSP-A dimensions, but physical impairment was negatively associated with leisure activities and vitality (p < .001 and p < .01, respectively). Adolescents with ventilatory support did not express lower scores than adolescents not requiring ventilatory support (67.7 ± 11 vs. 62.9 ± 15, p = .39).ConclusionsThese surprising results should lead us question our medical, educational, and rehabilitation practices. Already well-managed disabled adolescents should benefit from less compassionate but more daring and dynamic interpersonal contacts.